wikidoc - User contributions [en]

Transfusion related acute lung injury

2012-05-27T18:37:03Z

Robert Killeen:

{{Infobox_Disease |
Name = Transfusion related acute lung injury |
Image = |
Caption = |
DiseasesDB = |
ICD10 = |
ICD9 = |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = |
eMedicineTopic = |
}}
{{SI}}
{{EH}}

In [[medicine]], '''transfusion related acute lung injury''' (TRALI) is a serious [[blood transfusion]] [[Complication (medicine)|complication]] characterized by the acute onset of non-cardiogenic [[pulmonary edema]] following transfusion of blood products.<ref>Gajic O, Moore SB. Transfusion-related acute lung injury. Mayo Clin Proc. 2005 Jun;80(6):766-70. PMID 15945528.</ref>

==Definition==
TRALI is defined as an acute lung injury that is temporally related to a blood transfusion; specifically, it must occur within the first six hours following a transfusion.<ref>Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005 Apr;33(4):721-6. PMID 15818095.</ref>

==Differential diagnosis==
*[[Acute respiratory distress syndrome]]

==Etiology/Risks==
The etiology of TRALI is currently not fully understood is thought to be [[immune system|immune]] mediated.<ref>Dykes A, Smallwood D, Kotsimbos T, Street A. Transfusion-related acute lung injury (Trali) in a patient with a single lung transplant. Br J Haematol. 2000 Jun;109(3):674-6. PMID 10886228.</ref><ref name=muller_15894508>Muller JY. [TRALI: from diagnosis to prevention] Transfus Clin Biol. 2005 Jun;12(2):95-102. PMID 15894508.</ref> Antibodies directed toward Human Leukocyte Antigens (HLA) or Human Neutrophil Antigens (HNA) have been implicated. [[Multiparous]] women (women that have had more than one child) develop these antibodies through exposure to fetal blood; transfusion of blood components obtained from these donors is thought to carry a higher risk of inducing immune-mediated TRALI.<ref name=muller_15894508/> Previous transfusion or transplantation can also lead to donor sensitization. Additional recipient risk factors include high IL-8 levels, liver surgery, chronic alcohol abuse, shock, current tobacco use, positive fluid balance and a high peak airway pressure while being mechanically ventilated<ref>Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirshler N, Sanchez R, Mathay MA;TRALI Study Group. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012 Feb; 119(7):1757-1767. PMID 22117051.</ref> The recipient, to be at risk of TRALI via this mechanism, must express the specific HLA or neutrophil receptors to which the implicated donor has formed antibodies. Some authors suggest a two-hit hypothesis wherein pre-existing pulmonary pathology (ie, the first-hit) leads to localization of neutrophils to the pulmonary microvasculature. The second hit occurs when the aforementioned antibodies are transfused and attach to and activate neutrophils, leading to release of cytokines and vasoactive substances that induce non-cardiac pulmonary edema.

A non-immune mechanism has been studied and proposed by Silliman, involving the accumulation of bioactive lipids in stored blood components (red cells, platelets, plasma) that possess neutrophil priming capabilities. This mechanism is thought to involve ~15% of TRALI cases where neither donor nor recipient antibodies are found.

TRALI is typically associated with plasma-rich products such as FFP, but can also occur in recipients of packed RBCs due to the residual plasma present in the unit. Antiplatelet antibodies may also cause a delayed TRALI.<ref>Torii Y, Shimizu T, Yokoi T, Sugimoto H, Katashiba Y, Ozasa R, Fujita S, Adachi Y, Maki M, Nomura S. Antiplatelet antibody may cause delayed transfusion-related acute lung injury. Internat J Gen Medicine. 2011 Sep; 2011(4):677-680.</ref>

==Differential Diagnosis==
One of the main diagnostic dilemmas of TRALI is to differentiate it from clinically similar entities. The foremost of these is Transfusion-associated circulatory overload,(TACO).<ref>Cherry T, Steciuk M, Reddy V, Marques MB. Transfusion-related acute lung injury. Am J Clin Pathol 2008;129: 287-297.</ref> The incidence of TACO varies between <1% to 11%; the mortality between 3.6% to 20%. Clinically, these patients manifest tachypnea, cyanosis, dyspnea, hypertension, and tachycardia. They show evidence of overload such as jugular venous distention, an elevated pulmonary artery occlusive pressure, and an elevated BNP (brain natriuretic peptide). Other maladies that resemble TRALI include anaphylactic transfusion reactions where patients show tachypnea, cyanosis and wheezing. To differentiate it from TRALI one must see other manifestations such as hypotension and skin changes (urticaria, erythema, and facial/trunk edema). The pulmonary symptoms come from broncholaryngeal edema instead of the interstitial pulmonary regions. Sepsis, from bacterially-contaminated blood products, can also lead to respiratory distress along with concurrent hypotension and fever. Hemolytic transfusion reactions, too, manifest with respiratory distress.

==Mortality & morbidity==
The immune mediated form of TRALI occurs approximately once every 5000 transfusions and has a mortality of 6-9%.<ref>Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang. 2005 Jul;89(1):1-10. PMID 15938734.</ref> TRALI is one of the leading causes of transfusion-related fatalities in the US.

==Treatment==
Treatment for TRALI is primarily supportive measures. Many patients with TRALI need [[mechanical ventilation]]. TRALI is associated with microvascular damage and not fluid overload, so diuretics are not recommended.

==References==
<references/>

==See also==
*[[Flash pulmonary edema]]

==External links==
*[http://www.fda.gov/cber/ltr/trali101901.htm Transfusion Related Acute Lung Injury] - US [[Food and Drug Administration]] (FDA).

{{transfusion medicine}}
{{SIB}}

[[Category:Surgery]]
[[Category:Transfusion medicine]]
[[Category:Pulmonology]]

[[zh:輸血相關急性肺損傷]]

{{WH}}
{{WS}}
{{jb1}}

Transfusion related acute lung injury

2012-05-27T02:26:29Z

Robert Killeen:

{{Infobox_Disease |
Name = Transfusion related acute lung injury |
Image = |
Caption = |
DiseasesDB = |
ICD10 = |
ICD9 = |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = |
eMedicineTopic = |
}}
{{SI}}
{{EH}}

In [[medicine]], '''transfusion related acute lung injury''' (TRALI) is a serious [[blood transfusion]] [[Complication (medicine)|complication]] characterized by the acute onset of non-cardiogenic [[pulmonary edema]] following transfusion of blood products.<ref>Gajic O, Moore SB. Transfusion-related acute lung injury. Mayo Clin Proc. 2005 Jun;80(6):766-70. PMID 15945528.</ref>

==Definition==
TRALI is defined as an acute lung injury that is temporally related to a blood transfusion; specifically, it must occur within the first six hours following a transfusion.<ref>Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005 Apr;33(4):721-6. PMID 15818095.</ref>

==Differential diagnosis==
*[[Acute respiratory distress syndrome]]

==Etiology/Risks==
The etiology of TRALI is currently not fully understood is thought to be [[immune system|immune]] mediated.<ref>Dykes A, Smallwood D, Kotsimbos T, Street A. Transfusion-related acute lung injury (Trali) in a patient with a single lung transplant. Br J Haematol. 2000 Jun;109(3):674-6. PMID 10886228.</ref><ref name=muller_15894508>Muller JY. [TRALI: from diagnosis to prevention] Transfus Clin Biol. 2005 Jun;12(2):95-102. PMID 15894508.</ref> Antibodies directed toward Human Leukocyte Antigens (HLA) or Human Neutrophil Antigens (HNA) have been implicated. [[Multiparous]] women (women that have had more than one child) develop these antibodies through exposure to fetal blood; transfusion of blood components obtained from these donors is thought to carry a higher risk of inducing immune-mediated TRALI.<ref name=muller_15894508/> Previous transfusion or transplantation can also lead to donor sensitization. Additional recipient risk factors include high IL-8 levels, liver surgery, chronic alcohol abuse, shock, current tobacco use, positive fluid balance and a high peak airway pressure while being mechanically ventilated<ref>Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirshler N, Sanchez R, MA Mathay;TRALI Study Group. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012 Feb; 119(7):1757-1767. PMID 22117051.</ref> The recipient, to be at risk of TRALI via this mechanism, must express the specific HLA or neutrophil receptors to which the implicated donor has formed antibodies. Some authors suggest a two-hit hypothesis wherein pre-existing pulmonary pathology (ie, the first-hit) leads to localization of neutrophils to the pulmonary microvasculature. The second hit occurs when the aforementioned antibodies are transfused and attach to and activate neutrophils, leading to release of cytokines and vasoactive substances that induce non-cardiac pulmonary edema.

A non-immune mechanism has been studied and proposed by Silliman, involving the accumulation of bioactive lipids in stored blood components (red cells, platelets, plasma) that possess neutrophil priming capabilities. This mechanism is thought to involve ~15% of TRALI cases where neither donor nor recipient antibodies are found.

TRALI is typically associated with plasma-rich products such as FFP, but can also occur in recipients of packed RBCs due to the residual plasma present in the unit. Antiplatelet antibodies may also cause a delayed TRALI.<ref>Torii Y, Shimizu T, Yokoi T, Sugimoto H, Katashiba Y, Ozasa R, Fujita S, Adachi Y, Maki M, Nomura S. Antiplatelet antibody may cause delayed transfusion-related acute lung injury. Internat J Gen Medicine. 2011 Sep; 2011(4):677-680.</ref>

==Differential Diagnosis==
One of the main diagnostic dilemmas of TRALI is to differentiate it from clinically similar entities. The foremost of these is Transfusion-associated circulatory overload,(TACO).<ref>Cherry T, Steciuk M, Reddy V, MB Marques. Transfusion-related acute lung injury. Am J Clin Pathol 2008;129: 287-297.</ref> The incidence of TACO varies between <1% to 11%; the mortality between 3.6% to 20%. Clinically, these patients manifest tachypnea, cyanosis, dyspnea, hypertension, and tachycardia. They show evidence of overload such as jugular venous distention, an elevated pulmonary artery occlusive pressure, and an elevated BNP (brain natriuretic peptide). Other maladies that resemble TRALI include anaphylactic transfusion reactions where patients show tachypnea, cyanosis and wheezing. To differentiate it from TRALI one must see other manifestations such as hypotension and skin changes (urticaria, erythema, and facial/trunk edema). The pulmonary symptoms come from broncholaryngeal edema instead of the interstitial pulmonary regions. Sepsis, from bacterially-contaminated blood products, can also lead to respiratory distress along with concurrent hypotension and fever. Hemolytic transfusion reactions, too, manifest with respiratory distress.

==Mortality & morbidity==
The immune mediated form of TRALI occurs approximately once every 5000 transfusions and has a mortality of 6-9%.<ref>Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang. 2005 Jul;89(1):1-10. PMID 15938734.</ref> TRALI is one of the leading causes of transfusion-related fatalities in the US.

==Treatment==
Treatment for TRALI is primarily supportive measures. Many patients with TRALI need [[mechanical ventilation]]. TRALI is associated with microvascular damage and not fluid overload, so diuretics are not recommended.

==References==
<references/>

==See also==
*[[Flash pulmonary edema]]

==External links==
*[http://www.fda.gov/cber/ltr/trali101901.htm Transfusion Related Acute Lung Injury] - US [[Food and Drug Administration]] (FDA).

{{transfusion medicine}}
{{SIB}}

[[Category:Surgery]]
[[Category:Transfusion medicine]]
[[Category:Pulmonology]]

[[zh:輸血相關急性肺損傷]]

{{WH}}
{{WS}}
{{jb1}}

Transfusion related acute lung injury

2012-05-27T02:24:49Z

Robert Killeen:

{{Infobox_Disease |
Name = Transfusion related acute lung injury |
Image = |
Caption = |
DiseasesDB = |
ICD10 = |
ICD9 = |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = |
eMedicineTopic = |
}}
{{SI}}
{{EH}}

In [[medicine]], '''transfusion related acute lung injury''' (TRALI) is a serious [[blood transfusion]] [[Complication (medicine)|complication]] characterized by the acute onset of non-cardiogenic [[pulmonary edema]] following transfusion of blood products.<ref>Gajic O, Moore SB. Transfusion-related acute lung injury. Mayo Clin Proc. 2005 Jun;80(6):766-70. PMID 15945528.</ref>

==Definition==
TRALI is defined as an acute lung injury that is temporally related to a blood transfusion; specifically, it must occur within the first six hours following a transfusion.<ref>Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005 Apr;33(4):721-6. PMID 15818095.</ref>

==Differential diagnosis==
*[[Acute respiratory distress syndrome]]

==Etiology/Risks==
The etiology of TRALI is currently not fully understood is thought to be [[immune system|immune]] mediated.<ref>Dykes A, Smallwood D, Kotsimbos T, Street A. Transfusion-related acute lung injury (Trali) in a patient with a single lung transplant. Br J Haematol. 2000 Jun;109(3):674-6. PMID 10886228.</ref><ref name=muller_15894508>Muller JY. [TRALI: from diagnosis to prevention] Transfus Clin Biol. 2005 Jun;12(2):95-102. PMID 15894508.</ref> Antibodies directed toward Human Leukocyte Antigens (HLA) or Human Neutrophil Antigens (HNA) have been implicated. [[Multiparous]] women (women that have had more than one child) develop these antibodies through exposure to fetal blood; transfusion of blood components obtained from these donors is thought to carry a higher risk of inducing immune-mediated TRALI.<ref name=muller_15894508/> Previous transfusion or transplantation can also lead to donor sensitization. Additional recipient risk factors include high IL-8 levels, liver surgery, chronic alcohol abuse, shock, current tobacco use, positive fluid balance and a high peak airway pressure while being mechanically ventilated<ref>Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirshler N, Sanchez R, MA Mathay;TRALI Study Group. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012 Feb; 119(7):1757-1767. PMID 22117051.</ref> The recipient, to be at risk of TRALI via this mechanism, must express the specific HLA or neutrophil receptors to which the implicated donor has formed antibodies. Some authors suggest a two-hit hypothesis wherein pre-existing pulmonary pathology (ie, the first-hit) leads to localization of neutrophils to the pulmonary microvasculature. The second hit occurs when the aforementioned antibodies are transfused and attach to and activate neutrophils, leading to release of cytokines and vasoactive substances that induce non-cardiac pulmonary edema.

A non-immune mechanism has been studied and proposed by Silliman, involving the accumulation of bioactive lipids in stored blood components (red cells, platelets, plasma) that possess neutrophil priming capabilities. This mechanism is thought to involve ~15% of TRALI cases where neither donor nor recipient antibodies are found.

TRALI is typically associated with plasma-rich products such as FFP, but can also occur in recipients of packed RBCs due to the residual plasma present in the unit. Antiplatelet antibodies may also cause a delayed TRALI.<ref>Torii Y, Shimizu T, Yokoi T, Sugimoto H, Katashiba Y, Ozasa R, Fujita S, Adachi Y, Maki M, Nomura S. Antiplatelet antibody may cause delayed transfusion-related acute lung injury. Internat J Gen Medicine. 2011 Sep; 2011(4):677-680.</ref>

==Differential Diagnosis==
One of the main diagnostic dilemmas of TRALI is to differentiate it from clinically similar entities. The foremost of these is Transfusion-associated circulatory overload,(TACO).<ref>Cherry T, Steciuk M, Reddy V, MB Marques. Transfusion-related acute lung injury. 2008;129: 287-297.</ref> The incidence of TACO varies between <1% to 11%; the mortality between 3.6% to 20%. Clinically, these patients manifest tachypnea, cyanosis, dyspnea, hypertension, and tachycardia. They show evidence of overload such as jugular venous distention, an elevated pulmonary artery occlusive pressure, and an elevated BNP (brain natriuretic peptide). Other maladies that resemble TRALI include anaphylactic transfusion reactions where patients show tachypnea, cyanosis and wheezing. To differentiate it from TRALI one must see other manifestations such as hypotension and skin changes (urticaria, erythema, and facial/trunk edema). The pulmonary symptoms come from broncholaryngeal edema instead of the interstitial pulmonary regions. Sepsis, from bacterially-contaminated blood products, can also lead to respiratory distress along with concurrent hypotension and fever. Hemolytic transfusion reactions, too, manifest with respiratory distress.

==Mortality & morbidity==
The immune mediated form of TRALI occurs approximately once every 5000 transfusions and has a mortality of 6-9%.<ref>Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang. 2005 Jul;89(1):1-10. PMID 15938734.</ref> TRALI is one of the leading causes of transfusion-related fatalities in the US.

==Treatment==
Treatment for TRALI is primarily supportive measures. Many patients with TRALI need [[mechanical ventilation]]. TRALI is associated with microvascular damage and not fluid overload, so diuretics are not recommended.

==References==
<references/>

==See also==
*[[Flash pulmonary edema]]

==External links==
*[http://www.fda.gov/cber/ltr/trali101901.htm Transfusion Related Acute Lung Injury] - US [[Food and Drug Administration]] (FDA).

{{transfusion medicine}}
{{SIB}}

[[Category:Surgery]]
[[Category:Transfusion medicine]]
[[Category:Pulmonology]]

[[zh:輸血相關急性肺損傷]]

{{WH}}
{{WS}}
{{jb1}}

Transfusion related acute lung injury

2012-05-26T20:36:06Z

Robert Killeen:

{{Infobox_Disease |
Name = Transfusion related acute lung injury |
Image = |
Caption = |
DiseasesDB = |
ICD10 = |
ICD9 = |
ICDO = |
OMIM = |
MedlinePlus = |
eMedicineSubj = |
eMedicineTopic = |
}}
{{SI}}
{{EH}}

In [[medicine]], '''transfusion related acute lung injury''' (TRALI) is a serious [[blood transfusion]] [[Complication (medicine)|complication]] characterized by the acute onset of non-cardiogenic [[pulmonary edema]] following transfusion of blood products.<ref>Gajic O, Moore SB. Transfusion-related acute lung injury. Mayo Clin Proc. 2005 Jun;80(6):766-70. PMID 15945528.</ref>

==Definition==
TRALI is defined as an acute lung injury that is temporally related to a blood transfusion; specifically, it must occur within the first six hours following a transfusion.<ref>Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005 Apr;33(4):721-6. PMID 15818095.</ref>

==Differential diagnosis==
*[[Acute respiratory distress syndrome]]

==Etiology/Risks==
The etiology of TRALI is currently not fully understood. TRALI is thought to be [[immune system|immune]] mediated.<ref>Dykes A, Smallwood D, Kotsimbos T, Street A. Transfusion-related acute lung injury (Trali) in a patient with a single lung transplant. Br J Haematol. 2000 Jun;109(3):674-6. PMID 10886228.</ref><ref name=muller_15894508>Muller JY. [TRALI: from diagnosis to prevention] Transfus Clin Biol. 2005 Jun;12(2):95-102. PMID 15894508.</ref> Antibodies directed toward Human Leukocyte Antigens (HLA) or Human Neutrophil Antigens (HNA) have been implicated. [[Multiparous]] women (women that have had more than one child) develop these antibodies through exposure to fetal blood; transfusion of blood components obtained from these donors is thought to carry a higher risk of inducing immune-mediated TRALI.<ref name=muller_15894508/> Previous transfusion or transplantation can also lead to donor sensitization. Additional recipient risk factors include high IL-8 levels, liver surgery, chronic alcohol abuse, shock, current smoking, positive fluid balance and a high peak airway pressure while being mechanically ventilated<ref>Toy P, Gajic O, Bacchetti P, Looney MR, Gropper MA, Hubmayr R, Hubmayr R, Lowell CA, Norris PJ, Murphy EL, Weiskopf RB, Wilson G, Koenigsberg M, Lee D, Schuller R, Wu P, Grimes B, Gandhi MJ, Winters JL, Mair D, Hirshler N, Sanchez R, MA Mathay;TRALI Study Group. Transfusion-related acute lung injury: incidence and risk factors. Blood. 2012 Feb; 119(7):1757-1767. PMID 22117051.</ref> The recipient, to be at risk of TRALI via this mechanism, must express the specific HLA or neutrophil receptors to which the implicated donor has formed antibodies. Some authors suggest a two-hit hypothesis wherein pre-existing pulmonary pathology (ie, the first-hit) leads to localization of neutrophils to the pulmonary microvasculature. The second hit occurs when the aforementioned antibodies are transfused and attach to and activate neutrophils, leading to release of cytokines and vasoactive substances that induce non-cardiac pulmonary edema.

A non-immune mechanism has been studied and proposed by Silliman, involving the accumulation of bioactive lipids in stored blood components (red cells, platelets, plasma) that possess neutrophil priming capabilities. This mechanism is thought to involve ~15% of TRALI cases where neither donor nor recipient antibodies are found.

TRALI is typically associated with plasma products such as FFP, but can also occur in recipients of packed RBCs due to the residual plasma present in the unit. Antiplatelet antibodies may also cause a delayed TRALI.<ref>Torii Y, Shimizu T, Yokoi T, Sugimoto H, Katashiba Y, Ozasa R, Fujita S, Adachi Y, Maki M, Nomura S. Anitplatelet antibody may cause delayed transfusion-related acute lung injury. Internat J Gen Medicine. 2010 Sep; 2011(4):677-680.</ref> The AABB (formerly the American Association of Blood Banks) recommended on 11/03/2006 in association bulletin 06-07 that blood banks use high plasma volume components from female donors for further manufacturing instead of transfusion due to the higher risk of TRALI.

==Mortality & morbidity==
The immune mediated form of TRALI occurs approximately once every 5000 transfusions and has a mortality of 6-9%.<ref>Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang. 2005 Jul;89(1):1-10. PMID 15938734.</ref> TRALI is one of the leading causes of transfusion-related fatalities in the US.

==Treatment==
Treatment for TRALI is primarily supportive measures. Many patients with TRALI need [[mechanical ventilation]]. TRALI is associated with microvascular damage and not fluid overload, so diuretics are not recommended.

==References==
<references/>

==See also==
*[[Flash pulmonary edema]]

==External links==
*[http://www.fda.gov/cber/ltr/trali101901.htm Transfusion Related Acute Lung Injury] - US [[Food and Drug Administration]] (FDA).

{{transfusion medicine}}
{{SIB}}

[[Category:Surgery]]
[[Category:Transfusion medicine]]
[[Category:Pulmonology]]

[[zh:輸血相關急性肺損傷]]

{{WH}}
{{WS}}
{{jb1}}

Myelodysplastic syndrome

2011-04-16T22:57:30Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 8604|
ICD10 = {{ICD10|D|46||d|37}} |
ICD9 = {{ICD9|238.7}} |
ICDO = 9980/0-9989/3 |
OMIM = |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2695 |
eMedicine_mult = {{eMedicine2|ped|1527}} |
MeshID = D009190 |
}}
{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==

The '''myelodysplastic syndromes''' (MDS, formerly known as "preleukemia") are a diverse collection of [[hematology|hematological]] conditions united by ineffective production of blood cells and varying risks of transformation to [[acute myelogenous leukemia]]. [[Anemia]] requiring chronic [[blood transfusion]] is frequently present. Although not truly [[cancer|malignant]], MDS is nevertheless classified within the [[Hematological malignancy|haematological neoplasms]].

Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

== Signs and symptoms ==
Abnormalities include:
* [[neutropenia]], [[anemia]] and [[thrombocytopenia]] (low cell counts of white and red blood cells, and platelets, respectively)
* abnormal granules in cells, abnormal nuclear shape and size
* [[chromosome|chromosomal]] abnormalities, including [[chromosomal translocation]]s and abnormal chromosome number.

Symptoms of myelodysplastic conditions:
* [[Anemia]]—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
* [[Neutropenia]] (low neutrophil count) —increased susceptibility to [[infection]]
* [[Thrombocytopenia]] (low platelet count) —increased susceptibility to [[bleeding]]

Although there is some risk for developing [[acute myelogenous leukemia]], about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

==Diagnosis==
Investigation:
* [[Full blood count]] and examination of [[blood film]]
* [[Bone marrow examination]] by an experienced [[hematopathologist]]
* [[Cytogenetics]] or chromosomal studies. This is performed on the bone marrow aspirate.

==Diagnosistic Workup==
The differential diagnosis is that of [[anemia]], [[thrombocytopenia]], and/or [[leukopenia]]. Usually, the elimination of known [[etiologies]] of [[cytopenias]], along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

Investigation:
* [[Full blood count]] and examination of [[blood film]]. The [[blood film]] morphology can provide clues about [[hemolytic anemia]], clumping of the [[platelets]] leading to spurious [[thrombocytopenia]], or [[leukemia]].
* Blood tests to eliminate other common causes of [[cytopenias]], such as [[lupus]], [[hepatitis]], [[B12]], [[folate]], or other [[vitamin]] deficiencies, [[renal failure]] or [[heart failure]], [[HIV]], [[hemolytic anemia]], [[monoclonal gammopathy]]. Age-appropriate cancer screening should be considered for all [[anemic]] patients.
* [[Bone marrow examination]] by an experienced [[hematopathologist]]. This is required to establish the diagnosis, since all hematopathologists recognize a dysplastic marrow as the key feature of myelodysplasia.
* [[Cytogenetics]] or chromosomal studies. This is ideally performed on the bone marrow aspirate. These require a fresh specimen, since live cells are induced to enter [[metaphase]] to enhance [[chromosomal]] staining.
* [[Flow cytometry]] is helpful to establish the presence of any [[lymphoproliferative]] disorder in the [[marrow]]

==Genetics==

{| class="wikitable"
|-
! Abnormality
! Frequency in MDS
|-
| -5/del(5q)
| 10-20%
|-
| +8
| 10%
|-
| -7/del(7q)
| 5-10%
|-
| -Y
|10%
|-
| 17p-
| 7%
|-
| del(20q)
| 5-6%
|-
| t(11q23)
| 5-6%
|-
| complex karyotype
| 10-20%
|}

Overall, the mutations in the RUNX1/AML1 are the most common point mutations described in MDS to date but RUNX1/AML1 mutations have no distinct hematologic phenotype and are most commonly associated with previous radiation exposure and with a higher risk disease (especially with excess blasts).

Hypermethylation leading to silencing of the p151NK-4b gene is also common in MDS. This phenomenon occurs in up to 80% of the cases with advanced MDS. The silencing of this gene can be reversed by the uyse of demethylating agents such as 5-azacytidine. These agents are pyrimidine analogues that inhibit DNA methyltransferase activity and could improve MDS hematopoiesis by reversing aberrant gene methylation and permitting cellular differentiation.

A number of studies suggest that erythropoietin (EPO) signaling and STAT5 activation is abnormal in MDS. The SOCS1 gene is hypermethylated in 31% of MDS patients which is associated with increased activity of the JAK/STAT pathway.

Microsatellite instability involving defects in the DNA mismatch repair system has been identified in some MDS patients, especially those with therapy-related disease.

The TP53 tumor suppressor gene, which regulates cell cycle progression, DNA repair and apoptosis is mutated in 5-10% of MDS cases. Inactivation of the TP53 gene may contribute to the leukemic progression from MDS.

==Pathophysiology==
MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multi-potent bone marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood. [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and there is a significant increase in levels of cell death [[apoptosis]] in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow [[Myeloblasts|blasts]] rises over a particular cutoff (20% for [[Myelodysplastic syndrome#WHO classification|WHO]] and 30% for [[Myelodysplastic syndrome#French-American-British (FAB) classification|FAB]]) then transformation to [[acute myeloid leukemia|leukemia]] (specifically [[acute myelogenous leukemia]] or AML) is said to have occurred. The progression of MDS to [[acute myeloid leukemia|leukemia]] is a good example of the ''[[Knudson hypothesis|multi-step theory of carcinogenesis]]'' in which a series of mutations occur in an initially normal cell and transform it into a [[cancer|cancer cell]]. The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs. This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1).

While recognition of leukemic transformation was historically important (see [[Myelodysplastic syndrome#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to [[acute myeloid leukemia|AML]] but rather from the [[cytopenia]]s seen in all MDS patients. While [[anemia]] is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]] MDS patients rarely suffer injury from severe [[anemia]]. However, if an MDS patient is fortunate enough to suffer nothing more than [[anemia]] over several years, they then risk [[iron overload#secondary iron overload|iron overload]]. The two most serious complications in MDS patients resulting from their [[cytopenia]]s are bleeding (due to lack of [[platelet]]s) or infection (due to lack of [[white blood cell]]s).

The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two of three commercially available medications approved by the US FDA to treat MDS. Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of [[DNA methylation]] control can lead to uncontrolled cell growth, and [[cytopenias]]. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly [[DNA methylation]] profile in the [[hematopoietic stem cell]] [[nucleus]], and thereby restore normal blood counts and retard the progression of MDS to [[acute leukemia]].

Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA [[mutation]]s in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of [[mitochondrial]] [[iron]] deposits in the [[ringed sideroblast]] as evidence of [[mitochondrial]] dysfunction in MDS.<ref name="pmid12406866">{{cite journal |author=Cazzola M, Invernizzi R, Bergamaschi G, ''et al'' |title=Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia |journal=Blood |volume=101 |issue=5 |pages=1996–2000 |year=2003 |pmid=12406866 |doi=10.1182/blood-2002-07-2006}}</ref>

==Types and classification==
===French-American-British (FAB) classification===
In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This [[French-American-British classification | French-American-British (FAB) classification]] was published in 1976 and revised in 1982. Cases were classified into 5 categories: ([[ICD-O]] codes are provided where available)

* ({{ICDO|9980|3}}) '''Refractory [[anemia]]''' (RA) - characterized by less than 5% primitive blood cells ([[myeloblasts]]) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
* ({{ICDO|9982|3}}) '''Refractory anemia with ringed sideroblasts''' (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
* ({{ICDO|9983|3}}) '''Refractory anemia with excess blasts''' (RAEB) - characterized by 5-19% myeloblasts in the marrow;
* ({{ICDO|9984|3}}) '''Refractory anemia with excess blasts in transformation''' (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
* ({{ICDO|9945|3}}) '''Chronic myelomonocytic leukemia''' (CMML) - not to be confused with [[chronic myelogenous leukemia]] or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

A table comparing these is available from the [http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm Cleveland Clinic].

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. Leukemic transformation occurs in about 10-17% of patients with RA/RARS; it is approximately 40-60% for patients with RAEB. The others die of complications of low blood count or unrelated disease.

The FAB classification was used by pathologists and clinicians for almost 20 years. By the early 21st century the WHO classification had replaced it.

===WHO classification===
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

The list of dysplastic syndromes under the new WHO system includes:
# Refractory anemia (RA)
# Refractory anemia with ringed sideroblasts (RARS)
# Refractory cytopenia with multilineage dysplasia (RCMD)
# Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
# Refractory anemia with excess blasts I and II
# [[5q- syndrome]]
# Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)

RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia. The presence of 20% or more blasts denotes the diagnosis of AML. (In the new WHO classification RAEB-T no longer exists).

5q- syndrome, typically seen in older women was added to the classification. The diagnosis of 5q minus syndrome requires that 5q minus MUST be an isolated abnormality. Clinical manifestations include a tendency towards a hypercellular bone marrow, macrocytosis/RA, normal or high platelet counts and hypolobulated megakaryocytes. It carries a good prognosis, with a median survival > 5 years, a low risk of AML and a benign course. 14(RPS4) is the underlying genetic defect of 5q minus syndrome. Haploinsufficiency of the ribosomal gene 14(RPS4)occurs here; it is required for the maturation of the 40s ribosomal subunit and it maps to the deleted region on 5q minus. 67% of patients with 5q minus achieve transfusion independence with the administration of Lenalidomide. Lenalidomide in 5q minus causes a response by decreasing Cdc25c and PP2A mRNA expression. Lenalidomide has such high clinical activity for this type of MDS that it is almost comparable to teh track record of imatinib in CML.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

==Diagnosis==

Differential Diagnosis (for dysplasia)
* Arsenic, Lead, Benzene, Xylene, petroleum, Agent Orange (Vietnam Veterans).
* Congenital Dyserythropoietic anemia
* HIV
* Vitamin B12 / folate
* Parvovirus
* Alcohol abuse
* Prior chemotherapy (eg. melphalan, mustard, chlorambucil, busulfan, cyclophosphamide).
* Radiation (with or without chemotherapy).

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
*Granulocytic series
*# Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
*# Hyposegmented neutrophils (Pseudo-Pelger Huet)
*# Hypogranular neutrophils or pseudo Chediak Higashi large granules
*# Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
* Erythroid series
*# Binucleated erythroid percursors and karyorrhexis
*# Erythroid nuclear budding
*# Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
*# PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
*# Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
* Megakaryocytic series (can be the most subjective)
*# Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
*# Hypersegmented (osteoclastic appearing) megakaryocytes
*# Ballooning of the platelets (seen with interference contrast microscopy)

Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

MDS can appear a lot like megaloblastic anemia however megaloblastic anemia has cell lysis thereby causing an increase in the bilirubin and LDH whereas, in MDS, these aren't elevated.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells/(blasts) clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. ALIP is thought to be a preleukemic harbinger and associated with a poor outcome in RA and RARS.

Hypoplastic MDS has a cellularity of less than 25-30% and shares features that appear to overlap with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). In these patients the administration of anti-thymocyte globulin (ATG) and cyclosporine have produced response rates of 44% and 84% respectively. The presence of a PNH clone, bone marrow hypocellularity and <5% bone marrow blasts are positive predictors of response to immunomodulation.

Malfunctions can occur in the cells of MDS patients. These can manifest as poor platelet aggregation or impaired neutrophil chemotaxis. One of the more phenotypically obvious acquired red blood cell disorders in MDS is alpha thalassemia which is usually associated with a microcytic and hypochromic erythrocyte indices and with somatic point mutation in ATRX, a chromatin remodeling factor encoded by the X-chromosome.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, [[vitamin]] deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, [[Sideroblastic anemia|Pearson's syndrome (sideroblastic anemia)]], Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood ([[red blood cell|red cell]]s, [[white blood cell|white cell]]s other than [[lymphocyte]]s and [[platelets]] or their progenitor cells, [[megakaryocyte]]s).

==Epidemiology==
The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the [[United States]] alone. The incidence is probably increasing as the age of the population increases

==Therapy==
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to [[acute myelogenous leukemia]].

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. [[bone marrow transplant]]) as well as help determine the best timing of this therapy.<ref>{{cite journal | author=Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyshiki K, Toyama K, Aul C, Hufti G, Bennett J | volume=89 | issue=6 | id=PMID 9058730}}</ref> <ref>{{cite journal | author=Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM | title=A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. | journal=Blood | year=2004 | pages=579-85 | volume=104 | issue=2 | id=PMID 15039286}}</ref> Supportive care with blood product support and hematopoeitic growth factors (e.g. [[erythropoietin]]) is the mainstay of therapy. The regulatory environment for the use of [[erythropoietin]]s is evolving, according to a recent [[Medicare (United States)|US Medicare]] National Coverage Determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.<ref>{{cite web |url=http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203 |title=Centers for Medicare & Medicaid Services |accessdate=2007-10-29 |format= |work=}}</ref>

The IPSS uses 3 criteria; cytogenetic abnormalities, proportion of bone marrow myeloblasts and number of cytopenias. Points are assigned to these variables and are added to create 4 risk groups; low, intermediate 1, intermediate 2 and high risk. If patients have >10% blasts in their bone marrow by morphology they are automatically classified as having higher risk MDS. Patients with chromosome 7 abnormalities, loss of chromosome 7 or complex cytogenetics typically have high-risk MDS. A major limitation of the IPSS is that it does not distinguish between patients with severe and modest degrees of cytopenias; this may influence outcome.

Survival and AML evolution score
{| class="wikitable"
|-
! Prognostic Variable
! 0
! 0.5
! 1
! 1.5
! 2
|-
| Bone marrow blasts (%)
| <5
| 5-10
| X
| 11-20
| 21-30
|-
| Karyotype *
| good
| intermediate
| poor
| X
| X
|-
| Cytopenias **
| 0 or 1
| 2 or 3
| X
| X
| X
|}

*Good = normal or any 1 of the following; deletion Y, deletion 5q, deletion 20q.
Intermediate = other abnormalities.
Poor = complex (>/= 3 abnormalities) or chromosome 7 abnormalities.
** Hemoglobin < 10 g/dl, ANC<1800 /uL, Platelets <100,000.

{| class="wikitable"
|-
! IPSS Risk Category
! Low
! Intermediate 1
! Intermediate 2
! High
|-
| Combined score
| 0
| 0.5-1
| 1.5-2
| >/=2.5
|-
| AML evolution
| 19%
| 30%
| 33%
| 45%
|-
| Median time to AML (years)
| 9.4
| 3.3
| 1.1
| 0.2
|-
| Median survival (years)
| 5.7
| 3.5
| 1.2
| 0.4
|}

Lower risk disease includes those classified as low or intermediate 1 with a combined IPSS score of 1 or lower. For these patients observation and supportive care only has been advocated. (However, once blood transfusions are required then some form of treatment should be considered.)

Since 2004 3 medications have been approved for MDS; 5-azacytidine and decitabine are hypomethylating agents, lenalidomide is immunomodulatory. Lenalidomide is especially useful in the treatment of 5q minus syndrome; for these patients the medication not only improves counts but it also has a high complete response rate in the bone marrow and a high remission rate for the chromosome. For non-5q deletion, low-risk MDS patients treatment options include lenalidomide and demethylating agents.

DNA-methyltransferase inhibitors; normally methylation of cytosine in gene promoters causes them to become silent; they would otherwise cause terminal differentiation. There is survival benefit with the hypomethylating agents (Decitabine & Azacitadine)in higher-risk disease (intermediate-2 or high risk disease).Azacitidine and Decitabine are different chemically and patients whose disease doesn't respond or becomes refractory to one may respond to the other. The recommendation is to proceed until progression; sometimes stopping allows the disease to relapse or it relapses as it is resistant disease. The major toxicities are nausea, vomiting, diarrhea, cytopenias and fatigue.
<ref name="pmid10694544">{{cite journal |author=Wijermans P, Lübbert M, Verhoef G, ''et al'' |title=Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients |journal=J. Clin. Oncol. |volume=18 |issue=5 |pages=956–62 |year=2000 |pmid=10694544 |doi=}}</ref><ref name="pmid11529854">{{cite journal |author=Lübbert M, Wijermans P, Kunzmann R, ''et al'' |title=Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine |journal=Br. J. Haematol. |volume=114 |issue=2 |pages=349–57 |year=2001 |pmid=11529854 |doi=}}</ref><ref name="pmid12011120">{{cite journal |author=Silverman LR, Demakos EP, Peterson BL, ''et al'' |title=Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B |journal=J. Clin. Oncol. |volume=20 |issue=10 |pages=2429–40 |year=2002 |pmid=12011120 |doi=}}</ref><ref name="pmid16921040">{{cite journal |author=Silverman LR, McKenzie DR, Peterson BL, ''et al'' |title=Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B |journal=J. Clin. Oncol. |volume=24 |issue=24 |pages=3895–903 |year=2006 |pmid=16921040 |doi=10.1200/JCO.2005.05.4346}}</ref>
<ref name="pmid17133405">{{cite journal |author=Kantarjian HM, O'Brien S, Shan J, ''et al'' |title=Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome |journal=Cancer |volume=109 |issue=2 |pages=265–73 |year=2007 |pmid=17133405 |doi=10.1002/cncr.22376}}</ref><ref name="pmid16532500">{{cite journal |author=Kantarjian H, Issa JP, Rosenfeld CS, ''et al'' |title=Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study |journal=Cancer |volume=106 |issue=8 |pages=1794–803 |year=2006 |pmid=16532500 |doi=10.1002/cncr.21792}}</ref><ref name="pmid16882708">{{cite journal |author=Kantarjian H, Oki Y, Garcia-Manero G, ''et al'' |title=Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia |journal=Blood |volume=109 |issue=1 |pages=52–7 |year=2007 |pmid=16882708 |doi=10.1182/blood-2006-05-021162}}</ref><ref name="pmid17679729">{{cite journal |author=Blum W, Klisovic RB, Hackanson B, ''et al'' |title=Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3884–91 |year=2007 |pmid=17679729 |doi=10.1200/JCO.2006.09.4169}}</ref>

IMiDS, such as Lenalidomide are for erythroid failure such as in transfusion-dependent del(5q). The response rate (~67%)is independent of the karyoptype. Treatment can give a positive cytopgenetic response, the patient becomes transfusion-free and would no longer require Erythropoietin. With treatment there is a transient decrease in the leukocytes and platelets. It has been known to be useful in paients without the 5q deletion with ~25% of patients experiencing a significant response in hemoglobin levels.
<ref name="pmid17021321">{{cite journal |author=List A, Dewald G, Bennett J, ''et al'' |title=Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion |journal=N. Engl. J. Med. |volume=355 |issue=14 |pages=1456–65 |year=2006 |pmid=17021321 |doi=10.1056/NEJMoa061292}}</ref>
<ref name="pmid16625140">{{cite journal |author= |title=Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome |journal=The Medical letter on drugs and therapeutics |volume=48 |issue=1232 |pages=31–2 |year=2006 |pmid=16625140 |doi=}}</ref>.

[[Stem cell transplantation]], particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.<ref>{{cite journal |author=Oosterveld M, Wittebol S, Lemmens W, Kiemeney B, Catik A, Muus P, Schattenberg A, de Witte T |title=The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups |journal=Br J Haematol |volume=123 |issue=1 |pages=81-9 |year=2003 |pmid=14510946}}</ref>

==References==
{{Reflist|2}}

==Additional Readings==
* Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. ''Proposals for the classification of the myelodysplastic syndromes.'' Br J Haematol 1982;51:189. PMID 6952920.
* Block M, Jacobson LO, Bethard WF. ''Preleukemic acute human leukemia.'' [[Journal of the American Medical Association|JAMA]] 1953;152:1018-28. PMID 13052490.
* Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. ''World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.'' J Clin Oncol 1999;17:3835-49. PMID 10577857.
* Foucar, K Bone Marrow Pathology, 2nd Edition, ASCP Press. c 2001
* Greenberg, Peter L. (editor) "Myelodysplastic Syndromes: Clinical and Biological Advances" Cambridge University Press, New York 2006 ISBN 978-0521496681 ISBN 0521496683
* Steensma DP, Gibbons RJ, Higgs DR. "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies." Blood 2005;105:443-452. PMID 15358626.
* List A, Dewald G, Bennett J, Giagnounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Store R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R. "Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion." NEJM 2006;355(14):1456-1465. PMID 17021321.
* Fenaux P, Mufti GJ, Lindberg EH, Santini V, Finelli C, Giagounidis A, Schoch R, Gatterman N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrum J, Zimmerman JF, McKenzie D, Beach CL, Silverman LR. "Efficacy of Azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised open-label phase III study." Lancet Oncology 2009;10(3):223-232. PMID 19230772.

==External links==
* ''[http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?rid=cmed.chapter.32804 Cancer Medicine]''. Online textbook. Chapter by Lewis R. Silverman on Myelodysplastic Syndrome.
* [http://www.aamds.org Website of the Aplastic Anemia & MDS International Foundation which provides information and support and hope to patients and their families]
*[http://www.mds-foundation.org Website of MDS-Foundation with a lot of helpful materials]
* [http://www.mayoclinic.com/print/myelodysplastic-syndromes/DS00596/DSECTION=all&METHOD=print Myelodysplastic syndromes]. Comprehensive article from MayoClinic.com.
* [http://www.virtualcancercentre.com/diseases.asp?did=68 Myelodysplastic syndrome (MDS)]. article from virtualcancercentre.com.
* [http://www.va.gov/vetapp04/files4/0434293.txt] Agent Orange and MDS, 100% service connected.

==See also==
*[[Myeloproliferative syndrome]]
*[[Acute myeloid leukemia]]
*[[Chloroma]]

{{Hematology}}
{{Hematological malignancy histology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Syndromes]]
[[Category:Oncology]]
[[ar:متلازمة خلل التنسج النقوي]]
[[de:Myelodysplastisches Syndrom]]
[[fr:Syndrome myélodysplasique]]
[[ja:骨髄異形成症候群]]
[[pt:Síndrome mielodisplásica]]
[[sv:Myelodysplastiskt syndrom]]

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Myelodysplastic syndrome

2011-03-29T01:10:56Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 8604|
ICD10 = {{ICD10|D|46||d|37}} |
ICD9 = {{ICD9|238.7}} |
ICDO = 9980/0-9989/3 |
OMIM = |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2695 |
eMedicine_mult = {{eMedicine2|ped|1527}} |
MeshID = D009190 |
}}
{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==

The '''myelodysplastic syndromes''' (MDS, formerly known as "preleukemia") are a diverse collection of [[hematology|hematological]] conditions united by ineffective production of blood cells and varying risks of transformation to [[acute myelogenous leukemia]]. [[Anemia]] requiring chronic [[blood transfusion]] is frequently present. Although not truly [[cancer|malignant]], MDS is nevertheless classified within the [[Hematological malignancy|haematological neoplasms]].

Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

== Signs and symptoms ==
Abnormalities include:
* [[neutropenia]], [[anemia]] and [[thrombocytopenia]] (low cell counts of white and red blood cells, and platelets, respectively)
* abnormal granules in cells, abnormal nuclear shape and size
* [[chromosome|chromosomal]] abnormalities, including [[chromosomal translocation]]s and abnormal chromosome number.

Symptoms of myelodysplastic conditions:
* [[Anemia]]—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
* [[Neutropenia]] (low neutrophil count) —increased susceptibility to [[infection]]
* [[Thrombocytopenia]] (low platelet count) —increased susceptibility to [[bleeding]]

Although there is some risk for developing [[acute myelogenous leukemia]], about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

==Diagnosis==
Investigation:
* [[Full blood count]] and examination of [[blood film]]
* [[Bone marrow examination]] by an experienced [[hematopathologist]]
* [[Cytogenetics]] or chromosomal studies. This is performed on the bone marrow aspirate.

==Diagnosistic Workup==
The differential diagnosis is that of [[anemia]], [[thrombocytopenia]], and/or [[leukopenia]]. Usually, the elimination of known [[etiologies]] of [[cytopenias]], along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

Investigation:
* [[Full blood count]] and examination of [[blood film]]. The [[blood film]] morphology can provide clues about [[hemolytic anemia]], clumping of the [[platelets]] leading to spurious [[thrombocytopenia]], or [[leukemia]].
* Blood tests to eliminate other common causes of [[cytopenias]], such as [[lupus]], [[hepatitis]], [[B12]], [[folate]], or other [[vitamin]] deficiencies, [[renal failure]] or [[heart failure]], [[HIV]], [[hemolytic anemia]], [[monoclonal gammopathy]]. Age-appropriate cancer screening should be considered for all [[anemic]] patients.
* [[Bone marrow examination]] by an experienced [[hematopathologist]]. This is required to establish the diagnosis, since all hematopathologists recognize a dysplastic marrow as the key feature of myelodysplasia.
* [[Cytogenetics]] or chromosomal studies. This is ideally performed on the bone marrow aspirate. These require a fresh specimen, since live cells are induced to enter [[metaphase]] to enhance [[chromosomal]] staining.
* [[Flow cytometry]] is helpful to establish the presence of any [[lymphoproliferative]] disorder in the [[marrow]]

==Genetics==

{| class="wikitable"
|-
! Abnormality
! Frequency in MDS
|-
| -5/del(5q)
| 10-20%
|-
| +8
| 10%
|-
| -7/del(7q)
| 5-10%
|-
| -Y
|10%
|-
| 17p-
| 7%
|-
| del(20q)
| 5-6%
|-
| t(11q23)
| 5-6%
|-
| complex karyotype
| 10-20%
|}

Overall, the mutations in the RUNX1/AML1 are the most common point mutations described in MDS to date but RUNX1/AML1 mutations have no distinct hematologic phenotype and are most commonly associated with previous radiation exposure and with a higher risk disease (especially with excess blasts).

Hypermethylation leading to silencing of the p151NK-4b gene is also common in MDS. This phenomenon occurs in up to 80% of the cases with advanced MDS. The silencing of this gene can be reversed by the uyse of demethylating agents such as 5-azacytidine. These agents are pyrimidine analogues that inhibit DNA methyltransferase activity and could improve MDS hematopoiesis by reversing aberrant gene methylation and permitting cellular differentiation.

A number of studies suggest that erythropoietin (EPO) signaling and STAT5 activation is abnormal in MDS. The SOCS1 gene is hypermethylated in 31% of MDS patients which is associated with increased activity of the JAK/STAT pathway.

Microsatellite instability involving defects in the DNA mismatch repair system has been identified in some MDS patients, especially those with therapy-related disease.

The TP53 tumor suppressor gene, which regulates cell cycle progression, DNA repair and apoptosis is mutated in 5-10% of MDS cases. Inactivation of the TP53 gene may contribute to the leukemic progression from MDS.

==Pathophysiology==
MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multi-potent bone marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood. [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and there is a significant increase in levels of cell death [[apoptosis]] in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow [[Myeloblasts|blasts]] rises over a particular cutoff (20% for [[Myelodysplastic syndrome#WHO classification|WHO]] and 30% for [[Myelodysplastic syndrome#French-American-British (FAB) classification|FAB]]) then transformation to [[acute myeloid leukemia|leukemia]] (specifically [[acute myelogenous leukemia]] or AML) is said to have occurred. The progression of MDS to [[acute myeloid leukemia|leukemia]] is a good example of the ''[[Knudson hypothesis|multi-step theory of carcinogenesis]]'' in which a series of mutations occur in an initially normal cell and transform it into a [[cancer|cancer cell]]. The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs. This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1).

While recognition of leukemic transformation was historically important (see [[Myelodysplastic syndrome#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to [[acute myeloid leukemia|AML]] but rather from the [[cytopenia]]s seen in all MDS patients. While [[anemia]] is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]] MDS patients rarely suffer injury from severe [[anemia]]. However, if an MDS patient is fortunate enough to suffer nothing more than [[anemia]] over several years, they then risk [[iron overload#secondary iron overload|iron overload]]. The two most serious complications in MDS patients resulting from their [[cytopenia]]s are bleeding (due to lack of [[platelet]]s) or infection (due to lack of [[white blood cell]]s).

The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two of three commercially available medications approved by the US FDA to treat MDS. Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of [[DNA methylation]] control can lead to uncontrolled cell growth, and [[cytopenias]]. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly [[DNA methylation]] profile in the [[hematopoietic stem cell]] [[nucleus]], and thereby restore normal blood counts and retard the progression of MDS to [[acute leukemia]].

Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA [[mutation]]s in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of [[mitochondrial]] [[iron]] deposits in the [[ringed sideroblast]] as evidence of [[mitochondrial]] dysfunction in MDS.<ref name="pmid12406866">{{cite journal |author=Cazzola M, Invernizzi R, Bergamaschi G, ''et al'' |title=Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia |journal=Blood |volume=101 |issue=5 |pages=1996–2000 |year=2003 |pmid=12406866 |doi=10.1182/blood-2002-07-2006}}</ref>

==Types and classification==
===French-American-British (FAB) classification===
In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This [[French-American-British classification | French-American-British (FAB) classification]] was published in 1976 and revised in 1982. Cases were classified into 5 categories: ([[ICD-O]] codes are provided where available)

* ({{ICDO|9980|3}}) '''Refractory [[anemia]]''' (RA) - characterized by less than 5% primitive blood cells ([[myeloblasts]]) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
* ({{ICDO|9982|3}}) '''Refractory anemia with ringed sideroblasts''' (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
* ({{ICDO|9983|3}}) '''Refractory anemia with excess blasts''' (RAEB) - characterized by 5-19% myeloblasts in the marrow;
* ({{ICDO|9984|3}}) '''Refractory anemia with excess blasts in transformation''' (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
* ({{ICDO|9945|3}}) '''Chronic myelomonocytic leukemia''' (CMML) - not to be confused with [[chronic myelogenous leukemia]] or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

A table comparing these is available from the [http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm Cleveland Clinic].

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. Leukemic transformation occurs in about 10-17% of patients with RA/RARS; it is approximately 40-60% for patients with RAEB. The others die of complications of low blood count or unrelated disease.

The FAB classification was used by pathologists and clinicians for almost 20 years. By the early 21st century the WHO classification had replaced it.

===WHO classification===
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

The list of dysplastic syndromes under the new WHO system includes:
# Refractory anemia (RA)
# Refractory anemia with ringed sideroblasts (RARS)
# Refractory cytopenia with multilineage dysplasia (RCMD)
# Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
# Refractory anemia with excess blasts I and II
# [[5q- syndrome]]
# Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)

RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia. The presence of 20% or more blasts denotes the diagnosis of AML. (In the new WHO classification RAEB-T no longer exists).

5q- syndrome, typically seen in older women was added to the classification. The diagnosis of 5q minus syndrome requires that 5q minus MUST be an isolated abnormality. Clinical manifestations include a tendency towards a hypercellular bone marrow, macrocytosis/RA, normal or high platelet counts and hypolobulated megakaryocytes. It carries a good prognosis, with a median survival > 5 years, a low risk of AML and a benign course. 14(RPS4) is the underlying genetic defect of 5q minus syndrome. Haploinsufficiency of the ribosomal gene 14(RPS4)occurs here; it is required for the maturation of the 40s ribosomal subunit and it maps to the deleted region on 5q minus. 67% of patients with 5q minus achieve transfusion independence with the administration of Lenalidomide. Lenalidomide in 5q minus causes a response by decreasing Cdc25c and PP2A mRNA expression. Lenalidomide has such high clinical activity for this type of MDS that it is almost comparable to teh track record of imatinib in CML.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

==Diagnosis==

Differential Diagnosis (for dysplasia)
* Arsenic, Lead, Benzene, Xylene, petroleum, Agent Orange (Vietnam Veterans).
* Congenital Dyserythropoietic anemia
* HIV
* Vitamin B12 / folate
* Parvovirus
* Alcohol abuse
* Prior chemotherapy (eg. melphalan, mustard, chlorambucil, busulfan, cyclophosphamide).
* Radiation (with or without chemotherapy).

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
*Granulocytic series
*# Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
*# Hyposegmented neutrophils (Pseudo-Pelger Huet)
*# Hypogranular neutrophils or pseudo Chediak Higashi large granules
*# Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
* Erythroid series
*# Binucleated erythroid percursors and karyorrhexis
*# Erythroid nuclear budding
*# Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
*# PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
*# Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
* Megakaryocytic series (can be the most subjective)
*# Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
*# Hypersegmented (osteoclastic appearing) megakaryocytes
*# Ballooning of the platelets (seen with interference contrast microscopy)

Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

MDS can appear a lot like megaloblastic anemia however megaloblastic anemia has cell lysis thereby causing an increase in the bilirubin and LDH whereas, in MDS, these aren't elevated.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells/(blasts) clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. ALIP is thought to be a preleukemic harbinger and associated with a poor outcome in RA and RARS.

Hypoplastic MDS has a cellularity of less than 25-30% and shares features that appear to overlap with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). In these patients the administration of anti-thymocyte globulin (ATG) and cyclosporine have produced response rates of 44% and 84% respectively. The presence of a PNH clone, bone marrow hypocellularity and <5% bone marrow blasts are positive predictors of response to immunomodulation.

Malfunctions can occur in the cells of MDS patients. These can manifest as poor platelet aggregation or impaired neutrophil chemotaxis. One of the more phenotypically obvious acquired red blood cell disorders in MDS is alpha thalassemia which is usually associated with a microcytic and hypochromic erythrocyte indices and with somatic point mutation in ATRX, a chromatin remodeling factor encoded by the X-chromosome.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, [[vitamin]] deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, [[Sideroblastic anemia|Pearson's syndrome (sideroblastic anemia)]], Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood ([[red blood cell|red cell]]s, [[white blood cell|white cell]]s other than [[lymphocyte]]s and [[platelets]] or their progenitor cells, [[megakaryocyte]]s).

==Epidemiology==
The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the [[United States]] alone. The incidence is probably increasing as the age of the population increases

==Therapy==
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to [[acute myelogenous leukemia]].

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. [[bone marrow transplant]]) as well as help determine the best timing of this therapy.<ref>{{cite journal | author=Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyshiki K, Toyama K, Aul C, Hufti G, Bennett J | volume=89 | issue=6 | id=PMID 9058730}}</ref> <ref>{{cite journal | author=Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM | title=A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. | journal=Blood | year=2004 | pages=579-85 | volume=104 | issue=2 | id=PMID 15039286}}</ref> Supportive care with blood product support and hematopoeitic growth factors (e.g. [[erythropoietin]]) is the mainstay of therapy. The regulatory environment for the use of [[erythropoietin]]s is evolving, according to a recent [[Medicare (United States)|US Medicare]] National Coverage Determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.<ref>{{cite web |url=http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203 |title=Centers for Medicare & Medicaid Services |accessdate=2007-10-29 |format= |work=}}</ref>

The IPSS uses 3 criteria; cytogenetic abnormalities, proportion of bone marrow myeloblasts and number of cytopenias. Points are assigned to these variables and are added to create 4 risk groups; low, intermediate 1, intermediate 2 and high risk. If patients have >10% blasts in their bone marrow by morphology they are automatically classified as having higher risk MDS. Patients with chromosome 7 abnormalities, loss of chromosome 7 or complex cytogenetics typically have high-risk MDS. A major limitation of the IPSS is that it does not distinguish between patients with severe and modest degrees of cytopenias; this may influence outcome.

Survival and AML evolution score
{| class="wikitable"
|-
! Prognostic Variable
! 0
! 0.5
! 1
! 1.5
! 2
|-
| Bone marrow blasts (%)
| <5
| 5-10
| X
| 11-20
| 21-30
|-
| Karyotype *
| good
| intermediate
| poor
| X
| X
|-
| Cytopenias **
| 0 or 1
| 2 or 3
| X
| X
| X
|}

*Good = normal or any 1 of the following; deletion Y, deletion 5q, deletion 20q.
Intermediate = other abnormalities.
Poor = complex (>/= 3 abnormalities) or chromosome 7 abnormalities.
** Hemoglobin < 10 g/dl, ANC<1800 /uL, Platelets <100,000.

{| class="wikitable"
|-
! IPSS Risk Category
! Low
! Intermediate 1
! Intermediate 2
! High
|-
| Combined score
| 0
| 0.5-1
| 1.5-2
| >/=2.5
|-
| AML evolution
| 19%
| 30%
| 33%
| 45%
|-
| Median time to AML (years)
| 9.4
| 3.3
| 1.1
| 0.2
|-
| Median survival (years)
| 5.7
| 3.5
| 1.2
| 0.4
|}

Lower risk disease includes those classified as low or intermediate 1 with a combined IPSS score of 1 or lower. For these patients observation and supportive care only has been advocated. (However, once blood transfusions are required then some form of treatment should be considered.)

Since 2004 3 medications have been approved for MDS; 5-azacytidine and decitabine are hypomethylating agents, lenalidomide is immunomodulatory. Lenalidomide is especially useful in the treatment of 5q minus syndrome; for these patients the medication not only improves counts but it also has a high complete response rate in the bone marrow and a high remission rate for the chromosome. For non-5q deletion, low-risk MDS patients treatment options include lenalidomide and demethylating agents.

{| class="wikitable"
|-
! Name
! Comments
! References
|-
| [[5-azacytidine]]
| 21 month median survival similar to that of [[decitabine]]
| <ref name="pmid10694544">{{cite journal |author=Wijermans P, Lübbert M, Verhoef G, ''et al'' |title=Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients |journal=J. Clin. Oncol. |volume=18 |issue=5 |pages=956–62 |year=2000 |pmid=10694544 |doi=}}</ref><ref name="pmid11529854">{{cite journal |author=Lübbert M, Wijermans P, Kunzmann R, ''et al'' |title=Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine |journal=Br. J. Haematol. |volume=114 |issue=2 |pages=349–57 |year=2001 |pmid=11529854 |doi=}}</ref><ref name="pmid12011120">{{cite journal |author=Silverman LR, Demakos EP, Peterson BL, ''et al'' |title=Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B |journal=J. Clin. Oncol. |volume=20 |issue=10 |pages=2429–40 |year=2002 |pmid=12011120 |doi=}}</ref><ref name="pmid16921040">{{cite journal |author=Silverman LR, McKenzie DR, Peterson BL, ''et al'' |title=Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B |journal=J. Clin. Oncol. |volume=24 |issue=24 |pages=3895–903 |year=2006 |pmid=16921040 |doi=10.1200/JCO.2005.05.4346}}</ref>
|-
| [[Decitabine]]
| Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with [[valproic acid]].
| <ref name="pmid17133405">{{cite journal |author=Kantarjian HM, O'Brien S, Shan J, ''et al'' |title=Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome |journal=Cancer |volume=109 |issue=2 |pages=265–73 |year=2007 |pmid=17133405 |doi=10.1002/cncr.22376}}</ref><ref name="pmid16532500">{{cite journal |author=Kantarjian H, Issa JP, Rosenfeld CS, ''et al'' |title=Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study |journal=Cancer |volume=106 |issue=8 |pages=1794–803 |year=2006 |pmid=16532500 |doi=10.1002/cncr.21792}}</ref><ref name="pmid16882708">{{cite journal |author=Kantarjian H, Oki Y, Garcia-Manero G, ''et al'' |title=Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia |journal=Blood |volume=109 |issue=1 |pages=52–7 |year=2007 |pmid=16882708 |doi=10.1182/blood-2006-05-021162}}</ref><ref name="pmid17679729">{{cite journal |author=Blum W, Klisovic RB, Hackanson B, ''et al'' |title=Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3884–91 |year=2007 |pmid=17679729 |doi=10.1200/JCO.2006.09.4169}}</ref>

|-
| [[Lenalidomide]]
| Most effective in reducing red cell transfusion requirement
| <ref name="pmid17021321">{{cite journal |author=List A, Dewald G, Bennett J, ''et al'' |title=Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion |journal=N. Engl. J. Med. |volume=355 |issue=14 |pages=1456–65 |year=2006 |pmid=17021321 |doi=10.1056/NEJMoa061292}}</ref>
|}

[[Chemotherapy]] with the [[DNA methylation|hypomethylating agents]] [[5-azacytidine]] and [[decitabine]] has been shown to decrease blood transfusion requirements and to retard the progression of MDS to [[AML]].

[[Lenalidomide]] was approved by the [[FDA]] in December 2005 only for use in the [[5q- syndrome]]. It was approved in July, 2006 for use in [[multiple myeloma]]. The retail price of [[lenalidomide]] is estimated at $7,000 per month <ref name="pmid16625140">{{cite journal |author= |title=Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome |journal=The Medical letter on drugs and therapeutics |volume=48 |issue=1232 |pages=31–2 |year=2006 |pmid=16625140 |doi=}}</ref>.

[[Stem cell transplantation]], particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.<ref>{{cite journal |author=Oosterveld M, Wittebol S, Lemmens W, Kiemeney B, Catik A, Muus P, Schattenberg A, de Witte T |title=The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups |journal=Br J Haematol |volume=123 |issue=1 |pages=81-9 |year=2003 |pmid=14510946}}</ref>

==References==
{{Reflist|2}}

==Additional Readings==
* Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. ''Proposals for the classification of the myelodysplastic syndromes.'' Br J Haematol 1982;51:189. PMID 6952920.
* Block M, Jacobson LO, Bethard WF. ''Preleukemic acute human leukemia.'' [[Journal of the American Medical Association|JAMA]] 1953;152:1018-28. PMID 13052490.
* Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. ''World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.'' J Clin Oncol 1999;17:3835-49. PMID 10577857.
* Foucar, K Bone Marrow Pathology, 2nd Edition, ASCP Press. c 2001
* Greenberg, Peter L. (editor) "Myelodysplastic Syndromes: Clinical and Biological Advances" Cambridge University Press, New York 2006 ISBN 978-0521496681 ISBN 0521496683
* Steensma DP, Gibbons RJ, Higgs DR. "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies." Blood 2005;105:443-452. PMID 15358626.

==External links==
* ''[http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?rid=cmed.chapter.32804 Cancer Medicine]''. Online textbook. Chapter by Lewis R. Silverman on Myelodysplastic Syndrome.
* [http://www.aamds.org Website of the Aplastic Anemia & MDS International Foundation which provides information and support and hope to patients and their families]
*[http://www.mds-foundation.org Website of MDS-Foundation with a lot of helpful materials]
* [http://www.mayoclinic.com/print/myelodysplastic-syndromes/DS00596/DSECTION=all&METHOD=print Myelodysplastic syndromes]. Comprehensive article from MayoClinic.com.
* [http://www.virtualcancercentre.com/diseases.asp?did=68 Myelodysplastic syndrome (MDS)]. article from virtualcancercentre.com.
* [http://www.va.gov/vetapp04/files4/0434293.txt] Agent Orange and MDS, 100% service connected.

==See also==
*[[Myeloproliferative syndrome]]
*[[Acute myeloid leukemia]]
*[[Chloroma]]

{{Hematology}}
{{Hematological malignancy histology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Syndromes]]
[[Category:Oncology]]
[[ar:متلازمة خلل التنسج النقوي]]
[[de:Myelodysplastisches Syndrom]]
[[fr:Syndrome myélodysplasique]]
[[ja:骨髄異形成症候群]]
[[pt:Síndrome mielodisplásica]]
[[sv:Myelodysplastiskt syndrom]]

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Myelodysplastic syndrome

2011-03-25T00:52:48Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 8604|
ICD10 = {{ICD10|D|46||d|37}} |
ICD9 = {{ICD9|238.7}} |
ICDO = 9980/0-9989/3 |
OMIM = |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2695 |
eMedicine_mult = {{eMedicine2|ped|1527}} |
MeshID = D009190 |
}}
{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==

The '''myelodysplastic syndromes''' (MDS, formerly known as "preleukemia") are a diverse collection of [[hematology|hematological]] conditions united by ineffective production of blood cells and varying risks of transformation to [[acute myelogenous leukemia]]. [[Anemia]] requiring chronic [[blood transfusion]] is frequently present. Although not truly [[cancer|malignant]], MDS is nevertheless classified within the [[Hematological malignancy|haematological neoplasms]].

Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

== Signs and symptoms ==
Abnormalities include:
* [[neutropenia]], [[anemia]] and [[thrombocytopenia]] (low cell counts of white and red blood cells, and platelets, respectively)
* abnormal granules in cells, abnormal nuclear shape and size
* [[chromosome|chromosomal]] abnormalities, including [[chromosomal translocation]]s and abnormal chromosome number.

Symptoms of myelodysplastic conditions:
* [[Anemia]]—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
* [[Neutropenia]] (low neutrophil count) —increased susceptibility to [[infection]]
* [[Thrombocytopenia]] (low platelet count) —increased susceptibility to [[bleeding]]

Although there is some risk for developing [[acute myelogenous leukemia]], about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

==Diagnosis==
Investigation:
* [[Full blood count]] and examination of [[blood film]]
* [[Bone marrow examination]] by an experienced [[hematopathologist]]
* [[Cytogenetics]] or chromosomal studies. This is performed on the bone marrow aspirate.

==Differential Diagnosis and Workup==
The differential diagnosis is that of [[anemia]], [[thrombocytopenia]], and/or [[leukopenia]]. Usually, the elimination of known [[etiologies]] of [[cytopenias]], along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

Investigation:
* [[Full blood count]] and examination of [[blood film]]. The [[blood film]] morphology can provide clues about [[hemolytic anemia]], clumping of the [[platelets]] leading to spurious [[thrombocytopenia]], or [[leukemia]].
* Blood tests to eliminate other common causes of [[cytopenias]], such as [[lupus]], [[hepatitis]], [[B12]], [[folate]], or other [[vitamin]] deficiencies, [[renal failure]] or [[heart failure]], [[HIV]], [[hemolytic anemia]], [[monoclonal gammopathy]]. Age-appropriate cancer screening should be considered for all [[anemic]] patients.
* [[Bone marrow examination]] by an experienced [[hematopathologist]]. This is required to establish the diagnosis, since all hematopathologists recognize a dysplastic marrow as the key feature of myelodysplasia.
* [[Cytogenetics]] or chromosomal studies. This is ideally performed on the bone marrow aspirate. These require a fresh specimen, since live cells are induced to enter [[metaphase]] to enhance [[chromosomal]] staining.
* [[Flow cytometry]] is helpful to establish the presence of any [[lymphoproliferative]] disorder in the [[marrow]]

==Genetics==

{| class="wikitable"
|-
! Abnormality
! Frequency in MDS
|-
| -5/del(5q)
| 10-20%
|-
| +8
| 10%
|-
| -7/del(7q)
| 5-10%
|-
| -Y
|10%
|-
| 17p-
| 7%
|-
| del(20q)
| 5-6%
|-
| t(11q23)
| 5-6%
|-
| complex karyotype
| 10-20%
|}

Overall, the mutations in the RUNX1/AML1 are the most common point mutations described in MDS to date but RUNX1/AML1 mutations have no distinct hematologic phenotype and are most commonly associated with previous radiation exposure and with a higher risk disease (especially with excess blasts).

Hypermethylation leading to silencing of the p151NK-4b gene is also common in MDS. This phenomenon occurs in up to 80% of the cases with advanced MDS. The silencing of this gene can be reversed by the uyse of demethylating agents such as 5-azacytidine. These agents are pyrimidine analogues that inhibit DNA methyltransferase activity and could improve MDS hematopoiesis by reversing aberrant gene methylation and permitting cellular differentiation.

A number of studies suggest that erythropoietin (EPO) signaling and STAT5 activation is abnormal in MDS. The SOCS1 gene is hypermethylated in 31% of MDS patients which is associated with increased activity of the JAK/STAT pathway.

Microsatellite instability involving defects in the DNA mismatch repair system has been identified in some MDS patients, especially those with therapy-related disease.

The TP53 tumor suppressor gene, which regulates cell cycle progression, DNA repair and apoptosis is mutated in 5-10% of MDS cases. Inactivation of the TP53 gene may contribute to the leukemic progression from MDS.

==Pathophysiology==
MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multi-potent bone marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood. [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and there is a significant increase in levels of cell death [[apoptosis]] in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow [[Myeloblasts|blasts]] rises over a particular cutoff (20% for [[Myelodysplastic syndrome#WHO classification|WHO]] and 30% for [[Myelodysplastic syndrome#French-American-British (FAB) classification|FAB]]) then transformation to [[acute myeloid leukemia|leukemia]] (specifically [[acute myelogenous leukemia]] or AML) is said to have occurred. The progression of MDS to [[acute myeloid leukemia|leukemia]] is a good example of the ''[[Knudson hypothesis|multi-step theory of carcinogenesis]]'' in which a series of mutations occur in an initially normal cell and transform it into a [[cancer|cancer cell]]. The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs. This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1).

While recognition of leukemic transformation was historically important (see [[Myelodysplastic syndrome#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to [[acute myeloid leukemia|AML]] but rather from the [[cytopenia]]s seen in all MDS patients. While [[anemia]] is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]] MDS patients rarely suffer injury from severe [[anemia]]. However, if an MDS patient is fortunate enough to suffer nothing more than [[anemia]] over several years, they then risk [[iron overload#secondary iron overload|iron overload]]. The two most serious complications in MDS patients resulting from their [[cytopenia]]s are bleeding (due to lack of [[platelet]]s) or infection (due to lack of [[white blood cell]]s).

The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two of three commercially available medications approved by the US FDA to treat MDS. Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of [[DNA methylation]] control can lead to uncontrolled cell growth, and [[cytopenias]]. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly [[DNA methylation]] profile in the [[hematopoietic stem cell]] [[nucleus]], and thereby restore normal blood counts and retard the progression of MDS to [[acute leukemia]].

Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA [[mutation]]s in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of [[mitochondrial]] [[iron]] deposits in the [[ringed sideroblast]] as evidence of [[mitochondrial]] dysfunction in MDS.<ref name="pmid12406866">{{cite journal |author=Cazzola M, Invernizzi R, Bergamaschi G, ''et al'' |title=Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia |journal=Blood |volume=101 |issue=5 |pages=1996–2000 |year=2003 |pmid=12406866 |doi=10.1182/blood-2002-07-2006}}</ref>

==Types and classification==
===French-American-British (FAB) classification===
In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This [[French-American-British classification | French-American-British (FAB) classification]] was published in 1976 and revised in 1982. Cases were classified into 5 categories: ([[ICD-O]] codes are provided where available)

* ({{ICDO|9980|3}}) '''Refractory [[anemia]]''' (RA) - characterized by less than 5% primitive blood cells ([[myeloblasts]]) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
* ({{ICDO|9982|3}}) '''Refractory anemia with ringed sideroblasts''' (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
* ({{ICDO|9983|3}}) '''Refractory anemia with excess blasts''' (RAEB) - characterized by 5-19% myeloblasts in the marrow;
* ({{ICDO|9984|3}}) '''Refractory anemia with excess blasts in transformation''' (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
* ({{ICDO|9945|3}}) '''Chronic myelomonocytic leukemia''' (CMML) - not to be confused with [[chronic myelogenous leukemia]] or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

A table comparing these is available from the [http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm Cleveland Clinic].

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. Leukemic transformation occurs in about 10-17% of patients with RA/RARS; it is approximately 40-60% for patients with RAEB. The others die of complications of low blood count or unrelated disease.

The FAB classification was used by pathologists and clinicians for almost 20 years. By the early 21st century the WHO classification had replaced it.

===WHO classification===
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

The list of dysplastic syndromes under the new WHO system includes:
# Refractory anemia (RA)
# Refractory anemia with ringed sideroblasts (RARS)
# Refractory cytopenia with multilineage dysplasia (RCMD)
# Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
# Refractory anemia with excess blasts I and II
# [[5q- syndrome]]
# Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)

RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia. The presence of 20% or more blasts denotes the diagnosis of AML. (In the new WHO classification RAEB-T no longer exists).

5q- syndrome, typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

==Diagnosis==
The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as [[melphalan]], mustard, [[cyclophosphamide]], [[busulfan]], and [[chlorambucil]]) or [[radiation]] (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS.

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
*Granulocytic series
*# Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
*# Hyposegmented neutrophils (Pseudo-Pelger Huet)
*# Hypogranular neutrophils or pseudo Chediak Higashi large granules
*# Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
* Erythroid series
*# Binucleated erythroid percursors and karyorrhexis
*# Erythroid nuclear budding
*# Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
*# PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
*# Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
* Megakaryocytic series (can be the most subjective)
*# Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
*# Hypersegmented (osteoclastic appearing) megakaryocytes
*# Ballooning of the platelets (seen with interference contrast microscopy)

Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells/(blasts) clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. ALIP is thought to be a preleukemic harbinger and associated with a poor outcome in RA and RARS.

Hypoplastic MDS has a cellularity of less than 25-30% and shares features that appear to overlap with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). In these patients the administration of anti-thymocyte globulin (ATG) and cyclosporine have produced response rates of 44% and 84% respectively. The presence of a PNH clone, bone marrow hypocellularity and <5% bone marrow blasts are positive predictors of response to immunomodulation.

Malfunctions can occur in the cells of MDS patients. These can manifest as poor platelet aggregation or impaired neutrophil chemotaxis. One of the more phenotypically obvious acquired red blood cell disorders in MDS is alpha thalassemia which is usually associated with a microcytic and hypochromic erythrocyte indices and with somatic point mutation in ATRX, a chromatin remodeling factor encoded by the X-chromosome.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, [[vitamin]] deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, [[Sideroblastic anemia|Pearson's syndrome (sideroblastic anemia)]], Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood ([[red blood cell|red cell]]s, [[white blood cell|white cell]]s other than [[lymphocyte]]s and [[platelets]] or their progenitor cells, [[megakaryocyte]]s).

==Epidemiology==
The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the [[United States]] alone. The incidence is probably increasing as the age of the population increases

==Therapy==
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to [[acute myelogenous leukemia]].

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. [[bone marrow transplant]]) as well as help determine the best timing of this therapy.<ref>{{cite journal | author=Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyshiki K, Toyama K, Aul C, Hufti G, Bennett J | volume=89 | issue=6 | id=PMID 9058730}}</ref> <ref>{{cite journal | author=Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM | title=A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. | journal=Blood | year=2004 | pages=579-85 | volume=104 | issue=2 | id=PMID 15039286}}</ref> Supportive care with blood product support and hematopoeitic growth factors (e.g. [[erythropoietin]]) is the mainstay of therapy. The regulatory environment for the use of [[erythropoietin]]s is evolving, according to a recent [[Medicare (United States)|US Medicare]] National Coverage Determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.<ref>{{cite web |url=http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203 |title=Centers for Medicare & Medicaid Services |accessdate=2007-10-29 |format= |work=}}</ref>

The IPSS uses 3 criteria; cytogenetic abnormalities, proportion of bone marrow myeloblasts and number of cytopenias. Points are assigned to these variables and are added to create 4 risk groups; low, intermediate 1, intermediate 2 and high risk. If patients have >10% blasts in their bone marrow by morphology they are automatically classified as having higher risk MDS. Patients with chromosome 7 abnormalities, loss of chromosome 7 or complex cytogenetics typically have high-risk MDS. A major limitation of the IPSS is that it does not distinguish between patients with severe and modest degrees of cytopenias; this may influence outcome.

Survival and AML evolution score
{| class="wikitable"
|-
! Prognostic Variable
! 0
! 0.5
! 1
! 1.5
! 2
|-
| Bone marrow blasts (%)
| <5
| 5-10
| X
| 11-20
| 21-30
|-
| Karyotype *
| good
| intermediate
| poor
| X
| X
|-
| Cytopenias **
| 0 or 1
| 2 or 3
| X
| X
| X
|}

*Good = normal or any 1 of the following; deletion Y, deletion 5q, deletion 20q.
Intermediate = other abnormalities.
Poor = complex (>/= 3 abnormalities) or chromosome 7 abnormalities.
** Hemoglobin < 10 g/dl, ANC<1800 /uL, Platelets <100,000.

{| class="wikitable"
|-
! IPSS Risk Category
! Low
! Intermediate 1
! Intermediate 2
! High
|-
| Combined score
| 0
| 0.5-1
| 1.5-2
| >/=2.5
|-
| AML evolution
| 19%
| 30%
| 33%
| 45%
|-
| Median time to AML (years)
| 9.4
| 3.3
| 1.1
| 0.2
|-
| Median survival (years)
| 5.7
| 3.5
| 1.2
| 0.4
|}

Lower risk disease includes those classified as low or intermediate 1 with a combined IPSS score of 1 or lower. For these patients observation and supportive care only has been advocated. (However, once blood transfusions are required then some form of treatment should be considered.)

Three agents have been approved by the US [[FDA]] for the treatment of MDS:
{| class="wikitable"
|-
! Name
! Comment
! References
|-
| [[5-azacytidine]]
| 21 month median survival similar to that of [[decitabine]]
| <ref name="pmid10694544">{{cite journal |author=Wijermans P, Lübbert M, Verhoef G, ''et al'' |title=Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients |journal=J. Clin. Oncol. |volume=18 |issue=5 |pages=956–62 |year=2000 |pmid=10694544 |doi=}}</ref><ref name="pmid11529854">{{cite journal |author=Lübbert M, Wijermans P, Kunzmann R, ''et al'' |title=Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine |journal=Br. J. Haematol. |volume=114 |issue=2 |pages=349–57 |year=2001 |pmid=11529854 |doi=}}</ref><ref name="pmid12011120">{{cite journal |author=Silverman LR, Demakos EP, Peterson BL, ''et al'' |title=Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B |journal=J. Clin. Oncol. |volume=20 |issue=10 |pages=2429–40 |year=2002 |pmid=12011120 |doi=}}</ref><ref name="pmid16921040">{{cite journal |author=Silverman LR, McKenzie DR, Peterson BL, ''et al'' |title=Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B |journal=J. Clin. Oncol. |volume=24 |issue=24 |pages=3895–903 |year=2006 |pmid=16921040 |doi=10.1200/JCO.2005.05.4346}}</ref>
|-
| [[Decitabine]]
| Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with [[valproic acid]].
| <ref name="pmid17133405">{{cite journal |author=Kantarjian HM, O'Brien S, Shan J, ''et al'' |title=Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome |journal=Cancer |volume=109 |issue=2 |pages=265–73 |year=2007 |pmid=17133405 |doi=10.1002/cncr.22376}}</ref><ref name="pmid16532500">{{cite journal |author=Kantarjian H, Issa JP, Rosenfeld CS, ''et al'' |title=Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study |journal=Cancer |volume=106 |issue=8 |pages=1794–803 |year=2006 |pmid=16532500 |doi=10.1002/cncr.21792}}</ref><ref name="pmid16882708">{{cite journal |author=Kantarjian H, Oki Y, Garcia-Manero G, ''et al'' |title=Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia |journal=Blood |volume=109 |issue=1 |pages=52–7 |year=2007 |pmid=16882708 |doi=10.1182/blood-2006-05-021162}}</ref><ref name="pmid17679729">{{cite journal |author=Blum W, Klisovic RB, Hackanson B, ''et al'' |title=Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3884–91 |year=2007 |pmid=17679729 |doi=10.1200/JCO.2006.09.4169}}</ref>

|-
| [[Lenalidomide]]
| Most effective in reducing red cell transfusion requirement
| <ref name="pmid17021321">{{cite journal |author=List A, Dewald G, Bennett J, ''et al'' |title=Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion |journal=N. Engl. J. Med. |volume=355 |issue=14 |pages=1456–65 |year=2006 |pmid=17021321 |doi=10.1056/NEJMoa061292}}</ref>
|}
[[Chemotherapy]] with the [[DNA methylation|hypomethylating agents]] [[5-azacytidine]] and [[decitabine]] has been shown to decrease blood transfusion requirements and to retard the progression of MDS to [[AML]]. [[Lenalidomide]] was approved by the [[FDA]] in December 2005 only for use in the [[5q- syndrome]]. It was approved in July, 2006 for use in [[multiple myeloma]]. The retail price of [[lenalidomide]] is estimated at $7,000 per month <ref name="pmid16625140">{{cite journal |author= |title=Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome |journal=The Medical letter on drugs and therapeutics |volume=48 |issue=1232 |pages=31–2 |year=2006 |pmid=16625140 |doi=}}</ref>.

[[Stem cell transplantation]], particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.<ref>{{cite journal |author=Oosterveld M, Wittebol S, Lemmens W, Kiemeney B, Catik A, Muus P, Schattenberg A, de Witte T |title=The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups |journal=Br J Haematol |volume=123 |issue=1 |pages=81-9 |year=2003 |pmid=14510946}}</ref>

==References==
{{Reflist|2}}

==Additional Readings==
* Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. ''Proposals for the classification of the myelodysplastic syndromes.'' Br J Haematol 1982;51:189. PMID 6952920.
* Block M, Jacobson LO, Bethard WF. ''Preleukemic acute human leukemia.'' [[Journal of the American Medical Association|JAMA]] 1953;152:1018-28. PMID 13052490.
* Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. ''World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.'' J Clin Oncol 1999;17:3835-49. PMID 10577857.
* Foucar, K Bone Marrow Pathology, 2nd Edition, ASCP Press. c 2001
* Greenberg, Peter L. (editor) "Myelodysplastic Syndromes: Clinical and Biological Advances" Cambridge University Press, New York 2006 ISBN 978-0521496681 ISBN 0521496683
* Steensma DP, Gibbons RJ, Higgs DR. "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies." Blood 2005;105:443-452. PMID 15358626.

==External links==
* ''[http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?rid=cmed.chapter.32804 Cancer Medicine]''. Online textbook. Chapter by Lewis R. Silverman on Myelodysplastic Syndrome.
* [http://www.aamds.org Website of the Aplastic Anemia & MDS International Foundation which provides information and support and hope to patients and their families]
*[http://www.mds-foundation.org Website of MDS-Foundation with a lot of helpful materials]
* [http://www.mayoclinic.com/print/myelodysplastic-syndromes/DS00596/DSECTION=all&METHOD=print Myelodysplastic syndromes]. Comprehensive article from MayoClinic.com.
* [http://www.virtualcancercentre.com/diseases.asp?did=68 Myelodysplastic syndrome (MDS)]. article from virtualcancercentre.com.
* [http://www.va.gov/vetapp04/files4/0434293.txt] Agent Orange and MDS, 100% service connected.

==See also==
*[[Myeloproliferative syndrome]]
*[[Acute myeloid leukemia]]
*[[Chloroma]]

{{Hematology}}
{{Hematological malignancy histology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Syndromes]]
[[Category:Oncology]]
[[ar:متلازمة خلل التنسج النقوي]]
[[de:Myelodysplastisches Syndrom]]
[[fr:Syndrome myélodysplasique]]
[[ja:骨髄異形成症候群]]
[[pt:Síndrome mielodisplásica]]
[[sv:Myelodysplastiskt syndrom]]

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Myelodysplastic syndrome

2011-03-24T23:28:39Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 8604|
ICD10 = {{ICD10|D|46||d|37}} |
ICD9 = {{ICD9|238.7}} |
ICDO = 9980/0-9989/3 |
OMIM = |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2695 |
eMedicine_mult = {{eMedicine2|ped|1527}} |
MeshID = D009190 |
}}
{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==

The '''myelodysplastic syndromes''' (MDS, formerly known as "preleukemia") are a diverse collection of [[hematology|hematological]] conditions united by ineffective production of blood cells and varying risks of transformation to [[acute myelogenous leukemia]]. [[Anemia]] requiring chronic [[blood transfusion]] is frequently present. Although not truly [[cancer|malignant]], MDS is nevertheless classified within the [[Hematological malignancy|haematological neoplasms]].

Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

== Signs and symptoms ==
Abnormalities include:
* [[neutropenia]], [[anemia]] and [[thrombocytopenia]] (low cell counts of white and red blood cells, and platelets, respectively)
* abnormal granules in cells, abnormal nuclear shape and size
* [[chromosome|chromosomal]] abnormalities, including [[chromosomal translocation]]s and abnormal chromosome number.

Symptoms of myelodysplastic conditions:
* [[Anemia]]—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
* [[Neutropenia]] (low neutrophil count) —increased susceptibility to [[infection]]
* [[Thrombocytopenia]] (low platelet count) —increased susceptibility to [[bleeding]]

Although there is some risk for developing [[acute myelogenous leukemia]], about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

==Diagnosis==
Investigation:
* [[Full blood count]] and examination of [[blood film]]
* [[Bone marrow examination]] by an experienced [[hematopathologist]]
* [[Cytogenetics]] or chromosomal studies. This is performed on the bone marrow aspirate.

==Differential Diagnosis and Workup==
The differential diagnosis is that of [[anemia]], [[thrombocytopenia]], and/or [[leukopenia]]. Usually, the elimination of known [[etiologies]] of [[cytopenias]], along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

Investigation:
* [[Full blood count]] and examination of [[blood film]]. The [[blood film]] morphology can provide clues about [[hemolytic anemia]], clumping of the [[platelets]] leading to spurious [[thrombocytopenia]], or [[leukemia]].
* Blood tests to eliminate other common causes of [[cytopenias]], such as [[lupus]], [[hepatitis]], [[B12]], [[folate]], or other [[vitamin]] deficiencies, [[renal failure]] or [[heart failure]], [[HIV]], [[hemolytic anemia]], [[monoclonal gammopathy]]. Age-appropriate cancer screening should be considered for all [[anemic]] patients.
* [[Bone marrow examination]] by an experienced [[hematopathologist]]. This is required to establish the diagnosis, since all hematopathologists recognize a dysplastic marrow as the key feature of myelodysplasia.
* [[Cytogenetics]] or chromosomal studies. This is ideally performed on the bone marrow aspirate. These require a fresh specimen, since live cells are induced to enter [[metaphase]] to enhance [[chromosomal]] staining.
* [[Flow cytometry]] is helpful to establish the presence of any [[lymphoproliferative]] disorder in the [[marrow]]

==Pathophysiology==
MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multi-potent bone marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood. [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and there is a significant increase in levels of cell death [[apoptosis]] in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow [[Myeloblasts|blasts]] rises over a particular cutoff (20% for [[Myelodysplastic syndrome#WHO classification|WHO]] and 30% for [[Myelodysplastic syndrome#French-American-British (FAB) classification|FAB]]) then transformation to [[acute myeloid leukemia|leukemia]] (specifically [[acute myelogenous leukemia]] or AML) is said to have occurred. The progression of MDS to [[acute myeloid leukemia|leukemia]] is a good example of the ''[[Knudson hypothesis|multi-step theory of carcinogenesis]]'' in which a series of mutations occur in an initially normal cell and transform it into a [[cancer|cancer cell]]. The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs. This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1).

While recognition of leukemic transformation was historically important (see [[Myelodysplastic syndrome#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to [[acute myeloid leukemia|AML]] but rather from the [[cytopenia]]s seen in all MDS patients. While [[anemia]] is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]] MDS patients rarely suffer injury from severe [[anemia]]. However, if an MDS patient is fortunate enough to suffer nothing more than [[anemia]] over several years, they then risk [[iron overload#secondary iron overload|iron overload]]. The two most serious complications in MDS patients resulting from their [[cytopenia]]s are bleeding (due to lack of [[platelet]]s) or infection (due to lack of [[white blood cell]]s).

The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two of three commercially available medications approved by the US FDA to treat MDS. Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of [[DNA methylation]] control can lead to uncontrolled cell growth, and [[cytopenias]]. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly [[DNA methylation]] profile in the [[hematopoietic stem cell]] [[nucleus]], and thereby restore normal blood counts and retard the progression of MDS to [[acute leukemia]].

Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA [[mutation]]s in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of [[mitochondrial]] [[iron]] deposits in the [[ringed sideroblast]] as evidence of [[mitochondrial]] dysfunction in MDS.<ref name="pmid12406866">{{cite journal |author=Cazzola M, Invernizzi R, Bergamaschi G, ''et al'' |title=Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia |journal=Blood |volume=101 |issue=5 |pages=1996–2000 |year=2003 |pmid=12406866 |doi=10.1182/blood-2002-07-2006}}</ref>

==Types and classification==
===French-American-British (FAB) classification===
In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This [[French-American-British classification | French-American-British (FAB) classification]] was published in 1976 and revised in 1982. Cases were classified into 5 categories: ([[ICD-O]] codes are provided where available)

* ({{ICDO|9980|3}}) '''Refractory [[anemia]]''' (RA) - characterized by less than 5% primitive blood cells ([[myeloblasts]]) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
* ({{ICDO|9982|3}}) '''Refractory anemia with ringed sideroblasts''' (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
* ({{ICDO|9983|3}}) '''Refractory anemia with excess blasts''' (RAEB) - characterized by 5-19% myeloblasts in the marrow;
* ({{ICDO|9984|3}}) '''Refractory anemia with excess blasts in transformation''' (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
* ({{ICDO|9945|3}}) '''Chronic myelomonocytic leukemia''' (CMML) - not to be confused with [[chronic myelogenous leukemia]] or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

A table comparing these is available from the [http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm Cleveland Clinic].

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. Leukemic transformation occurs in about 10-17% of patients with RA/RARS; it is approximately 40-60% for patients with RAEB. The others die of complications of low blood count or unrelated disease.

The FAB classification was used by pathologists and clinicians for almost 20 years. By the early 21st century the WHO classification had replaced it.

===WHO classification===
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

The list of dysplastic syndromes under the new WHO system includes:
# Refractory anemia (RA)
# Refractory anemia with ringed sideroblasts (RARS)
# Refractory cytopenia with multilineage dysplasia (RCMD)
# Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
# Refractory anemia with excess blasts I and II
# [[5q- syndrome]]
# Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)

RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia. The presence of 20% or more blasts denotes the diagnosis of AML. (In the new WHO classification RAEB-T no longer exists).

5q- syndrome, typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

==Diagnosis==
The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as [[melphalan]], mustard, [[cyclophosphamide]], [[busulfan]], and [[chlorambucil]]) or [[radiation]] (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS.

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
*Granulocytic series
*# Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
*# Hyposegmented neutrophils (Pseudo-Pelger Huet)
*# Hypogranular neutrophils or pseudo Chediak Higashi large granules
*# Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
* Erythroid series
*# Binucleated erythroid percursors and karyorrhexis
*# Erythroid nuclear budding
*# Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
*# PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
*# Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
* Megakaryocytic series (can be the most subjective)
*# Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
*# Hypersegmented (osteoclastic appearing) megakaryocytes
*# Ballooning of the platelets (seen with interference contrast microscopy)

Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. ALIP is thought to be a preleukemic harbinger and associated with a poor outcome in RA and RARS.

Hypoplastic MDS has a cellularity of less than 25-30% and shares features that appear to overlap with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). In these patients the administration of anti-thymocyte globulin (ATG) and cyclosporine have produced response rates of 44% and 84% respectively. The presence of a PNH clone, bone marrow hypocellularity and <5% bone marrow blasts are positive predictors of response to immunomodulation.

Malfunctions can occur in the cells of MDS patients. These can manifest as poor platelet aggregation or impaired neutrophil chemotaxis. One of the more phenotypically obvious acquired red blood cell disorders in MDS is alpha thalassemia which is usually associated with a microcytic and hypochromic erythrocyte indices and with somatic point mutation in ATRX, a chromatin remodeling factor encoded by the X-chromosome.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, [[vitamin]] deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, [[Sideroblastic anemia|Pearson's syndrome (sideroblastic anemia)]], Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood ([[red blood cell|red cell]]s, [[white blood cell|white cell]]s other than [[lymphocyte]]s and [[platelets]] or their progenitor cells, [[megakaryocyte]]s).

==Epidemiology==
The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the [[United States]] alone. The incidence is probably increasing as the age of the population increases

==Therapy==
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to [[acute myelogenous leukemia]].

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. [[bone marrow transplant]]) as well as help determine the best timing of this therapy.<ref>{{cite journal | author=Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyshiki K, Toyama K, Aul C, Hufti G, Bennett J | volume=89 | issue=6 | id=PMID 9058730}}</ref> <ref>{{cite journal | author=Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM | title=A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. | journal=Blood | year=2004 | pages=579-85 | volume=104 | issue=2 | id=PMID 15039286}}</ref> Supportive care with blood product support and hematopoeitic growth factors (e.g. [[erythropoietin]]) is the mainstay of therapy. The regulatory environment for the use of [[erythropoietin]]s is evolving, according to a recent [[Medicare (United States)|US Medicare]] National Coverage Determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.<ref>{{cite web |url=http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203 |title=Centers for Medicare & Medicaid Services |accessdate=2007-10-29 |format= |work=}}</ref>

The IPSS uses 3 criteria; cytogenetic abnormalities, proportion of bone marrow myeloblasts and number of cytopenias. Points are assigned to these variables and are added to create 4 risk groups; low, intermediate 1, intermediate 2 and high risk. If patients have >10% blasts in their bone marrow by morphology they are automatically classified as having higher risk MDS. Patients with chromosome 7 abnormalities, loss of chromosome 7 or complex cytogenetics typically have high-risk MDS. A major limitation of the IPSS is that it does not distinguish between patients with severe and modest degrees of cytopenias; this may influence outcome.

Survival and AML evolution score
{| class="wikitable"
|-
! Prognostic Variable
! 0
! 0.5
! 1
! 1.5
! 2
|-
| Bone marrow blasts (%)
| <5
| 5-10
| X
| 11-20
| 21-30
|-
| Karyotype *
| good
| intermediate
| poor
| X
| X
|-
| Cytopenias **
| 0 or 1
| 2 or 3
| X
| X
|X
|}

*Good = normal or any 1 of the following; deletion Y, deletion 5q, deletion 20q.
Intermediate = other abnormalities.
Poor = complex (>/= 3 abnormalities) or chromosome 7 abnormalities.
** Hemoglobin < 10 g/dl, ANC<1800 /uL, Platelets <100,000.

IPSS Risk Category
{| class="wikitable"
|-
! Low
! Intermediate 1
! Intermediate 2
! High
|-
| Combined score
| 0
| 0.5-1
| 1.5-2
| >/=2.5
|-
| AML evolution
| 19%
| 30%
| 33%
| 45%
|-
| Median time to AML (years)
| 9.4
| 3.3
| 1.1
| 0.2
|-
| Median survival (years)
| 5.7
| 3.5
| 1.2
| 0.4
|}

Lower risk disease includes those classified as low or intermediate 1 with a combined IPSS score of 1 or lower. For these patients observation and supportive care only has been advocated. (However, once blood transfusions are required then some form of treatment should be considered.)

Three agents have been approved by the US [[FDA]] for the treatment of MDS:
{| class="wikitable"
|-
! Name
! Comment
! References
|-
| [[5-azacytidine]]
| 21 month median survival similar to that of [[decitabine]]
| <ref name="pmid10694544">{{cite journal |author=Wijermans P, Lübbert M, Verhoef G, ''et al'' |title=Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients |journal=J. Clin. Oncol. |volume=18 |issue=5 |pages=956–62 |year=2000 |pmid=10694544 |doi=}}</ref><ref name="pmid11529854">{{cite journal |author=Lübbert M, Wijermans P, Kunzmann R, ''et al'' |title=Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine |journal=Br. J. Haematol. |volume=114 |issue=2 |pages=349–57 |year=2001 |pmid=11529854 |doi=}}</ref><ref name="pmid12011120">{{cite journal |author=Silverman LR, Demakos EP, Peterson BL, ''et al'' |title=Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B |journal=J. Clin. Oncol. |volume=20 |issue=10 |pages=2429–40 |year=2002 |pmid=12011120 |doi=}}</ref><ref name="pmid16921040">{{cite journal |author=Silverman LR, McKenzie DR, Peterson BL, ''et al'' |title=Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B |journal=J. Clin. Oncol. |volume=24 |issue=24 |pages=3895–903 |year=2006 |pmid=16921040 |doi=10.1200/JCO.2005.05.4346}}</ref>
|-
| [[Decitabine]]
| Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with [[valproic acid]].
| <ref name="pmid17133405">{{cite journal |author=Kantarjian HM, O'Brien S, Shan J, ''et al'' |title=Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome |journal=Cancer |volume=109 |issue=2 |pages=265–73 |year=2007 |pmid=17133405 |doi=10.1002/cncr.22376}}</ref><ref name="pmid16532500">{{cite journal |author=Kantarjian H, Issa JP, Rosenfeld CS, ''et al'' |title=Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study |journal=Cancer |volume=106 |issue=8 |pages=1794–803 |year=2006 |pmid=16532500 |doi=10.1002/cncr.21792}}</ref><ref name="pmid16882708">{{cite journal |author=Kantarjian H, Oki Y, Garcia-Manero G, ''et al'' |title=Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia |journal=Blood |volume=109 |issue=1 |pages=52–7 |year=2007 |pmid=16882708 |doi=10.1182/blood-2006-05-021162}}</ref><ref name="pmid17679729">{{cite journal |author=Blum W, Klisovic RB, Hackanson B, ''et al'' |title=Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3884–91 |year=2007 |pmid=17679729 |doi=10.1200/JCO.2006.09.4169}}</ref>

|-
| [[Lenalidomide]]
| Most effective in reducing red cell transfusion requirement
| <ref name="pmid17021321">{{cite journal |author=List A, Dewald G, Bennett J, ''et al'' |title=Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion |journal=N. Engl. J. Med. |volume=355 |issue=14 |pages=1456–65 |year=2006 |pmid=17021321 |doi=10.1056/NEJMoa061292}}</ref>
|}
[[Chemotherapy]] with the [[DNA methylation|hypomethylating agents]] [[5-azacytidine]] and [[decitabine]] has been shown to decrease blood transfusion requirements and to retard the progression of MDS to [[AML]]. [[Lenalidomide]] was approved by the [[FDA]] in December 2005 only for use in the [[5q- syndrome]]. It was approved in July, 2006 for use in [[multiple myeloma]]. The retail price of [[lenalidomide]] is estimated at $7,000 per month <ref name="pmid16625140">{{cite journal |author= |title=Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome |journal=The Medical letter on drugs and therapeutics |volume=48 |issue=1232 |pages=31–2 |year=2006 |pmid=16625140 |doi=}}</ref>.

[[Stem cell transplantation]], particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.<ref>{{cite journal |author=Oosterveld M, Wittebol S, Lemmens W, Kiemeney B, Catik A, Muus P, Schattenberg A, de Witte T |title=The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups |journal=Br J Haematol |volume=123 |issue=1 |pages=81-9 |year=2003 |pmid=14510946}}</ref>

==References==
{{Reflist|2}}

==Additional Readings==
* Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. ''Proposals for the classification of the myelodysplastic syndromes.'' Br J Haematol 1982;51:189. PMID 6952920.
* Block M, Jacobson LO, Bethard WF. ''Preleukemic acute human leukemia.'' [[Journal of the American Medical Association|JAMA]] 1953;152:1018-28. PMID 13052490.
* Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. ''World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.'' J Clin Oncol 1999;17:3835-49. PMID 10577857.
* Foucar, K Bone Marrow Pathology, 2nd Edition, ASCP Press. c 2001
* Greenberg, Peter L. (editor) "Myelodysplastic Syndromes: Clinical and Biological Advances" Cambridge University Press, New York 2006 ISBN 978-0521496681 ISBN 0521496683
* Steensma DP, Gibbons RJ, Higgs DR. "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies." Blood 2005;105:443-452. PMID 15358626.

==External links==
* ''[http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?rid=cmed.chapter.32804 Cancer Medicine]''. Online textbook. Chapter by Lewis R. Silverman on Myelodysplastic Syndrome.
* [http://www.aamds.org Website of the Aplastic Anemia & MDS International Foundation which provides information and support and hope to patients and their families]
*[http://www.mds-foundation.org Website of MDS-Foundation with a lot of helpful materials]
* [http://www.mayoclinic.com/print/myelodysplastic-syndromes/DS00596/DSECTION=all&METHOD=print Myelodysplastic syndromes]. Comprehensive article from MayoClinic.com.
* [http://www.virtualcancercentre.com/diseases.asp?did=68 Myelodysplastic syndrome (MDS)]. article from virtualcancercentre.com.
* [http://www.va.gov/vetapp04/files4/0434293.txt] Agent Orange and MDS, 100% service connected.

==See also==
*[[Myeloproliferative syndrome]]
*[[Acute myeloid leukemia]]
*[[Chloroma]]

{{Hematology}}
{{Hematological malignancy histology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Syndromes]]
[[Category:Oncology]]
[[ar:متلازمة خلل التنسج النقوي]]
[[de:Myelodysplastisches Syndrom]]
[[fr:Syndrome myélodysplasique]]
[[ja:骨髄異形成症候群]]
[[pt:Síndrome mielodisplásica]]
[[sv:Myelodysplastiskt syndrom]]

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Myelodysplastic syndrome

2011-03-23T02:03:49Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 8604|
ICD10 = {{ICD10|D|46||d|37}} |
ICD9 = {{ICD9|238.7}} |
ICDO = 9980/0-9989/3 |
OMIM = |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2695 |
eMedicine_mult = {{eMedicine2|ped|1527}} |
MeshID = D009190 |
}}
{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==

The '''myelodysplastic syndromes''' (MDS, formerly known as "preleukemia") are a diverse collection of [[hematology|hematological]] conditions united by ineffective production of blood cells and varying risks of transformation to [[acute myelogenous leukemia]]. [[Anemia]] requiring chronic [[blood transfusion]] is frequently present. Although not truly [[cancer|malignant]], MDS is nevertheless classified within the [[Hematological malignancy|haematological neoplasms]].

Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

== Signs and symptoms ==
Abnormalities include:
* [[neutropenia]], [[anemia]] and [[thrombocytopenia]] (low cell counts of white and red blood cells, and platelets, respectively)
* abnormal granules in cells, abnormal nuclear shape and size
* [[chromosome|chromosomal]] abnormalities, including [[chromosomal translocation]]s and abnormal chromosome number.

Symptoms of myelodysplastic conditions:
* [[Anemia]]—chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
* [[Neutropenia]] (low neutrophil count) —increased susceptibility to [[infection]]
* [[Thrombocytopenia]] (low platelet count) —increased susceptibility to [[bleeding]]

Although there is some risk for developing [[acute myelogenous leukemia]], about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.

==Diagnosis==
Investigation:
* [[Full blood count]] and examination of [[blood film]]
* [[Bone marrow examination]] by an experienced [[hematopathologist]]
* [[Cytogenetics]] or chromosomal studies. This is performed on the bone marrow aspirate.

==Differential Diagnosis and Workup==
The differential diagnosis is that of [[anemia]], [[thrombocytopenia]], and/or [[leukopenia]]. Usually, the elimination of known [[etiologies]] of [[cytopenias]], along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.

Investigation:
* [[Full blood count]] and examination of [[blood film]]. The [[blood film]] morphology can provide clues about [[hemolytic anemia]], clumping of the [[platelets]] leading to spurious [[thrombocytopenia]], or [[leukemia]].
* Blood tests to eliminate other common causes of [[cytopenias]], such as [[lupus]], [[hepatitis]], [[B12]], [[folate]], or other [[vitamin]] deficiencies, [[renal failure]] or [[heart failure]], [[HIV]], [[hemolytic anemia]], [[monoclonal gammopathy]]. Age-appropriate cancer screening should be considered for all [[anemic]] patients.
* [[Bone marrow examination]] by an experienced [[hematopathologist]]. This is required to establish the diagnosis, since all hematopathologists recognize a dysplastic marrow as the key feature of myelodysplasia.
* [[Cytogenetics]] or chromosomal studies. This is ideally performed on the bone marrow aspirate. These require a fresh specimen, since live cells are induced to enter [[metaphase]] to enhance [[chromosomal]] staining.
* [[Flow cytometry]] is helpful to establish the presence of any [[lymphoproliferative]] disorder in the [[marrow]]

==Pathophysiology==
MDS is thought to arise from [[mutation]]s in the [[hematopoietic stem cell|multi-potent bone marrow stem cell]], but the specific defects responsible for these diseases remain poorly understood. [[Cellular differentiation|Differentiation]] of blood precursor cells is impaired, and there is a significant increase in levels of cell death [[apoptosis]] in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow [[Myeloblasts|blasts]] rises over a particular cutoff (20% for [[Myelodysplastic syndrome#WHO classification|WHO]] and 30% for [[Myelodysplastic syndrome#French-American-British (FAB) classification|FAB]]) then transformation to [[acute myeloid leukemia|leukemia]] (specifically [[acute myelogenous leukemia]] or AML) is said to have occurred. The progression of MDS to [[acute myeloid leukemia|leukemia]] is a good example of the ''[[Knudson hypothesis|multi-step theory of carcinogenesis]]'' in which a series of mutations occur in an initially normal cell and transform it into a [[cancer|cancer cell]]. The mechanism involved was initially thought to be an increase in apoptosis but, as the disease progresses, more cytogenetic damage occurs. This eventually heralds a decrease in apoptosis leading to leukemia (showing abnormal clones with point mutations in Nras and AML1).

While recognition of leukemic transformation was historically important (see [[Myelodysplastic syndrome#History|History]]), a significant proportion of the [[morbidity]] and [[death|mortality]] attributable to MDS results not from transformation to [[acute myeloid leukemia|AML]] but rather from the [[cytopenia]]s seen in all MDS patients. While [[anemia]] is the most common [[cytopenia]] in MDS patients, given the ready availability of [[blood transfusion]] MDS patients rarely suffer injury from severe [[anemia]]. However, if an MDS patient is fortunate enough to suffer nothing more than [[anemia]] over several years, they then risk [[iron overload#secondary iron overload|iron overload]]. The two most serious complications in MDS patients resulting from their [[cytopenia]]s are bleeding (due to lack of [[platelet]]s) or infection (due to lack of [[white blood cell]]s).

The recognition of [[epigenetic]] changes in [[DNA]] structure in MDS has explained the success of two of three commercially available medications approved by the US FDA to treat MDS. Proper [[DNA methylation]] is critical in the regulation of proliferation genes, and the loss of [[DNA methylation]] control can lead to uncontrolled cell growth, and [[cytopenias]]. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly [[DNA methylation]] profile in the [[hematopoietic stem cell]] [[nucleus]], and thereby restore normal blood counts and retard the progression of MDS to [[acute leukemia]].

Some authors have proposed that the loss of [[mitochondrial]] function over time leads to the accumulation of DNA [[mutation]]s in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of [[mitochondrial]] [[iron]] deposits in the [[ringed sideroblast]] as evidence of [[mitochondrial]] dysfunction in MDS.<ref name="pmid12406866">{{cite journal |author=Cazzola M, Invernizzi R, Bergamaschi G, ''et al'' |title=Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia |journal=Blood |volume=101 |issue=5 |pages=1996–2000 |year=2003 |pmid=12406866 |doi=10.1182/blood-2002-07-2006}}</ref>

==Types and classification==
===French-American-British (FAB) classification===
In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This [[French-American-British classification | French-American-British (FAB) classification]] was published in 1976 and revised in 1982. Cases were classified into 5 categories: ([[ICD-O]] codes are provided where available)

* ({{ICDO|9980|3}}) '''Refractory [[anemia]]''' (RA) - characterized by less than 5% primitive blood cells ([[myeloblasts]]) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
* ({{ICDO|9982|3}}) '''Refractory anemia with ringed sideroblasts''' (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
* ({{ICDO|9983|3}}) '''Refractory anemia with excess blasts''' (RAEB) - characterized by 5-19% myeloblasts in the marrow;
* ({{ICDO|9984|3}}) '''Refractory anemia with excess blasts in transformation''' (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
* ({{ICDO|9945|3}}) '''Chronic myelomonocytic leukemia''' (CMML) - not to be confused with [[chronic myelogenous leukemia]] or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

A table comparing these is available from the [http://www.clevelandclinicmeded.com/diseasemanagement/hematology/myelo/table1.htm Cleveland Clinic].

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of 3-5 years, although long term remission is possible if a bone marrow transplant is successful); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. Leukemic transformation occurs in about 10-17% of patients with RA/RARS; it is approximately 40-60% for patients with RAEB. The others die of complications of low blood count or unrelated disease.

The FAB classification was used by pathologists and clinicians for almost 20 years. By the early 21st century the WHO classification had replaced it.

===WHO classification===
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precursor and platelet precursor (megakaryocyte) dysplasia. See below for morphologic definitions of dysplasia.

The list of dysplastic syndromes under the new WHO system includes:
# Refractory anemia (RA)
# Refractory anemia with ringed sideroblasts (RARS)
# Refractory cytopenia with multilineage dysplasia (RCMD)
# Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS)
# Refractory anemia with excess blasts I and II
# [[5q- syndrome]]
# Myelodysplasia unclassifiable (seen in those cases of megakaryocyte dysplasia with fibrosis and others)

RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I. Auer rods may be seen in RAEB-II which may be difficult to distinguish from acute myeloid leukemia. The presence of 20% or more blasts denotes the diagnosis of AML. (In the new WHO classification RAEB-T no longer exists).

5q- syndrome, typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

==Diagnosis==
The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as [[melphalan]], mustard, [[cyclophosphamide]], [[busulfan]], and [[chlorambucil]]) or [[radiation]] (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS.

Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
*Granulocytic series
*# Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
*# Hyposegmented neutrophils (Pseudo-Pelger Huet)
*# Hypogranular neutrophils or pseudo Chediak Higashi large granules
*# Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
* Erythroid series
*# Binucleated erythroid percursors and karyorrhexis
*# Erythroid nuclear budding
*# Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
*# PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
*# Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
* Megakaryocytic series (can be the most subjective)
*# Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
*# Hypersegmented (osteoclastic appearing) megakaryocytes
*# Ballooning of the platelets (seen with interference contrast microscopy)

Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.

On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature cells clustering together. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands. ALIP is thought to be a preleukemic harbinger and associated with a poor outcome in RA and RARS.

Hypoplastic MDS has a cellularity of less than 25-30% and shares features that appear to overlap with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH). In these patients the administration of anti-thymocyte globulin (ATG) and cyclosporine have produced response rates of 44% and 84% respectively. The presence of a PNH clone, bone marrow hypocellularity and <5% bone marrow blasts are positive predictors of response to immunomodulation.

Malfunctions can occur in the cells of MDS patients. These can manifest as poor platelet aggregation or impaired neutrophil chemotaxis. One of the more phenotypically obvious acquired red blood cell disorders in MDS is alpha thalassemia which is usually associated with a microcytic and hypochromic erythrocyte indices and with somatic point mutation in ATRX, a chromatin remodeling factor encoded by the X-chromosome.

Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, [[vitamin]] deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserthropoietic anemia (CDA I through IV) has been recognized, [[Sideroblastic anemia|Pearson's syndrome (sideroblastic anemia)]], Jacobson's syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood ([[red blood cell|red cell]]s, [[white blood cell|white cell]]s other than [[lymphocyte]]s and [[platelets]] or their progenitor cells, [[megakaryocyte]]s).

==Epidemiology==
The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the [[United States]] alone. The incidence is probably increasing as the age of the population increases

==Therapy==
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to [[acute myelogenous leukemia]].

The IPSS scoring system can help triage patients for more aggressive treatment (i.e. [[bone marrow transplant]]) as well as help determine the best timing of this therapy.<ref>{{cite journal | author=Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyshiki K, Toyama K, Aul C, Hufti G, Bennett J | volume=89 | issue=6 | id=PMID 9058730}}</ref> <ref>{{cite journal | author=Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, Bolwell BJ, Cairo MS, Gale RP, Klein JP, Lazarus HM, Liesveld JL, McCarthy PL, Milone GA, Rizzo JD, Schultz KR, Trigg ME, Keating A, Weisdorf DJ, Antin JH, Horowitz MM | title=A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. | journal=Blood | year=2004 | pages=579-85 | volume=104 | issue=2 | id=PMID 15039286}}</ref> Supportive care with blood product support and hematopoeitic growth factors (e.g. [[erythropoietin]]) is the mainstay of therapy. The regulatory environment for the use of [[erythropoietin]]s is evolving, according to a recent [[Medicare (United States)|US Medicare]] National Coverage Determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.<ref>{{cite web |url=http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203 |title=Centers for Medicare & Medicaid Services |accessdate=2007-10-29 |format= |work=}}</ref>

Three agents have been approved by the US [[FDA]] for the treatment of MDS:
{| class="wikitable"
|-
! Name
! Comment
! References
|-
| [[5-azacytidine]]
| 21 month median survival similar to that of [[decitabine]]
| <ref name="pmid10694544">{{cite journal |author=Wijermans P, Lübbert M, Verhoef G, ''et al'' |title=Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients |journal=J. Clin. Oncol. |volume=18 |issue=5 |pages=956–62 |year=2000 |pmid=10694544 |doi=}}</ref><ref name="pmid11529854">{{cite journal |author=Lübbert M, Wijermans P, Kunzmann R, ''et al'' |title=Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine |journal=Br. J. Haematol. |volume=114 |issue=2 |pages=349–57 |year=2001 |pmid=11529854 |doi=}}</ref><ref name="pmid12011120">{{cite journal |author=Silverman LR, Demakos EP, Peterson BL, ''et al'' |title=Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B |journal=J. Clin. Oncol. |volume=20 |issue=10 |pages=2429–40 |year=2002 |pmid=12011120 |doi=}}</ref><ref name="pmid16921040">{{cite journal |author=Silverman LR, McKenzie DR, Peterson BL, ''et al'' |title=Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B |journal=J. Clin. Oncol. |volume=24 |issue=24 |pages=3895–903 |year=2006 |pmid=16921040 |doi=10.1200/JCO.2005.05.4346}}</ref>
|-
| [[Decitabine]]
| Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with [[valproic acid]].
| <ref name="pmid17133405">{{cite journal |author=Kantarjian HM, O'Brien S, Shan J, ''et al'' |title=Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome |journal=Cancer |volume=109 |issue=2 |pages=265–73 |year=2007 |pmid=17133405 |doi=10.1002/cncr.22376}}</ref><ref name="pmid16532500">{{cite journal |author=Kantarjian H, Issa JP, Rosenfeld CS, ''et al'' |title=Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study |journal=Cancer |volume=106 |issue=8 |pages=1794–803 |year=2006 |pmid=16532500 |doi=10.1002/cncr.21792}}</ref><ref name="pmid16882708">{{cite journal |author=Kantarjian H, Oki Y, Garcia-Manero G, ''et al'' |title=Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia |journal=Blood |volume=109 |issue=1 |pages=52–7 |year=2007 |pmid=16882708 |doi=10.1182/blood-2006-05-021162}}</ref><ref name="pmid17679729">{{cite journal |author=Blum W, Klisovic RB, Hackanson B, ''et al'' |title=Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia |journal=J. Clin. Oncol. |volume=25 |issue=25 |pages=3884–91 |year=2007 |pmid=17679729 |doi=10.1200/JCO.2006.09.4169}}</ref>

|-
| [[Lenalidomide]]
| Most effective in reducing red cell transfusion requirement
| <ref name="pmid17021321">{{cite journal |author=List A, Dewald G, Bennett J, ''et al'' |title=Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion |journal=N. Engl. J. Med. |volume=355 |issue=14 |pages=1456–65 |year=2006 |pmid=17021321 |doi=10.1056/NEJMoa061292}}</ref>
|}
[[Chemotherapy]] with the [[DNA methylation|hypomethylating agents]] [[5-azacytidine]] and [[decitabine]] has been shown to decrease blood transfusion requirements and to retard the progression of MDS to [[AML]]. [[Lenalidomide]] was approved by the [[FDA]] in December 2005 only for use in the [[5q- syndrome]]. It was approved in July, 2006 for use in [[multiple myeloma]]. The retail price of [[lenalidomide]] is estimated at $7,000 per month <ref name="pmid16625140">{{cite journal |author= |title=Lenalidomide (Revlimid) for anemia of myelodysplastic syndrome |journal=The Medical letter on drugs and therapeutics |volume=48 |issue=1232 |pages=31–2 |year=2006 |pmid=16625140 |doi=}}</ref>.

[[Stem cell transplantation]], particularly in younger patients (ie less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.<ref>{{cite journal |author=Oosterveld M, Wittebol S, Lemmens W, Kiemeney B, Catik A, Muus P, Schattenberg A, de Witte T |title=The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups |journal=Br J Haematol |volume=123 |issue=1 |pages=81-9 |year=2003 |pmid=14510946}}</ref>

==References==
{{Reflist|2}}

==Additional Readings==
* Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. ''Proposals for the classification of the myelodysplastic syndromes.'' Br J Haematol 1982;51:189. PMID 6952920.
* Block M, Jacobson LO, Bethard WF. ''Preleukemic acute human leukemia.'' [[Journal of the American Medical Association|JAMA]] 1953;152:1018-28. PMID 13052490.
* Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. ''World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.'' J Clin Oncol 1999;17:3835-49. PMID 10577857.
* Foucar, K Bone Marrow Pathology, 2nd Edition, ASCP Press. c 2001
* Greenberg, Peter L. (editor) "Myelodysplastic Syndromes: Clinical and Biological Advances" Cambridge University Press, New York 2006 ISBN 978-0521496681 ISBN 0521496683
* Steensma DP, Gibbons RJ, Higgs DR. "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies." Blood 2005;105:443-452. PMID 15358626.

==External links==
* ''[http://www.ncbi.nlm.nih.gov:80/books/bv.fcgi?rid=cmed.chapter.32804 Cancer Medicine]''. Online textbook. Chapter by Lewis R. Silverman on Myelodysplastic Syndrome.
* [http://www.aamds.org Website of the Aplastic Anemia & MDS International Foundation which provides information and support and hope to patients and their families]
*[http://www.mds-foundation.org Website of MDS-Foundation with a lot of helpful materials]
* [http://www.mayoclinic.com/print/myelodysplastic-syndromes/DS00596/DSECTION=all&METHOD=print Myelodysplastic syndromes]. Comprehensive article from MayoClinic.com.
* [http://www.virtualcancercentre.com/diseases.asp?did=68 Myelodysplastic syndrome (MDS)]. article from virtualcancercentre.com.
* [http://www.va.gov/vetapp04/files4/0434293.txt] Agent Orange and MDS, 100% service connected.

==See also==
*[[Myeloproliferative syndrome]]
*[[Acute myeloid leukemia]]
*[[Chloroma]]

{{Hematology}}
{{Hematological malignancy histology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Syndromes]]
[[Category:Oncology]]
[[ar:متلازمة خلل التنسج النقوي]]
[[de:Myelodysplastisches Syndrom]]
[[fr:Syndrome myélodysplasique]]
[[ja:骨髄異形成症候群]]
[[pt:Síndrome mielodisplásica]]
[[sv:Myelodysplastiskt syndrom]]

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Mastocytosis

2011-02-19T02:31:23Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = Mastocytosis.jpg |
Caption = Skin: Cutaneous Mastocytosis; childhood form (A), there is a tumoral dermal infiltrate devoid of epidermotropism and composed of bland cells with conspicuous cell boundaries and uniform, round, centrally located nuclei (B). Confirmatory cytoplasmic granules are only apparent with metachromatic stains, such as this Giemsa stain (C), or by upon ultrastructural examination (D). C, X1000. D, X65,000. [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] |
DiseasesDB = 7864 |
ICD10 = {{ICD10|Q|82|2|q|80}}, {{ICD10|C|96|2|c|81}} |
ICD9 = {{ICD9|757.33}}, {{ICD9|202.6}} |
ICDO = 9741/3 |
OMIM = 154800 |
MedlinePlus = |
eMedicineSubj = derm |
eMedicineTopic = 258 |
eMedicine_mult = {{eMedicine2|med|1401}} |
MeshID = D008415 |
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

==Overview==
'''Mastocytosis''' is a group of [[rare disease|rare]] disorders of both children and adults caused by the presence of too many [[mast cell]]s (''mastocytes'') and [[CD34]]+ mast cell precursors in a person's body.<ref name="pmid17587883">{{cite journal |author=Horny HP, Sotlar K, Valent P |title=Mastocytosis: state of the art |journal=Pathobiology |volume=74 |issue=2 |pages=121–32 |year=2007 |pmid=17587883 |doi=10.1159/000101711}}</ref> <ref>[http://www.diseasesdatabase.com/index.asp The Disease Database]</ref> <ref>Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3</ref> <ref>Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7</ref>

== Epidemiology ==
No one is sure how many people have either type of mastocytosis, but mastocytosis generally has been considered to be an "[[orphan disease]]" (orphan diseases affect 200,000 or fewer people in the United States). Mastocytosis, however, often may be misdiagnosed, and occur more frequently than assumed.

== Pathophysiology ==
[[Mast cell]]s are located in [[connective tissue]], including the [[skin]], the linings of the stomach and intestine, and other sites. They play an important role in helping defend these tissues from disease. By releasing chemical "alarms" such as [[histamine]], mast cells attract other key players of the [[immune system|immune defense system]] to areas of the body where they are needed.

Mast cells seem to have other roles as well. Because they gather together around [[wound]]s, mast cells may play a part in wound healing. For example, the typical itching felt around a healing scab may be caused by [[histamine]] released by mast cells. Researchers also think mast cells may have a role in the growth of [[blood vessel]]s ([[angiogenesis]]). No one with ''too few'' or no mast cells has been found, which indicates to some scientists that we may not be able to survive with too few mast cells.

Mast cells express a [[cell surface receptor]] termed ''c-kit''<ref name="pmid17555444">{{cite journal |author=Orfao A, Garcia-Montero AC, Sanchez L, Escribano L |title=Recent advances in the understanding of mastocytosis: the role of KIT mutations |journal=Br. J. Haematol. |volume=138 |issue=1 |pages=12–30 |year=2007 |pmid=17555444 |doi=10.1111/j.1365-2141.2007.06619.x}}</ref> ([[Cluster of Differentiation|CD117]]), which is the [[receptor (proteomics)|receptor]] for ''scf'' (stem cell factor). In laboratory studies, ''scf'' appears to be important for the proliferation of mast cells, and inhibiting the [[tyrosine kinase]] receptor with [[imatinib]] (see below) may reduce the symptoms of mastocytosis.
C-kit mutations (D816V & D816H) are the most common mutations found (80-95%) in mastocytosis. The D816V mutation is located in the catalytic domain of the tyrosine kinase receptor c-Kit occuring in systemic mastocytosis. C-Kit is the receptor for stem cell factor, a key cytokine involved in the generation and differentiation of mast cells from its progenitors; it is encoded by kit, located at 4q12. The presence of the Kit-D816V mutation denotes resistance to imatinib.

== History ==
Scientists first described urticaria pigmentosa in 1869.<ref>Nettleship E, Tay W. Rare forms of urticaria. Br Med J. 1869;2:323.</ref> Systemic mastocytosis was first reported by scientists in 1936.<ref>Sézary, A, Levy-Coblentz, G, Chauvillon, P: Dermographisme et mastocytose. Bull Soc Fr Dermatol Syphilol 1936;43:359–61. </ref>

== Classification ==
The presence of too many mast cells, or ''mastocytosis'', can occur in a variety of forms.

* Most cases are ''cutaneous'' (confined to the skin only). There are several forms of cutaneous mastocytosis. The most common is called [[urticaria pigmentosa]] (UP). It mostly affects children. Telangiectasia Macularis Eruptiva Perstans (TMEP) is a much rarer form of cutaneous mastocytosis that affects adults.<ref>Ellis DL. ''Treatment of telangiectasia macularis eruptiva perstans with the 585-nm flashlamp-pumped dye laser.'' Dermatol Surg 1996;22:33-7. PMID 8556255.</ref>

* ''Systemic'' mastocytosis involves the internal organs, usually in addition to involving the skin. Mast cells collect in various tissues and can affect organs such as the [[liver]], [[spleen]], [[lymph node]]s, and [[bone marrow]].

== Symptoms ==
In some rare cases chemicals released by [[mast cell]]s cause changes in the [[immune system]] leading to typical [[allergy]] symptoms such as:
* [[Itch]]ing; pruritis, may also have flushing.
* Abdominal [[cramping]]; diarrhea, multiple peptic ulcerations.
* [[Anaphylaxis]] ([[Shock (medical)|shock]] from allergic or immune causes); manifest with wheezing and dyspnea.

When too many mast cells exist in a person's body, the additional chemicals can cause:
*[[Dermatology|Skin lesions]]
*[[Abdominal pain|Abdominal discomfort]]
*Episodes of [[hypotension|very low blood pressure]] (including [[Shock (medical)|shock]]) and [[syncope|faintness]]
*[[Bone pain|Bone]] or [[muscle pain|muscle]] [[Pain and nociception|pain]]; may also have evidence of myelofibrosis and osteosclerosis.
*[[Nausea]] and [[vomiting]]
*Paroxysmal hypertension.

== Diagnosis ==
Can be diagnose ''[[urticaria pigmentosa]]'' (cutaneous mastocytosis, see below) by seeing the characteristic lesions that are dark-brown and fixed. A small skin sample ([[biopsy]]) may help confirm the diagnosis.

By taking a biopsy from a different organ, such as the [[bone marrow]], the doctor can diagnose ''systemic mastocytosis''. Using special techniques on a bone marrow sample, the doctor looks for an increase in mast cells. The bone marrow may show disordered bone formation and bizzare mast cells.

Serum levels of tryptase are high and are a useful marker, however, the serum tryptase of cutaneous mastocytosis is normal. Urinary tryptase is also increased.

WHO Diagnostic Criteria; to make the diagnosis have 1 Major and 1 Minor criteria or at least 3 minor ones.
Major Criteria; Mutlifocal dense infiltrates of mast cells in the bone marrow or other extracutaneous organ(s) (>15 mast cells in aggregate).
Minor Criteria;
1) Mast cells in the bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25% of cells).
2) C-kit mutation at codon 816 is found.
3) Mast cells in the bone marrow express CD2 and/or CD25.
4) Serum total tryptase >20 ng/ml.

== Treatment ==
There is currently no cure for mastocytosis. The treatment is palliative and there are a number of medicines to help treat the symptoms of mastocytosis:
*[[Antihistamine]]s block receptors targeted by histamine released from mast cells. Both H1 and H2 blockers may be helpful.
*[[Leukotriene antagonists]] block receptors targeted by leukotrienes released from mast cells.
*[[Mast cell stabilizer]]s help prevent mast cells from releasing their chemical contents. Cromolyn Sodium Oral Solution (Gastrocrom® / [[Cromoglicate]]) is the only medicine specifically approved by the U.S. FDA for the treatment of mastocytosis. [[Ketotifen]] is available in Canada and Europe, but is only available in the U.S. as ophthamic drops (Zaditor®).
*[[Proton pump inhibitor]]s help reduce production of gastric acid, which is often increased in patients with mastocytosis. Excess gastric acid can harm the stomach, esophagus, and small intestine.
*[[Epinephrine]] constricts blood vessels and opens airways to maintain adequate circulation and ventilation when excessive mast cell degranulation has caused [[anaphylaxis]].
*[[Albuterol]] and other beta-2 agonists open airways that can constrict in the presence of histamine.
*[[Corticosteroids]] can be used topically, inhaled, or systemically to reduce inflammation associated with mastocytosis.

*[[Antidepressant]]s are an important and often overlooked tool in the treatment of mastocytosis. The stress and physical discomfort of any chronic disease may increase the likelihood of a patient developing [[clinical depression|depression]]. Depression and other neurological symptoms have been noted in mastocytosis.<ref>Rogers MP, Bloomingdale K, Murawski BJ, Soter NA, Reich P, Austen KF. ''Mixed organic brain syndrome as a manifestation of systemic mastocytosis.'' Psychosom Med 1986;48:437-47. PMID 3749421</ref> Some antidepressants such as [[doxepin]] are themselves potent antihistamines and can help relieve physical as well as cognitive symptoms.

*[[Dihydropyridines]] are [[calcium channel blocker]]s that are sometimes used to treat [[hypertension|high blood pressure]]. At least one clinical study suggested that [[Nifedipine]], one of the dihydropyridines, may reduce mast cell degranulation in patients that exhibit [[urticaria pigmentosa]]. A 1984 study by Fairly et al. included a patient with symptomatic urticaria pigmentosa who responded to nifedipine at dose of 10 mg po tid.<ref>Fairley JA, et al: Urticaria pigmentosa responsive to nifedipine. J Am Acad Dermatol 11:740-743, 1984.</ref> However, Nifetipine has never been approved by the FDA for treatment of mastocytosis.

* In the surgical setting it is recommended to avoid beta-blockers as they interfere with endogenous epinephrine and may precipitate anaphylaxis. It is also recommended to avoid alpha-blockers as well as anti-cholinergics.

In rare cases in which mastocytosis is cancerous or associated with a blood disorder, the patient may have to use [[steroid]]s and/or [[chemotherapy]]. The novel agent [[imatinib]] (Glivec® or Gleevec®) has been found to be effective in certain types of mastocytosis.<ref>Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51. PMID 16779792</ref>
Recent literature shows that C-Kit (D816V) lends some resistance to imatinib and sorafenib but these cells are still sensitive to Nilotinib, Dasatinib and Rapamycin. Cladribine and Interferon have also been found to be effective.

There are clinical trials currently underway testing stem cell transplants as a form of treatment.

There are support groups for persons suffering from mastocytosis. Involvement can be emotionally therapeutic for some patients.

== Research ==
[[National Institute of Allergy and Infectious Diseases]] (NIAID) scientists have been studying and treating patients with mastocytosis for several years at the [[National Institutes of Health]] (NIH) Clinical Center.

Some of the most important research advances for this rare disorder include improved diagnosis of mast cell disease and identification of growth factors and genetic mechanisms responsible for increased mast cell production. Researchers are currently evaluating approaches to improve ways to treat mastocytosis.

Scientists also are focusing on identifying disease-associated mutations (changes in genes). NIH scientists have identified some mutations, which may help researchers understand the causes of mastocytosis, improve diagnosis, and develop better treatments.

== References==
{{Reflist|2}}

==Additional Resources==

* ''Based on an informative page by the [[National Institute of Allergy and Infectious Diseases]] (NIAID).''
* Shah NP, Lee FJ, Luo R, Jiang Y, Donker M, Akin C. Dasatinib (BMS-354825) inhibits KIT(D816V), an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood. 2006; 108(1):286-291. PMID 16434489.
* Pardanani A, Teffer A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Current Opinion in Hematology. 2010; 17(2): 125-132. PMID 20075725.

== External links ==
* [http://www.tmsforacure.org Mastocytosis Society, Inc.]
* [http://purl.org/net/masto Mastocytosis email lists]
* [http://www.mastokids.org Mastokids.org]
* [http://www.ukmasto.co.uk UK Mastocytosis support]

== Acknowledgements ==
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.

'''List of contributors:'''

== Suggested Reading and Key General References ==

== Suggested Links and Web Resources ==

== For Patients ==

{{Hematological malignancy histology}}
{{SIB}}
[[Category:DiseaseState]]
[[Category:Immunology]]
[[Category:Hematology]]
[[Category:Oncology]]

[[de:Mastozytose]]
[[es:Mastocitosis]]
[[fr:Mastocytose]]
[[nl:Mastocytose]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

Mastocytosis

2011-02-19T02:16:46Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = Mastocytosis.jpg |
Caption = Skin: Cutaneous Mastocytosis; childhood form (A), there is a tumoral dermal infiltrate devoid of epidermotropism and composed of bland cells with conspicuous cell boundaries and uniform, round, centrally located nuclei (B). Confirmatory cytoplasmic granules are only apparent with metachromatic stains, such as this Giemsa stain (C), or by upon ultrastructural examination (D). C, X1000. D, X65,000. [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] |
DiseasesDB = 7864 |
ICD10 = {{ICD10|Q|82|2|q|80}}, {{ICD10|C|96|2|c|81}} |
ICD9 = {{ICD9|757.33}}, {{ICD9|202.6}} |
ICDO = 9741/3 |
OMIM = 154800 |
MedlinePlus = |
eMedicineSubj = derm |
eMedicineTopic = 258 |
eMedicine_mult = {{eMedicine2|med|1401}} |
MeshID = D008415 |
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

==Overview==
'''Mastocytosis''' is a group of [[rare disease|rare]] disorders of both children and adults caused by the presence of too many [[mast cell]]s (''mastocytes'') and [[CD34]]+ mast cell precursors in a person's body.<ref name="pmid17587883">{{cite journal |author=Horny HP, Sotlar K, Valent P |title=Mastocytosis: state of the art |journal=Pathobiology |volume=74 |issue=2 |pages=121–32 |year=2007 |pmid=17587883 |doi=10.1159/000101711}}</ref> <ref>[http://www.diseasesdatabase.com/index.asp The Disease Database]</ref> <ref>Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3</ref> <ref>Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7</ref>

== Epidemiology ==
No one is sure how many people have either type of mastocytosis, but mastocytosis generally has been considered to be an "[[orphan disease]]" (orphan diseases affect 200,000 or fewer people in the United States). Mastocytosis, however, often may be misdiagnosed, and occur more frequently than assumed.

== Pathophysiology ==
[[Mast cell]]s are located in [[connective tissue]], including the [[skin]], the linings of the stomach and intestine, and other sites. They play an important role in helping defend these tissues from disease. By releasing chemical "alarms" such as [[histamine]], mast cells attract other key players of the [[immune system|immune defense system]] to areas of the body where they are needed.

Mast cells seem to have other roles as well. Because they gather together around [[wound]]s, mast cells may play a part in wound healing. For example, the typical itching felt around a healing scab may be caused by [[histamine]] released by mast cells. Researchers also think mast cells may have a role in the growth of [[blood vessel]]s ([[angiogenesis]]). No one with ''too few'' or no mast cells has been found, which indicates to some scientists that we may not be able to survive with too few mast cells.

Mast cells express a [[cell surface receptor]] termed ''c-kit''<ref name="pmid17555444">{{cite journal |author=Orfao A, Garcia-Montero AC, Sanchez L, Escribano L |title=Recent advances in the understanding of mastocytosis: the role of KIT mutations |journal=Br. J. Haematol. |volume=138 |issue=1 |pages=12–30 |year=2007 |pmid=17555444 |doi=10.1111/j.1365-2141.2007.06619.x}}</ref> ([[Cluster of Differentiation|CD117]]), which is the [[receptor (proteomics)|receptor]] for ''scf'' (stem cell factor). In laboratory studies, ''scf'' appears to be important for the proliferation of mast cells, and inhibiting the [[tyrosine kinase]] receptor with [[imatinib]] (see below) may reduce the symptoms of mastocytosis.
C-kit mutations (D816V & D816H) are the most common mutations found (80-95%) in mastocytosis. The D816V mutation is located in the catalytic domain of the tyrosine kinase receptor c-Kit occuring in systemic mastocytosis. C-Kit is the receptor for stem cell factor, a key cytokine involved in the generation and differentiation of mast cells from its progenitors; it is encoded by kit, located at 4q12. The presence of the Kit-D816V mutation denotes resistance to imatinib.

== History ==
Scientists first described urticaria pigmentosa in 1869.<ref>Nettleship E, Tay W. Rare forms of urticaria. Br Med J. 1869;2:323.</ref> Systemic mastocytosis was first reported by scientists in 1936.<ref>Sézary, A, Levy-Coblentz, G, Chauvillon, P: Dermographisme et mastocytose. Bull Soc Fr Dermatol Syphilol 1936;43:359–61. </ref>

== Classification ==
The presence of too many mast cells, or ''mastocytosis'', can occur in a variety of forms.

* Most cases are ''cutaneous'' (confined to the skin only). There are several forms of cutaneous mastocytosis. The most common is called [[urticaria pigmentosa]] (UP). It mostly affects children. Telangiectasia Macularis Eruptiva Perstans (TMEP) is a much rarer form of cutaneous mastocytosis that affects adults.<ref>Ellis DL. ''Treatment of telangiectasia macularis eruptiva perstans with the 585-nm flashlamp-pumped dye laser.'' Dermatol Surg 1996;22:33-7. PMID 8556255.</ref>

* ''Systemic'' mastocytosis involves the internal organs, usually in addition to involving the skin. Mast cells collect in various tissues and can affect organs such as the [[liver]], [[spleen]], [[lymph node]]s, and [[bone marrow]].

== Symptoms ==
In some rare cases chemicals released by [[mast cell]]s cause changes in the [[immune system]] leading to typical [[allergy]] symptoms such as:
* [[Itch]]ing; pruritis, may also have flushing.
* Abdominal [[cramping]]; diarrhea, multiple peptic ulcerations.
* [[Anaphylaxis]] ([[Shock (medical)|shock]] from allergic or immune causes); manifest with wheezing and dyspnea.

When too many mast cells exist in a person's body, the additional chemicals can cause:
*[[Dermatology|Skin lesions]]
*[[Abdominal pain|Abdominal discomfort]]
*Episodes of [[hypotension|very low blood pressure]] (including [[Shock (medical)|shock]]) and [[syncope|faintness]]
*[[Bone pain|Bone]] or [[muscle pain|muscle]] [[Pain and nociception|pain]]; may also have evidence of myelofibrosis and osteosclerosis.
*[[Nausea]] and [[vomiting]]
*Paroxysmal hypertension.

== Diagnosis ==
Can be diagnose ''[[urticaria pigmentosa]]'' (cutaneous mastocytosis, see below) by seeing the characteristic lesions that are dark-brown and fixed. A small skin sample ([[biopsy]]) may help confirm the diagnosis.

By taking a biopsy from a different organ, such as the [[bone marrow]], the doctor can diagnose ''systemic mastocytosis''. Using special techniques on a bone marrow sample, the doctor looks for an increase in mast cells. The bone marrow may show disordered bone formation and bizzare mast cells.

Serum levels of tryptase are high and are a useful marker, however, the serum tryptase of cutaneous mastocytosis is normal. Urinary tryptase is also increased.

WHO Diagnostic Criteria; to make the diagnosis have 1 Major and 1 Minor criteria or at least 3 minor ones.
Major Criteria; Mutlifocal dense infiltrates of mast cells in the bone marrow or other extracutaneous organ(s) (>15 mast cells in aggregate).
Minor Criteria;
1) Mast cells in the bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25% of cells).
2) C-kit mutation at codon 816 is found.
3) Mast cells in the bone marrow express CD2 and/or CD25.
4) Serum total tryptase >20 ng/ml.

== Treatment ==
There is currently no cure for mastocytosis. The treatment is palliative and there are a number of medicines to help treat the symptoms of mastocytosis:
*[[Antihistamine]]s block receptors targeted by histamine released from mast cells. Both H1 and H2 blockers may be helpful.
*[[Leukotriene antagonists]] block receptors targeted by leukotrienes released from mast cells.
*[[Mast cell stabilizer]]s help prevent mast cells from releasing their chemical contents. Cromolyn Sodium Oral Solution (Gastrocrom® / [[Cromoglicate]]) is the only medicine specifically approved by the U.S. FDA for the treatment of mastocytosis. [[Ketotifen]] is available in Canada and Europe, but is only available in the U.S. as ophthamic drops (Zaditor®).
*[[Proton pump inhibitor]]s help reduce production of gastric acid, which is often increased in patients with mastocytosis. Excess gastric acid can harm the stomach, esophagus, and small intestine.
*[[Epinephrine]] constricts blood vessels and opens airways to maintain adequate circulation and ventilation when excessive mast cell degranulation has caused [[anaphylaxis]].
*[[Albuterol]] and other beta-2 agonists open airways that can constrict in the presence of histamine.
*[[Corticosteroids]] can be used topically, inhaled, or systemically to reduce inflammation associated with mastocytosis.

*[[Antidepressant]]s are an important and often overlooked tool in the treatment of mastocytosis. The stress and physical discomfort of any chronic disease may increase the likelihood of a patient developing [[clinical depression|depression]]. Depression and other neurological symptoms have been noted in mastocytosis.<ref>Rogers MP, Bloomingdale K, Murawski BJ, Soter NA, Reich P, Austen KF. ''Mixed organic brain syndrome as a manifestation of systemic mastocytosis.'' Psychosom Med 1986;48:437-47. PMID 3749421</ref> Some antidepressants such as [[doxepin]] are themselves potent antihistamines and can help relieve physical as well as cognitive symptoms.

*[[Dihydropyridines]] are [[calcium channel blocker]]s that are sometimes used to treat [[hypertension|high blood pressure]]. At least one clinical study suggested that [[Nifedipine]], one of the dihydropyridines, may reduce mast cell degranulation in patients that exhibit [[urticaria pigmentosa]]. A 1984 study by Fairly et al. included a patient with symptomatic urticaria pigmentosa who responded to nifedipine at dose of 10 mg po tid.<ref>Fairley JA, et al: Urticaria pigmentosa responsive to nifedipine. J Am Acad Dermatol 11:740-743, 1984.</ref> However, Nifetipine has never been approved by the FDA for treatment of mastocytosis.

In rare cases in which mastocytosis is cancerous or associated with a blood disorder, the patient may have to use [[steroid]]s and/or [[chemotherapy]]. The novel agent [[imatinib]] (Glivec® or Gleevec®) has been found to be effective in certain types of mastocytosis.<ref>Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51. PMID 16779792</ref>
Recent literature shows that C-Kit (D816V) lends some resistance to imatinib and sorafenib but these cells are still sensitive to Nilotinib, Dasatinib and Rapamycin. Cladribine and Interferon have also been found to be effective.

There are clinical trials currently underway testing stem cell transplants as a form of treatment.

There are support groups for persons suffering from mastocytosis. Involvement can be emotionally therapeutic for some patients.

== Research ==
[[National Institute of Allergy and Infectious Diseases]] (NIAID) scientists have been studying and treating patients with mastocytosis for several years at the [[National Institutes of Health]] (NIH) Clinical Center.

Some of the most important research advances for this rare disorder include improved diagnosis of mast cell disease and identification of growth factors and genetic mechanisms responsible for increased mast cell production. Researchers are currently evaluating approaches to improve ways to treat mastocytosis.

Scientists also are focusing on identifying disease-associated mutations (changes in genes). NIH scientists have identified some mutations, which may help researchers understand the causes of mastocytosis, improve diagnosis, and develop better treatments.

== References==
{{Reflist|2}}

==Additional Resources==

* ''Based on an informative page by the [[National Institute of Allergy and Infectious Diseases]] (NIAID).''
* Shah NP, Lee FJ, Luo R, Jiang Y, Donker M, Akin C. Dasatinib (BMS-354825) inhibits KIT(D816V), an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood. 2006; 108(1):286-291. PMID 16434489.
* Pardanani A, Teffer A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Current Opinion in Hematology. 2010; 17(2): 125-132. PMID 20075725.

== External links ==
* [http://www.tmsforacure.org Mastocytosis Society, Inc.]
* [http://purl.org/net/masto Mastocytosis email lists]
* [http://www.mastokids.org Mastokids.org]
* [http://www.ukmasto.co.uk UK Mastocytosis support]

== Acknowledgements ==
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.

'''List of contributors:'''

== Suggested Reading and Key General References ==

== Suggested Links and Web Resources ==

== For Patients ==

{{Hematological malignancy histology}}
{{SIB}}
[[Category:DiseaseState]]
[[Category:Immunology]]
[[Category:Hematology]]
[[Category:Oncology]]

[[de:Mastozytose]]
[[es:Mastocitosis]]
[[fr:Mastocytose]]
[[nl:Mastocytose]]
{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

Chronic lymphocytic leukemia

2010-11-15T01:51:52Z

Robert Killeen:

'''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = Chronic_lymphocytic_leukemia.jpg |
Caption = Peripheral blood smear showing CLL cells |
DiseasesDB = 2641 |
ICD10 = {{ICD10|C|91|1|c|81}} |
ICD9 = {{ICD9|204.9}} |
ICDO = 9823/3 |
OMIM = |
MedlinePlus = 000532|
eMedicineSubj = med |
eMedicineTopic = 370 |
MeshID = D015462 |
}}

{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==
'''Chronic lymphocytic leukemia''' (also known as "chronic lymphoid leukemia" or "CLL"), is a type of [[leukemia]], or cancer of the white blood cells ([[lymphocytes]]). CLL affects a particular lymphocyte, the [[B cell]], which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.

CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to a disease called [[small lymphocytic lymphoma]] (SLL), a type of [[non-Hodgkin's lymphoma]] which presents primarily in the [[lymph nodes]]. The [[World Health Organization]] considers CLL and SLL to be "one disease at different stages, not two separate entities".<ref name="pmid10577857">{{cite journal |author=Harris NL, Jaffe ES, Diebold J, ''et al'' |title=World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997 |journal=J. Clin. Oncol. |volume=17 |issue=12 |pages=3835-49 |year=1999 |pmid=10577857 |doi=}}</ref>

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as [[T-cell prolymphocytic leukemia]]s.

[[Acute lymphocytic leukemia]] (ALL) is a disease of children, but CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over age 50, and two-thirds are men. In the United States during 2007, it is estimated there will be 15,340 new cases diagnosed and 4,500 deaths<ref name="NCI-CLL-page1">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page1 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: General Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>, but because of prolonged survival, many more people are living with CLL.

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in [[swollen lymph nodes]], [[splenomegaly|spleen]], and [[hepatomegaly|liver]], and eventually [[anemia]] and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies. Survival varies from 5 years to more than 25 years. It is now possible to diagnose patients with short and long survival more precisely by examining the DNA mutations, and patients with slowly-progressing disease can be reassured and may not need any treatment in their lifetimes.<ref name="pmid15728813">{{cite journal |author=Chiorazzi N, Rai KR, Ferrarini M |title=Chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=352 |issue=8 |pages=804-15 |year=2005 |pmid=15728813 |doi=10.1056/NEJMra041720}}</ref>

==Classification and prognosis==
===Clinical staging===
Staging is done with the Rai staging system and the Binet classification (see details<ref name="NCI-CLL-page2">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page2 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>).

===Gene mutation status===
Recent publications suggest that two<ref name="pmid11733578">{{cite journal |author=Rosenwald A, Alizadeh AA, Widhopf G, ''et al'' |title=Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia |journal=J. Exp. Med. |volume=194 |issue=11 |pages=1639-47 |year=2001 |pmid=11733578 |doi=}}</ref> or three<ref name="pmid12406914">{{cite journal |author=Ghia P, Guida G, Stella S, ''et al'' |title=The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression |journal=Blood |volume=101 |issue=4 |pages=1262-9 |year=2003 |pmid=12406914 |doi=10.1182/blood-2002-06-1801}}</ref> prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region [[heavy chain]] (IgVH) gene mutation status.<ref name="pmid16983131">{{cite journal |author=Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE |title=Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia |journal=Ann. Intern. Med. |volume=145 |issue=6 |pages=435-47 |year=2006 |pmid=16983131 |doi=|url=http://www.annals.org/cgi/content/full/145/6/435}}</ref> High risk patients have an immature cell pattern with few mutations in the DNA in the IgVH antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.

Since assessment of the IgVH antibody DNA changes is difficult to perform, the presence of either [[cluster of differentiation]] [[CD38|38]] ([[CD38]]) or Z-chain–associated protein kinase-70 ([[ZAP-70]]) may be surrogate markers of high risk subtype of CLL.<ref name="pmid16983131"/> Their expression correlates with a more immature cellular state and a more rapid disease course. Unmutated IGVH survive worse than mutated and are associated with aggressive CLL. The ZAP70 (AKA Zeta-Associated Protein) presence on the CLL cell correlates with unmutated immunoglobulin genes and a poor prognosis. Conversely, its absence indicates the presence of mutated genes and a good clinical outcome. Patients positive for ZAP70 have a CLL more aggressive in nature and more refractory to treatment. They are more likely to evolve to more unfavorable cytogenetic abnormalitites.

===Fluorescence in situ hybridization (FISH)===
In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as [[fluorescent in situ hybridization]] (FISH).<ref name="pmid16983131"/> Compared with fluorescence in-situ hybridization (FISH), conventional metaphase cytogenetics play ONLY a MINOR prognostic role in CLL, so far, due to technical problems resulting from a limited proliferation of CLL cells in-vitro. Therefore conventional cytogenetics may define subgroups with a high risk of progression. FISH can be done (in CLL) on dividing and non-dividing cells. FISH doesn't tell about IgVH mutations nor does it define the presence of trisomy either. FISH is useful as long as there are CLL cells to test; you can't do it in a complete response (CR).The application of FISH to study interphase nuclei gives important prognostic information with B-cell CLL, especially for patients with 11q-, trisomy 12, 13q- and 17q-.
The procedure of FISH involves cell cultures which are prepared after metaphase and prometaphase chromosomes are fixed to a glass slide. A DNA probe is then hybridized onto the chromosome; the probe is labeled with fluorochrome which can be detected with fluorescent microscopy. FISH can be done on dividing and non-dividing cells. Inversions will be missed as probes detect sequences not precise locations. Small mutations, such as small deletions and insertions, will also be missed. FISH is a cytogenetic technology that looks at 200-500 blood cells (obtained with a bone marrow biopsy). Because of the small size it is not as sensitive as PCR. (PCR has extreme sensitivity as well as being quite specific).
PCR amplifies a fragment of DNA. It is at least 2-3 logs more sensitive than cytogenetic technology like FISH. PCR measurement requires a sample blood draw which is less invasive and intense than a bone marrow biopsy (with FISH).
Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
# Deletions of part of the short arm of chromosome 17 (del 17p13) which target the cell cycle regulating protein p53 (a tumore suppressor gene) are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL.
# Deletions of the long arm on chromosome 11 (del 11q22-q23) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%).
# Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis. It has a higher frequency of DNA aneuploidy.
# Deletion of the long arm of chromosome 13 (del 13q14) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients (along with those of normal karyotype) have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting genes.

The presence of 17p- typifies cells that are resistant to fludarabine, alkylators and rituxumab.
11q- portends a decreased RR to fludrabine as well as an early relapse after bone marrow transplant (BMT).
Both the 17p- and the 11q- have a decreased progression-free survival (PFS) and overall survival (OS).

==Symptoms and signs==
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections.

Uncommonly, CLL presents as enlargement of the lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as [[small lymphocytic lymphoma]].

The increase in lymphocytes and precursors in the bone marrow impairs the production of other [[leucocytes]] causing a decrease in such cell types.

A high beta-2-microglobulin level may be seen and is an independent adverse prognostic factor for CR and OS.

==Diagnosis==
CLL is usually first suspected by the presence of a [[lymphocytosis]], an increase in one type of the white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per mm3 (microliter) of blood but can be much higher.

===Pathology===
<div align="left">
<gallery heights="175" widths="175">
Image:CLL.jpg|CLL (more cytoplasmic space)<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
Image:CLL Smudge Cell.jpg|CLL Smudge Cell<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
</gallery>
</div>

===Determining clonality===

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the co-expression of cells surface markers [[cluster of differentiation]] [[CD5 (protein)|5]] ([[CD5 (protein)|CD5]]) and [[cluster of differentiation]] [[CD23|23]] ([[CD23]]). In addition, all the CLL cells within one individual are functionally inert and clonal, that is genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive [[Light_chain#In_humans|antibody light chains]], kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody producing cells resulting in a mixture of both kappa and lambda expressing cells. The lack of the normal distribution of kappa and lambda producing B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell Non-Hodgkin lymphoma).

Clonality is confirmed by the combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by [[flow cytometry]]. The latter is easily accomplished on a small amount of blood. A [[flow cytometer]] is an instrument that can examine the marker molecule expression on individual cells in fluids. This is accomplished using antibodies with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules CD19 and CD20), and characteristically express the marker molecules [[CD5 (protein)|CD5]] and [[CD23]]. Morphologically, the cells resemble normal lymphocytes under the microscope, although slightly larger, and are fragile when smeared onto a glass slide giving rise to many broken cells (smudge cells).

===Differential diagnosis===
Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.
* [[B cell prolymphocytic leukemia]] (B PLL), which is a related but more aggressive disorder, has cells with similar phenotype but that are signficantly larger than normal lymphocytes and have a prominent nucleolus suggests a related.
* [[Hairy cell leukemia]] is also a neoplasm of B lymphocytes but differs significantly from CLL by its morphology under the microscope ([[hairy cell leukemia]] cells have delicate, hair-like projections on their surface) and marker molecule expression.

All the B cell malignancies of the blood and [[bone marrow]] can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow and occasionally lymph node cells by a [[pathologist]] with specific training in blood disorders. A sophisticated instrument called a [[flow cytometer]] is necessary for cell marker analysis and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by [[fluorescent in situ hybridization]] (FISH).
CLL is positive for CD5, CD19 & CD23; CLL is the only cell type that coexpresses CD5 & 19. It is negative for CD10 & cyclin D.
CD20 is +/- as is sIg. 90% of B-CLL have bcl-2.
The 2 most noteworthy lymphoproliferative diseases with CD5 positivity are CLL (which is CD23 positive) & mantle zone lymphoma (which is CD23 negative). Other CD5+ groups include peripheral & cutaneous T-cell lymphoma, lymphoblastic lymphoma, and Adult T-cell leukemia/lymphoma.

==Treatment==
While generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. No chemotherapy has clearly prolonged survival in CLL. Instead, the condition is monitored over time.
The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by [[chemotherapy]], [[radiation therapy]], [[biological therapy]], or [[bone marrow transplantation]]. Symptoms are sometimes treated surgically ([[splenectomy]] with removal of the enlarged spleen) or by [[radiation therapy]].

Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.<ref name="NCI-CLL-page2"/>

Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.<ref name="pmid8652811">{{cite journal |author=Cheson BD, Bennett JM, Grever M, ''et al'' |title=National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment |journal=Blood |volume=87 |issue=12 |pages=4990-7 |year=1996 |pmid=8652811 |doi=}}</ref>

Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page5 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage I, II, III, and IV Chronic Lymphocytic Leukemia|author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>

CLL (+12) has the capacity for autoimmune cytopenias. Although about 20% of patients have Coombs positivity only about 8% actually develop hemolytic anemia and about 20% have decreased platelets as well. For warm autoimmune hemolytic anemia give steroids initially, using immunoglobulin secondarily. Cyclosporine is used if steroids and IV-IgG fail. One might also consider Alemtuzumab +/- fludarabine or cytoxan with dexamethasone. For refractory AIHA do splenectomy or splenic irradiation.

===Alkylators===
Chlorambucil (CHB) should be considered for older patients (>90 years) with severe comorbidities (eg renal insufficiency) where they're likely to live less than a year regardless of treatment. CHB is associated with a median survival of about 2 years in patients with advanced stage CLL; a higher response rate (RR) may be achieved with more aggressive treatment regimens such as CHOP but without any clear survival advantage. This agent has been replaced by newer agents. Cytoxan, Oncovin, Prednisone (COP) is not superior to CHB alone, either in complete response rate (CR) or prolonged survival. CHOP does improve the RR to stage B patients but, again, with no survival advantage.

Bendamustine (treanda) is used in the treatment of CLL (& indolent NHL) that has progressed within 6 months after treatment with Rituxumab. Administer as 100 mg/m2 / 30" on days 1+2 of a 28 day cycle; up to 6 cycles. Bendamustine is superior to chlorambucil in the treatment of CLL. Bendamustine is also given with Ritux for relapsed CLL with the overall response rate (ORR) dependent on chromosomal subtype; 11p deletion = 92%, trisomy 12 = 100%, 17p deletion = 44%, umutated IgVH = 74%.

===Purine analogues===
Although the purine analogue [[fludarabine]] was shown to give superior response rates than [[chlorambucil]] as primary therapy,<ref name="pmid11114313">{{cite journal |author=Rai KR, Peterson BL, Appelbaum FR, ''et al'' |title=Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=24 |pages=1750-7 |year=2000 |pmid=11114313 |doi=}}</ref><ref name="pmid16856041">{{cite journal |author=Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R |title=Purine antagonists for chronic lymphocytic leukaemia |journal=Cochrane database of systematic reviews (Online) |volume=3 |issue= |pages=CD004270 |year=2006 |pmid=16856041 |doi=10.1002/14651858.CD004270.pub2}}</ref>
there is no evidence that early use of fludarabine improves overall survival. Fludara can actually make CLL-AIHA worse. It is indicated for patients who have refractory and / or relapsed disease refractory to alkylating agents. Adding prednisone to fludarabine does not increase the RR over fludarabine alone. Add prednisone to fludara only in the presence of autoimmune anemia or thrombocytopenia. Note that fludara with steroids increases the likelihood of P. carinii & Listeria infection. Patients who fail to respond to fludarabine after 2-3 courses should not receive additional courses. No further treatment is indicated if a CR has been achieved; otherwise 2 courses are given after the maximal response is achieved, not to exceed one year.

===Combination chemotherapy===

Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL. Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:

* [[fludarabine]] with [[cyclophosphamide]] <ref name="pmid16219797"> {{cite journal |author=Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M, German CLL Study Group. |title=Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia |journal=Blood |year=2006 |volume=107 |pages=885-91.|pmid16219797}} </ref>
* [[fludarabine]] with [[rituximab]]<ref name="pmid12393429">{{cite journal |author=Byrd JC, Peterson BL, Morrison VA, ''et al'' |title=Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) |journal=Blood |volume=101 |issue=1 |pages=6-14 |year=2003 |pmid=12393429 |doi=10.1182/blood-2002-04-1258}}</ref>
* FCR ([[fludarabine]], [[cyclophosphamide]], and [[rituximab]])<ref name="pmid15767648">{{cite journal |author=Keating MJ, O'Brien S, Albitar M, ''et al'' |title=Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia |journal=J. Clin. Oncol. |volume=23 |issue=18 |pages=4079-88 |year=2005 |pmid=15767648 |doi=10.1200/JCO.2005.12.051}}</ref> FCR are well tolerated in previously treated CLL. However most of their toxicity is myelosuppression. FCR had a high CR rate (25%), nodular PR (16%) & PR (32%). Molecular remissions are obtained in 1/3 of patients.
* CHOP ([[cyclophosphamide]], [[doxorubicin]], [[vincristine]] and [[prednisolone]])

===Stem cell transplantion===
Allogeneic [[Stem cell transplantation|bone marrow (stem cell) transplantation]] is rarely used as a first-line treatment for CLL due to its risk. There is increasing interest in the use of reduced intensity allogeneic stem cell transplantation, which offers the prospect of cure for selected patients with a suitable donor.<ref name="Dreger">{{cite journal | author=Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D; Chronic Leukemia Working Party of the EBMT | title=Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning | journal=Leukemia | year=2003 | pages=841-8 | volume=17 | issue=5 | id=PMID 12750695}}</ref>

===Refractory CLL===
"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including [[lenalidomide]], flavopiridol, and bone marrow (stem cell) transplantation, are considered.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page6 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Refractory Chronic Lymphocytic Leukemia|author=National Cancer Institute|accessdate=2007-09-04 |format= |work=}}</ref>
Prolymphocytic transformation of CLL requires treatment with CHOP.

===Monoclonal antibodies===
The monoclonal antibody, [[alemtuzumab]] (directed against [[CD52]]), may be used in patients with refractory, bone marrow-based disease.<ref name="Keating">{{cite journal | author=Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR | title=Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study | journal=Blood | year=2002 | pages=3554-61 | volume=99 | issue=10 | id=PMID 11986207}}</ref> Alemtuzumab (Campath) is an anti-CD52 monoclonal antibody; CD52 is on all B & T lymphocytes. Its use carries a RR = 33% with a CR = 2%. Patients with pre-exisiting cytopenias show improvement in bone marrow function due to the lack of stem cell (CD34) toxicity. Its toxicity against T-cells can lead to significant immunosuppression and infectious complications (esp CMV reactivation). Dose modifications are made for drug related cytopenias. Premedications for its administration are necessary and (almost always) the first dose can be characterized by fever, rigors and nausea. It is recommended to give benadryl, tylenol, hydrocortisone as well as Bactrin DS and Famciclovir. If a 17p del is found in a young CLL patient one could consider Alemtuzumab and early transplant. It is otherwise approved for CLL refractory to alkylating agents and fludarabine. Ofatumumab is a novel monoclonal antibody against CD20 but targets a different epitope than Rituximab. It is also different from Ritux in that it is a completely humanized anti-CD20 antibody whereas Ritux is a chimeric. Ofatumumab (HuMax-CD20) appears to work well for patients who have lower CD20 levels on the surface of their lymphocytes. Therefore it should be more effective than Ritux in treating CLL
(Ritux may not work as well because of low CD20 levels). It is an active treatment option for CLL patients refractory to both fludarabine and alemtuzumab.

==Epidemiology==
CLL is a disease of the elderly and is rarely encountered in individuals under the age of 40. Thereafter the disease incidence increases with age. Of note, subclinical "disease" can be identified in up to 7-8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

==References==
{{Reflist|2}}

==External links==

Forums:
*[http://www.ukcllforum.org.uk UK CLL Forum] - The UK's only specific forum for the patients, families, friends and carers of those diagnosed with Chronic Lymphocytic Leukaemia (CLL).
*[http://www.CLLForum.com CLL Forum] - Member supported, moderated, forum-based global community that provides friendly support, information and resources to people living with CLL and their caregivers.
*[http://www.cllsupport.org.uk UK CLL Support Association] - Registered charity that provides UK specific support to patients and caregivers.
Information Resources:
*[http://www.clltopics.org CLL Topics] - Non-profit educational and patient-advocacy organization (excellent resource.)
*[http://cll.ucsd.edu CLL Research Consortium] - NCI funded program project of leading clinician and scientists trying to cure CLL.
*[http://cllcanada.ca CLL Canada] - Repository of CLL research in laymen's terms.

*[http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=3221&cat_id=1209 Leukemia & Lymphoma Society] - General CLL information.
*[http://www.lymphomation.org/type-CLL.htm Lymphomation.org] - Lymphoma website with a CLL resource page.
*[http://www.cancer.gov/cancerinfo/pdq/treatment/CLL/patient/ US National Cancer Institute] - General information about CLL.
Listservs and Groups:
*[http://www.acor.org/index.html ACOR Homepage] - Non-profit ACOR (Association of Cancer Online Resources) mailing list. Sign-up and receive email messages from other members of the mailing list.

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Chronic lymphocytic leukemia

2010-11-13T03:20:13Z

Robert Killeen:

'''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = Chronic_lymphocytic_leukemia.jpg |
Caption = Peripheral blood smear showing CLL cells |
DiseasesDB = 2641 |
ICD10 = {{ICD10|C|91|1|c|81}} |
ICD9 = {{ICD9|204.9}} |
ICDO = 9823/3 |
OMIM = |
MedlinePlus = 000532|
eMedicineSubj = med |
eMedicineTopic = 370 |
MeshID = D015462 |
}}

{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==
'''Chronic lymphocytic leukemia''' (also known as "chronic lymphoid leukemia" or "CLL"), is a type of [[leukemia]], or cancer of the white blood cells ([[lymphocytes]]). CLL affects a particular lymphocyte, the [[B cell]], which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.

CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to a disease called [[small lymphocytic lymphoma]] (SLL), a type of [[non-Hodgkin's lymphoma]] which presents primarily in the [[lymph nodes]]. The [[World Health Organization]] considers CLL and SLL to be "one disease at different stages, not two separate entities".<ref name="pmid10577857">{{cite journal |author=Harris NL, Jaffe ES, Diebold J, ''et al'' |title=World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997 |journal=J. Clin. Oncol. |volume=17 |issue=12 |pages=3835-49 |year=1999 |pmid=10577857 |doi=}}</ref>

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as [[T-cell prolymphocytic leukemia]]s.

[[Acute lymphocytic leukemia]] (ALL) is a disease of children, but CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over age 50, and two-thirds are men. In the United States during 2007, it is estimated there will be 15,340 new cases diagnosed and 4,500 deaths<ref name="NCI-CLL-page1">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page1 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: General Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>, but because of prolonged survival, many more people are living with CLL.

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in [[swollen lymph nodes]], [[splenomegaly|spleen]], and [[hepatomegaly|liver]], and eventually [[anemia]] and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies. Survival varies from 5 years to more than 25 years. It is now possible to diagnose patients with short and long survival more precisely by examining the DNA mutations, and patients with slowly-progressing disease can be reassured and may not need any treatment in their lifetimes.<ref name="pmid15728813">{{cite journal |author=Chiorazzi N, Rai KR, Ferrarini M |title=Chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=352 |issue=8 |pages=804-15 |year=2005 |pmid=15728813 |doi=10.1056/NEJMra041720}}</ref>

==Classification and prognosis==
===Clinical staging===
Staging is done with the Rai staging system and the Binet classification (see details<ref name="NCI-CLL-page2">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page2 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>).

===Gene mutation status===
Recent publications suggest that two<ref name="pmid11733578">{{cite journal |author=Rosenwald A, Alizadeh AA, Widhopf G, ''et al'' |title=Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia |journal=J. Exp. Med. |volume=194 |issue=11 |pages=1639-47 |year=2001 |pmid=11733578 |doi=}}</ref> or three<ref name="pmid12406914">{{cite journal |author=Ghia P, Guida G, Stella S, ''et al'' |title=The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression |journal=Blood |volume=101 |issue=4 |pages=1262-9 |year=2003 |pmid=12406914 |doi=10.1182/blood-2002-06-1801}}</ref> prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region [[heavy chain]] (IgVH) gene mutation status.<ref name="pmid16983131">{{cite journal |author=Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE |title=Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia |journal=Ann. Intern. Med. |volume=145 |issue=6 |pages=435-47 |year=2006 |pmid=16983131 |doi=|url=http://www.annals.org/cgi/content/full/145/6/435}}</ref> High risk patients have an immature cell pattern with few mutations in the DNA in the IgVH antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.

Since assessment of the IgVH antibody DNA changes is difficult to perform, the presence of either [[cluster of differentiation]] [[CD38|38]] ([[CD38]]) or Z-chain–associated protein kinase-70 ([[ZAP-70]]) may be surrogate markers of high risk subtype of CLL.<ref name="pmid16983131"/> Their expression correlates with a more immature cellular state and a more rapid disease course. Unmutated IGVH survive worse than mutated and are associated with aggressive CLL. The ZAP70 (AKA Zeta-Associated Protein) presence on the CLL cell correlates with unmutated immunoglobulin genes and a poor prognosis. Conversely, its absence indicates the presence of mutated genes and a good clinical outcome. Patients positive for ZAP70 have a CLL more aggressive in nature and mor refractory to treatment. They are more likely to evolve to more unfavorable cytogenetic abnormalitites.

===Fluorescence in situ hybridization (FISH)===
In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as [[fluorescent in situ hybridization]] (FISH).<ref name="pmid16983131"/> Compared with fluorescence in-situ hybridization (FISH), conventional metaphase cytogenetics play ONLY a MINOR prognostic role in CLL, so far, due to technical problems resulting from a limited proliferation of CLL cells in-vitro. Therefore conventional cytogenetics may define subgroups with a high risk of progression. FISH can be done (in CLL) on dividing and non-dividing cells. FISH doesn't tell about IgVH mutations nor does it define the presence of trisomy either. FISH is useful as long as there are CLL cells to test; you can't do it in a complete response (CR).The application of FISH to study interphase nuclei gives important prognostic information with B-cell CLL, especially for patients with 11q-, trisomy 12, 13q- and 17q-. PCR has extreme sensitivity as well as being quite specific.
The procedure of FISH involves cell cultures which are prepared after which metaphase and prometaphase chromosomes are fixed to a glass slide. A DNA probe is then hybridized onto the chromosome; the probe is labeled with fluorochrome which can be detected with fluorescent microscopy. FISH can be done on dividing and non-dividing cells. Inversions will be missed as probes detect sequences not precise locations. Small mutations, such as small deletions and insertions, will also be missed. FISH is a cytogenetic technology that looks at 200-500 blood cells (obtained with a bone marrow biopsy). Because of the small size it is not as sensitive as PCR.
PCR amplifies a fragment of DNA. It is at least 2-3 logs more sensitive than cytogenetic technology like FISH. PCR measurement requires a sample blood draw which is less invasive and intense than a bone marrow biopsy (with FISH).
Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
# Deletions of part of the short arm of chromosome 17 (del 17p13) which target the cell cycle regulating protein p53 (a tumore suppressor gene) are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL.
# Deletions of the long arm on chromosome 11 (del 11q22-q23) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%).
# Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis. It has a higher frequency of DNA aneuploidy.
# Deletion of the long arm of chromosome 13 (del 13q14) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients (along with those of normal karyotype)have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting genes.

The presence of 17p- typifies cells that are resistant to fludarabine, alkylators and rituxumab.
11q- portends a decreased RR to fludrabine as well as an early relapse after bone marrow transplant (BMT).
Both the 17p- and the 11q- have a decreased progression-free survival (PFS) and overall survival (OS).

==Symptoms and signs==
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections.

Uncommonly, CLL presents as enlargement of the lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as [[small lymphocytic lymphoma]].

The increase in lymphocytes and precursors in the bone marrow impairs the production of other [[leucocytes]] causing a decrease in such cell types.

A high beta-2-microglobulin level may be seen and is an independent adverse prognostic factor for CR and OS.

==Diagnosis==
CLL is usually first suspected by the presence of a [[lymphocytosis]], an increase in one type of the white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per mm3 (microliter) of blood but can be much higher.

===Pathology===
<div align="left">
<gallery heights="175" widths="175">
Image:CLL.jpg|CLL (more cytoplasmic space)<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
Image:CLL Smudge Cell.jpg|CLL Smudge Cell<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
</gallery>
</div>

===Determining clonality===

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the co-expression of cells surface markers [[cluster of differentiation]] [[CD5 (protein)|5]] ([[CD5 (protein)|CD5]]) and [[cluster of differentiation]] [[CD23|23]] ([[CD23]]). In addition, all the CLL cells within one individual are functionally inert and clonal, that is genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive [[Light_chain#In_humans|antibody light chains]], kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody producing cells resulting in a mixture of both kappa and lambda expressing cells. The lack of the normal distribution of kappa and lambda producing B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell Non-Hodgkin lymphoma).

Clonality is confirmed by the combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by [[flow cytometry]]. The later is easily accomplished on a small amount of blood. A [[flow cytometer]] is an instrument that can examine the marker molecule expression on individual cells in fluids. This is accomplished using antibodies with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules [[cluster of differentiation]] [[CD19|19]] ([[CD19]]) and [[CD20]]), and characteristically express the marker molecules [[CD5 (protein)|CD5]] and [[CD23]]. Morphologically, the cells resemble normal lymphocytes under the microscope, although slightly larger, and are fragile when smeared onto a glass slide giving rise to many broken cells (smudge cells).

===Differential diagnosis===
Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.
* [[B cell prolymphocytic leukemia]] (B PLL), which is a related but more aggressive disorder, has cells with similar phenotype but that are signficantly larger than normal lymphocytes and have a prominent nucleolus suggests a related.
* [[Hairy cell leukemia]] is also a neoplasm of B lymphocytes but differs significantly from CLL by its morphology under the microscope ([[hairy cell leukemia]] cells have delicate, hair-like projections on their surface) and marker molecule expression.

All the B cell malignancies of the blood and [[bone marrow]] can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow and occasionally lymph node cells by a [[pathologist]] with specific training in blood disorders. A sophisticated instrument called a [[flow cytometer]] is necessary for cell marker analysis and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by [[fluorescent in situ hybridization]] (FISH).
CLL is positive for CD5, CD19 & CD23; CLL is the only cell type that coexpresses CD5 & 19. It is negative for CD10 & cyclin D.
CD20 is +/- as is sIg. 90% of B-CLL have bcl-2.
The 2 most noteworthy lymphoproliferative diseases with CD5 positivity are CLL(which is CD23 positive) & mantle zone lymphoma (which is CD23 negative). Other CD5+ groups include peripheral & cutaneous T-cell lymphoma, lymphoblastic lymphoma, and Adult T-cell leukemia/lymphoma.

==Treatment==
While generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. No chemotherapy has clearly prolonged survival in CLL. Instead, the condition is monitored over time.
The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by [[chemotherapy]], [[radiation therapy]], [[biological therapy]], or [[bone marrow transplantation]]. Symptoms are sometimes treated surgically ([[splenectomy]] removal of enlarged spleen) or by [[radiation therapy]].

Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.<ref name="NCI-CLL-page2"/>

Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.<ref name="pmid8652811">{{cite journal |author=Cheson BD, Bennett JM, Grever M, ''et al'' |title=National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment |journal=Blood |volume=87 |issue=12 |pages=4990-7 |year=1996 |pmid=8652811 |doi=}}</ref>

Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page5 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage I, II, III, and IV Chronic Lymphocytic Leukemia|author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>

CLL (+12) has the capacity for autoimmune cytopenias. Although about 20% of patients have Coombs positivity only about 8% actually develop hemolytic anemia and about 20% have decreased platelets as well. For warm autoimmune hemolytic anemia give steroids initially, using immunoglobulin secondarily. Cyclosporine is used if steroids and IV-IgG fail. One might also consider Alemtuzumab +/- fludarabine or cytoxan with dexamethasone. For refractory AIHA do splenectomy or splenic irradiation.

===Alkylators===
Chlorambucil (CHB) should be considered for older patients (>90 years) with severe comorbidities (eg renal insufficiency) where they're likely to live less than a year regardless of treatment. CHB is associated with a median survival of about 2 years in patients with advanced stage CLL; a higher response rate (RR) may be achieved with more aggressive treatment regimens such as CHOP but without any clear survival advantage. This agent has been replaced by newer agents. Cytoxan, Oncovin, Prednisone (COP) is not superior to CHB alone, either in complete response rate (CR) or prolonged survival. CHOP does improve the RR to stage B patients but, again, with no survival advantage.

Bendamustine (treanda) is used in the treatment of CLL (& indolent NHL) that has progressed within 6 months after treatment with Rituxumab. Administer as 100 mg/m2 / 30" on days 1+2 of a 28 day cycle; up to 6 cycles. Bendamustine is superior to chlorambucil in the treatment of CLL. Bendamustine is also given with Ritux for relapsed CLL with the overall response rate (ORR) dependent on chromosomal subtype; 11p deletion = 92%, trisomy 12 = 100%, 17p deletion = 44%, umutated IgVH = 74%.

===Purine analogues===
Although the purine analogue [[fludarabine]] was shown to give superior response rates than [[chlorambucil]] as primary therapy,<ref name="pmid11114313">{{cite journal |author=Rai KR, Peterson BL, Appelbaum FR, ''et al'' |title=Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=24 |pages=1750-7 |year=2000 |pmid=11114313 |doi=}}</ref><ref name="pmid16856041">{{cite journal |author=Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R |title=Purine antagonists for chronic lymphocytic leukaemia |journal=Cochrane database of systematic reviews (Online) |volume=3 |issue= |pages=CD004270 |year=2006 |pmid=16856041 |doi=10.1002/14651858.CD004270.pub2}}</ref>
there is no evidence that early use of fludarabine improves overall survival. Fludara can actually make CLL-AIHA worse. It is indicated for patients who have refractory and / or relapsed disease refractory to alkylating agents. Adding prednisone to fludarabine does not increase the RR over fludarabine alone. Add prednisone to fludara only in the presence of autoimmune anemia or thrombocytopenia. Note that fludara with steroids increases the likelihood of P. carinii & Listeria infection. Patients who fail to respond to fludarabine after 2-3 courses should not receive additional courses. No further treatment is indicated if a CR has been achieved; otherwise 2 courses are given after the maximal response is achieved, not to exceed one year.

===Combination chemotherapy===

Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL. Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:

* [[fludarabine]] with [[cyclophosphamide]] <ref name="pmid16219797"> {{cite journal |author=Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M, German CLL Study Group. |title=Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia |journal=Blood |year=2006 |volume=107 |pages=885-91.|pmid16219797}} </ref>
* [[fludarabine]] with [[rituximab]]<ref name="pmid12393429">{{cite journal |author=Byrd JC, Peterson BL, Morrison VA, ''et al'' |title=Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) |journal=Blood |volume=101 |issue=1 |pages=6-14 |year=2003 |pmid=12393429 |doi=10.1182/blood-2002-04-1258}}</ref>
* FCR ([[fludarabine]], [[cyclophosphamide]], and [[rituximab]])<ref name="pmid15767648">{{cite journal |author=Keating MJ, O'Brien S, Albitar M, ''et al'' |title=Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia |journal=J. Clin. Oncol. |volume=23 |issue=18 |pages=4079-88 |year=2005 |pmid=15767648 |doi=10.1200/JCO.2005.12.051}}</ref> FCR are well tolerated in previously treated CLL. However most of their toxicity is myelosuppression. FCR had a high CR rate (25%), nodular PR (16%) & PR (32%). Molecular remissions are obtained in 1/3 of patients.
* CHOP ([[cyclophosphamide]], [[doxorubicin]], [[vincristine]] and [[prednisolone]])

===Stem cell transplantion===
Allogeneic [[Stem cell transplantation|bone marrow (stem cell) transplantation]] is rarely used as a first-line treatment for CLL due to its risk. There is increasing interest in the use of reduced intensity allogeneic stem cell transplantation, which offers the prospect of cure for selected patients with a suitable donor.<ref name="Dreger">{{cite journal | author=Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D; Chronic Leukemia Working Party of the EBMT | title=Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning | journal=Leukemia | year=2003 | pages=841-8 | volume=17 | issue=5 | id=PMID 12750695}}</ref>

===Refractory CLL===
"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including [[lenalidomide]], flavopiridol, and bone marrow (stem cell) transplantation, are considered.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page6 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Refractory Chronic Lymphocytic Leukemia|author=National Cancer Institute|accessdate=2007-09-04 |format= |work=}}</ref>
Prolymphocytic transformation of CLL requires treatment with CHOP.

===Monoclonal antibodies===
The monoclonal antibody, [[alemtuzumab]] (directed against [[CD52]]), may be used in patients with refractory, bone marrow-based disease.<ref name="Keating">{{cite journal | author=Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR | title=Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study | journal=Blood | year=2002 | pages=3554-61 | volume=99 | issue=10 | id=PMID 11986207}}</ref> Alemtuzumab (Campath) is an anti-CD52 monoclonal antibody; CD52 is on all B & T lymphocytes. Its use carries a RR = 33% with a CR = 2%. Patients with pre-exisiting cytopenias show improvement in bone marrow function due to the lack of stem cell (CD34) toxicity. Its toxicity against T-cells can lead to significant immunosuppression and infectious complications (esp CMV reactivation). Dose modifications are made for drug related cytopenias. Premedications for its administration are necessary and (almost always) the first dose can be characterized by fever, rigors and nausea. It is recommended to give benadryl, tylenol, hydrocortisone as well as Bactrin DS and Famciclovir. If a 17p del is found in a young CLL patient one could consider Alemtuzumab and early transplant. It is otherwise approved for CLL refractory to alkylating agents and fludarabine. Ofatumumab is a novel monoclonal antibody against CD20 but targets a different epitope than Rituximab. It is also different from Ritux in that it is a completely humanized anti-CD20 antibody whereas Ritux is a chimeric. Ofatumumab (HuMax-CD20)appears to work well for patients who have lower CD20 levels on the surface of their lymphocytes. Therefore it should be more effective than Ritux in treating CLL
(Ritux not working as well because of the low CD20 levels). It is an active treatment option for CLL patients refractory to both fludarabine and alemtuzumab.

==Epidemiology==
CLL is a disease of the elderly and is rarely encountered in individuals under the age of 40. Thereafter the disease incidence increases with age. Of note, subclinical "disease" can be identified in up to 7-8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

==References==
{{Reflist|2}}

==External links==

Forums:
*[http://www.ukcllforum.org.uk UK CLL Forum] - The UK's only specific forum for the patients, families, friends and carers of those diagnosed with Chronic Lymphocytic Leukaemia (CLL).
*[http://www.CLLForum.com CLL Forum] - Member supported, moderated, forum-based global community that provides friendly support, information and resources to people living with CLL and their caregivers.
*[http://www.cllsupport.org.uk UK CLL Support Association] - Registered charity that provides UK specific support to patients and caregivers.
Information Resources:
*[http://www.clltopics.org CLL Topics] - Non-profit educational and patient-advocacy organization (excellent resource.)
*[http://cll.ucsd.edu CLL Research Consortium] - NCI funded program project of leading clinician and scientists trying to cure CLL.
*[http://cllcanada.ca CLL Canada] - Repository of CLL research in laymen's terms.

*[http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=3221&cat_id=1209 Leukemia & Lymphoma Society] - General CLL information.
*[http://www.lymphomation.org/type-CLL.htm Lymphomation.org] - Lymphoma website with a CLL resource page.
*[http://www.cancer.gov/cancerinfo/pdq/treatment/CLL/patient/ US National Cancer Institute] - General information about CLL.
Listservs and Groups:
*[http://www.acor.org/index.html ACOR Homepage] - Non-profit ACOR (Association of Cancer Online Resources) mailing list. Sign-up and receive email messages from other members of the mailing list.

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Chronic lymphocytic leukemia

2010-11-11T02:15:36Z

Robert Killeen:

'''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = Chronic_lymphocytic_leukemia.jpg |
Caption = Peripheral blood smear showing CLL cells |
DiseasesDB = 2641 |
ICD10 = {{ICD10|C|91|1|c|81}} |
ICD9 = {{ICD9|204.9}} |
ICDO = 9823/3 |
OMIM = |
MedlinePlus = 000532|
eMedicineSubj = med |
eMedicineTopic = 370 |
MeshID = D015462 |
}}

{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==
'''Chronic lymphocytic leukemia''' (also known as "chronic lymphoid leukemia" or "CLL"), is a type of [[leukemia]], or cancer of the white blood cells ([[lymphocytes]]). CLL affects a particular lymphocyte, the [[B cell]], which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.

CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to a disease called [[small lymphocytic lymphoma]] (SLL), a type of [[non-Hodgkin's lymphoma]] which presents primarily in the [[lymph nodes]]. The [[World Health Organization]] considers CLL and SLL to be "one disease at different stages, not two separate entities".<ref name="pmid10577857">{{cite journal |author=Harris NL, Jaffe ES, Diebold J, ''et al'' |title=World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997 |journal=J. Clin. Oncol. |volume=17 |issue=12 |pages=3835-49 |year=1999 |pmid=10577857 |doi=}}</ref>

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as [[T-cell prolymphocytic leukemia]]s.

[[Acute lymphocytic leukemia]] (ALL) is a disease of children, but CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over age 50, and two-thirds are men. In the United States during 2007, it is estimated there will be 15,340 new cases diagnosed and 4,500 deaths<ref name="NCI-CLL-page1">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page1 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: General Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>, but because of prolonged survival, many more people are living with CLL.

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in [[swollen lymph nodes]], [[splenomegaly|spleen]], and [[hepatomegaly|liver]], and eventually [[anemia]] and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies. Survival varies from 5 years to more than 25 years. It is now possible to diagnose patients with short and long survival more precisely by examining the DNA mutations, and patients with slowly-progressing disease can be reassured and may not need any treatment in their lifetimes.<ref name="pmid15728813">{{cite journal |author=Chiorazzi N, Rai KR, Ferrarini M |title=Chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=352 |issue=8 |pages=804-15 |year=2005 |pmid=15728813 |doi=10.1056/NEJMra041720}}</ref>

==Classification and prognosis==
===Clinical staging===
Staging is done with the Rai staging system and the Binet classification (see details<ref name="NCI-CLL-page2">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page2 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>).

===Gene mutation status===
Recent publications suggest that two<ref name="pmid11733578">{{cite journal |author=Rosenwald A, Alizadeh AA, Widhopf G, ''et al'' |title=Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia |journal=J. Exp. Med. |volume=194 |issue=11 |pages=1639-47 |year=2001 |pmid=11733578 |doi=}}</ref> or three<ref name="pmid12406914">{{cite journal |author=Ghia P, Guida G, Stella S, ''et al'' |title=The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression |journal=Blood |volume=101 |issue=4 |pages=1262-9 |year=2003 |pmid=12406914 |doi=10.1182/blood-2002-06-1801}}</ref> prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region [[heavy chain]] (IgVH) gene mutation status.<ref name="pmid16983131">{{cite journal |author=Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE |title=Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia |journal=Ann. Intern. Med. |volume=145 |issue=6 |pages=435-47 |year=2006 |pmid=16983131 |doi=|url=http://www.annals.org/cgi/content/full/145/6/435}}</ref> High risk patients have an immature cell pattern with few mutations in the DNA in the IgVH antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.

Since assessment of the IgVH antibody DNA changes is difficult to perform, the presence of either [[cluster of differentiation]] [[CD38|38]] ([[CD38]]) or Z-chain–associated protein kinase-70 ([[ZAP-70]]) may be surrogate markers of high risk subtype of CLL.<ref name="pmid16983131"/> Their expression correlates with a more immature cellular state and a more rapid disease course. Unmutated IGVH survive worse than mutated and are associated with aggressive CLL. The ZAP70 (AKA Zeta-Associated Protein) presence on the CLL cell correlates with unmutated immunoglobulin genes and a poor prognosis. Conversely, its absence indicates the presence of mutated genes and a good clinical outcome. Patients positive for ZAP70 have a CLL more aggressive in nature and mor refractory to treatment. They are more likely to evolve to more unfavorable cytogenetic abnormalitites.

===Fluorescence in situ hybridization (FISH)===
In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as [[fluorescent in situ hybridization]] (FISH).<ref name="pmid16983131"/> Compared with fluorescence in-situ hybridization (FISH), conventional metaphase cytogenetics play ONLY a MINOR prognostic role in CLL, so far, due to technical problems resulting from a limited proliferation of CLL cells in-vitro. Therefore conventional cytogenetics may define subgroups with a high risk of progression. FISH can be done (in CLL) on dividing and non-dividing cells. FISH doesn't tell about IgVH mutations nor does it define the presence of trisomy either. FISH is useful as long as there are CLL cells to test; you can't do it in a complete response (CR).The application of FISH to study interphase nuclei gives important prognostic information with B-cell CLL, especially for patients with 11q-, trisomy 12, 13q- and 17q-. PCR has extreme sensitivity as well as being quite specific.
The procedure of FISH involves cell cultures which are prepared after which metaphase and prometaphase chromosomes are fixed to a glass slide. A DNA probe is then hybridized onto the chromosome; the probe is labeled with fluorochrome which can be detected with fluorescent microscopy. FISH can be done on dividing and non-dividing cells. Inversions will be missed as probes detect sequences not precise locations. Small mutations, such as small deletions and insertions, will also be missed. FISH is a cytogenetic technology that looks at 200-500 blood cells (obtained with a bone marrow biopsy). Because of the small size it is not as sensitive as PCR.
PCR amplifies a fragment of DNA. It is at least 2-3 logs more sensitive than cytogenetic technology like FISH. PCR measurement requires a sample blood draw which is less invasive and intense than a bone marrow biopsy (with FISH).
Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
# Deletions of part of the short arm of chromosome 17 (del 17p13) which target the cell cycle regulating protein p53 (a tumore suppressor gene) are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL.
# Deletions of the long arm on chromosome 11 (del 11q22-q23) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%).
# Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis. It has a higher frequency of DNA aneuploidy.
# Deletion of the long arm of chromosome 13 (del 13q14) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients (along with those of normal karyotype)have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting genes.

The presence of 17p- typifies cells that are resistant to fludarabine, alkylators and rituxumab.
11q- portends a decreased RR to fludrabine as well as an early relapse after bone marrow transplant (BMT).
Both the 17p- and the 11q- have a decreased progression-free survival (PFS) and overall survival (OS).

==Symptoms and signs==
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections.

Uncommonly, CLL presents as enlargement of the lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as [[small lymphocytic lymphoma]].

The increase in lymphocytes and precursors in the bone marrow impairs the production of other [[leucocytes]] causing a decrease in such cell types.

A high beta-2-microglobulin level may be seen and is an independent adverse prognostic factor for CR and OS.

==Diagnosis==
CLL is usually first suspected by the presence of a [[lymphocytosis]], an increase in one type of the white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per mm3 (microliter) of blood but can be much higher.

===Pathology===
<div align="left">
<gallery heights="175" widths="175">
Image:CLL.jpg|CLL (more cytoplasmic space)<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
Image:CLL Smudge Cell.jpg|CLL Smudge Cell<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
</gallery>
</div>

===Determining clonality===

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the co-expression of cells surface markers [[cluster of differentiation]] [[CD5 (protein)|5]] ([[CD5 (protein)|CD5]]) and [[cluster of differentiation]] [[CD23|23]] ([[CD23]]). In addition, all the CLL cells within one individual are functionally inert and clonal, that is genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive [[Light_chain#In_humans|antibody light chains]], kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody producing cells resulting in a mixture of both kappa and lambda expressing cells. The lack of the normal distribution of kappa and lambda producing B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell Non-Hodgkin lymphoma).

Clonality is confirmed by the combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by [[flow cytometry]]. The later is easily accomplished on a small amount of blood. A [[flow cytometer]] is an instrument that can examine the marker molecule expression on individual cells in fluids. This is accomplished using antibodies with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules [[cluster of differentiation]] [[CD19|19]] ([[CD19]]) and [[CD20]]), and characteristically express the marker molecules [[CD5 (protein)|CD5]] and [[CD23]]. Morphologically, the cells resemble normal lymphocytes under the microscope, although slightly larger, and are fragile when smeared onto a glass slide giving rise to many broken cells (smudge cells).

===Differential diagnosis===
Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.
* [[B cell prolymphocytic leukemia]] (B PLL), which is a related but more aggressive disorder, has cells with similar phenotype but that are signficantly larger than normal lymphocytes and have a prominent nucleolus suggests a related.
* [[Hairy cell leukemia]] is also a neoplasm of B lymphocytes but differs significantly from CLL by its morphology under the microscope ([[hairy cell leukemia]] cells have delicate, hair-like projections on their surface) and marker molecule expression.

All the B cell malignancies of the blood and [[bone marrow]] can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow and occasionally lymph node cells by a [[pathologist]] with specific training in blood disorders. A sophisticated instrument called a [[flow cytometer]] is necessary for cell marker analysis and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by [[fluorescent in situ hybridization]] (FISH).
CLL is positive for CD5, CD19 & CD23; CLL is the only cell type that coexpresses CD5 & 19. It is negative for CD10 & cyclin D.
CD20 is +/- as is sIg. 90% of B-CLL have bcl-2.
The 2 most noteworthy lymphoproliferative diseases with CD5 positivity are CLL(which is CD23 positive) & mantle zone lymphoma (which is CD23 negative). Other CD5+ groups include peripheral & cutaneous T-cell lymphoma, lymphoblastic lymphoma, and Adult T-cell leukemia/lymphoma.

==Treatment==
While generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. No chemotherapy has clearly prolonged survival in CLL. Instead, the condition is monitored over time.
The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.
CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by [[chemotherapy]], [[radiation therapy]], [[biological therapy]], or [[bone marrow transplantation]]. Symptoms are sometimes treated surgically ([[splenectomy]] removal of enlarged spleen) or by [[radiation therapy]] ("de-bulking" swollen lymph nodes).

Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.<ref name="NCI-CLL-page2"/>

Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.<ref name="pmid8652811">{{cite journal |author=Cheson BD, Bennett JM, Grever M, ''et al'' |title=National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment |journal=Blood |volume=87 |issue=12 |pages=4990-7 |year=1996 |pmid=8652811 |doi=}}</ref>

Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page5 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage I, II, III, and IV Chronic Lymphocytic Leukemia|author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>

CLL (+12) has the capacity for autoimmune cytopenias. Although about 20% of patients have Coombs positivity only about 8% actually develop hemolytic anemia and about 20% have decreased platelets as well. For warm autoimmune hemolytic anemia give steroids initially, using immunoglobulin secondarily. Cyclosporine is used if steroids and IV-IgG fail. One might also consider Alemtuzumab +/- fludarabine or cytoxan with dexamethasone. For refractory AIHA do splenectomy or splenic irradiation.

===Alkylators===
Chlorambucil (CHB) should be considered for older patients (>90 years) with severe comorbidities (eg renal insufficiency) where they're likely to live less than a year regardless of treatment. CHB is associated with a median survival of about 2 years in patients with advanced stage CLL; a higher response rate (RR) may be achieved with more aggressive treatment regimens such as CHOP but without any clear survival advantage. This agent has been replaced by newer agents. Cytoxan, Oncovin, Prednisone (COP) is not superior to CHB alone, either in complete response rate (CR) or prolonged survival. CHOP does improve the RR to stage B patients but, again, with no survival advantage.

Bendamustine (treanda) is used in the treatment of CLL (& indolent NHL) that has progressed within 6 months after treatment with Rituxumab. Administer as 100 mg/m2 / 30" on days 1+2 of a 28 day cycle; up to 6 cycles. Bendamustine is superior to chlorambucil in the treatment of CLL. Bendamustine is also given with Ritux for relapsed CLL with the overall response rate (ORR) dependent on chromosomal subtype; 11p deletion = 92%, trisomy 12 = 100%, 17p deletion = 44%, umutated IgVH = 74%.

===Purine analogues===
Although the purine analogue [[fludarabine]] was shown to give superior response rates than [[chlorambucil]] as primary therapy,<ref name="pmid11114313">{{cite journal |author=Rai KR, Peterson BL, Appelbaum FR, ''et al'' |title=Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=24 |pages=1750-7 |year=2000 |pmid=11114313 |doi=}}</ref><ref name="pmid16856041">{{cite journal |author=Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R |title=Purine antagonists for chronic lymphocytic leukaemia |journal=Cochrane database of systematic reviews (Online) |volume=3 |issue= |pages=CD004270 |year=2006 |pmid=16856041 |doi=10.1002/14651858.CD004270.pub2}}</ref>
there is no evidence that early use of fludarabine improves overall survival. Fludara can actually make CLL-AIHA worse. It is indicated for patients who have refractory and / or relapsed disease refractory to alkylating agents. Adding prednisone to fludarabine does not increase the RR over fludarabine alone. Add prednisone to fludara only in the presence of autoimmune anemia or thrombocytopenia. Note that fludara with steroids increases the likelihood of P. carinii & Listeria infection. Patients who fail to respond to fludarabine after 2-3 courses should not receive additional courses. No further treatment is indicated if a CR has been achieved; otherwise 2 courses are given after the maximal response is achieved, not to exceed one year.

===Combination chemotherapy===

Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL. Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:

* [[fludarabine]] with [[cyclophosphamide]] <ref name="pmid16219797"> {{cite journal |author=Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M, German CLL Study Group. |title=Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia |journal=Blood |year=2006 |volume=107 |pages=885-91.|pmid16219797}} </ref>
* [[fludarabine]] with [[rituximab]]<ref name="pmid12393429">{{cite journal |author=Byrd JC, Peterson BL, Morrison VA, ''et al'' |title=Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) |journal=Blood |volume=101 |issue=1 |pages=6-14 |year=2003 |pmid=12393429 |doi=10.1182/blood-2002-04-1258}}</ref>
* FCR ([[fludarabine]], [[cyclophosphamide]], and [[rituximab]])<ref name="pmid15767648">{{cite journal |author=Keating MJ, O'Brien S, Albitar M, ''et al'' |title=Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia |journal=J. Clin. Oncol. |volume=23 |issue=18 |pages=4079-88 |year=2005 |pmid=15767648 |doi=10.1200/JCO.2005.12.051}}</ref> FCR are well tolerated in previously treated CLL. However most of their toxicity is myelosuppression. FCR had a high CR rate (25%), nodular PR (16%) & PR (32%). Molecular remissions are obtained in 1/3 of patients.
* CHOP ([[cyclophosphamide]], [[doxorubicin]], [[vincristine]] and [[prednisolone]])

===Stem cell transplantion===
Allogeneic [[Stem cell transplantation|bone marrow (stem cell) transplantation]] is rarely used as a first-line treatment for CLL due to its risk. There is increasing interest in the use of reduced intensity allogeneic stem cell transplantation, which offers the prospect of cure for selected patients with a suitable donor.<ref name="Dreger">{{cite journal | author=Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D; Chronic Leukemia Working Party of the EBMT | title=Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning | journal=Leukemia | year=2003 | pages=841-8 | volume=17 | issue=5 | id=PMID 12750695}}</ref>

===Refractory CLL===
"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including [[lenalidomide]], flavopiridol, and bone marrow (stem cell) transplantation, are considered.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page6 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Refractory Chronic Lymphocytic Leukemia|author=National Cancer Institute|accessdate=2007-09-04 |format= |work=}}</ref> The monoclonal antibody, [[alemtuzumab]] (directed against [[CD52]]), may be used in patients with refractory, bone marrow-based disease.<ref name="Keating">{{cite journal | author=Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR | title=Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study | journal=Blood | year=2002 | pages=3554-61 | volume=99 | issue=10 | id=PMID 11986207}}</ref>

==Epidemiology==
CLL is a disease of the elderly and is rarely encountered in individuals under the age of 40. Thereafter the disease incidence increases with age. Of note, subclinical "disease" can be identified in up to 7-8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

==References==
{{Reflist|2}}

==External links==

Forums:
*[http://www.ukcllforum.org.uk UK CLL Forum] - The UK's only specific forum for the patients, families, friends and carers of those diagnosed with Chronic Lymphocytic Leukaemia (CLL).
*[http://www.CLLForum.com CLL Forum] - Member supported, moderated, forum-based global community that provides friendly support, information and resources to people living with CLL and their caregivers.
*[http://www.cllsupport.org.uk UK CLL Support Association] - Registered charity that provides UK specific support to patients and caregivers.
Information Resources:
*[http://www.clltopics.org CLL Topics] - Non-profit educational and patient-advocacy organization (excellent resource.)
*[http://cll.ucsd.edu CLL Research Consortium] - NCI funded program project of leading clinician and scientists trying to cure CLL.
*[http://cllcanada.ca CLL Canada] - Repository of CLL research in laymen's terms.

*[http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=3221&cat_id=1209 Leukemia & Lymphoma Society] - General CLL information.
*[http://www.lymphomation.org/type-CLL.htm Lymphomation.org] - Lymphoma website with a CLL resource page.
*[http://www.cancer.gov/cancerinfo/pdq/treatment/CLL/patient/ US National Cancer Institute] - General information about CLL.
Listservs and Groups:
*[http://www.acor.org/index.html ACOR Homepage] - Non-profit ACOR (Association of Cancer Online Resources) mailing list. Sign-up and receive email messages from other members of the mailing list.

{{Hematology}}
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[[de:Chronische lymphatische Leukämie]]
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Chronic lymphocytic leukemia

2010-10-31T19:46:46Z

Robert Killeen:

'''For patient information click [[{{PAGENAME}} (patient information)|here]]'''
{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = Chronic_lymphocytic_leukemia.jpg |
Caption = Peripheral blood smear showing CLL cells |
DiseasesDB = 2641 |
ICD10 = {{ICD10|C|91|1|c|81}} |
ICD9 = {{ICD9|204.9}} |
ICDO = 9823/3 |
OMIM = |
MedlinePlus = 000532|
eMedicineSubj = med |
eMedicineTopic = 370 |
MeshID = D015462 |
}}

{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==
'''Chronic lymphocytic leukemia''' (also known as "chronic lymphoid leukemia" or "CLL"), is a type of [[leukemia]], or cancer of the white blood cells ([[lymphocytes]]). CLL affects a particular lymphocyte, the [[B cell]], which originates in the bone marrow, develops in the lymph nodes, and normally fights infection. In CLL, the DNA of a B cell is damaged, so that it can't fight infection, but it grows out of control and crowds out the healthy blood cells that can fight infection.

CLL is an abnormal neoplastic proliferation of B cells. The cells accumulate mainly in the bone marrow and blood. CLL is closely related to a disease called [[small lymphocytic lymphoma]] (SLL), a type of [[non-Hodgkin's lymphoma]] which presents primarily in the [[lymph nodes]]. The [[World Health Organization]] considers CLL and SLL to be "one disease at different stages, not two separate entities".<ref name="pmid10577857">{{cite journal |author=Harris NL, Jaffe ES, Diebold J, ''et al'' |title=World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997 |journal=J. Clin. Oncol. |volume=17 |issue=12 |pages=3835-49 |year=1999 |pmid=10577857 |doi=}}</ref>

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, it is now recognized that these so-called T-cell CLLs are in fact a separate disease group and are currently classified as [[T-cell prolymphocytic leukemia]]s.

[[Acute lymphocytic leukemia]] (ALL) is a disease of children, but CLL is a disease of adults. Most (>75%) people newly diagnosed with CLL are over age 50, and two-thirds are men. In the United States during 2007, it is estimated there will be 15,340 new cases diagnosed and 4,500 deaths<ref name="NCI-CLL-page1">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page1 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: General Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>, but because of prolonged survival, many more people are living with CLL.

Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in [[swollen lymph nodes]], [[splenomegaly|spleen]], and [[hepatomegaly|liver]], and eventually [[anemia]] and infections. Early CLL is not treated, and late CLL is treated with chemotherapy and monoclonal antibodies. Survival varies from 5 years to more than 25 years. It is now possible to diagnose patients with short and long survival more precisely by examining the DNA mutations, and patients with slowly-progressing disease can be reassured and may not need any treatment in their lifetimes.<ref name="pmid15728813">{{cite journal |author=Chiorazzi N, Rai KR, Ferrarini M |title=Chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=352 |issue=8 |pages=804-15 |year=2005 |pmid=15728813 |doi=10.1056/NEJMra041720}}</ref>

==Classification and prognosis==
===Clinical staging===
Staging is done with the Rai staging system and the Binet classification (see details<ref name="NCI-CLL-page2">{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page2 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage Information |author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>).

===Gene mutation status===
Recent publications suggest that two<ref name="pmid11733578">{{cite journal |author=Rosenwald A, Alizadeh AA, Widhopf G, ''et al'' |title=Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia |journal=J. Exp. Med. |volume=194 |issue=11 |pages=1639-47 |year=2001 |pmid=11733578 |doi=}}</ref> or three<ref name="pmid12406914">{{cite journal |author=Ghia P, Guida G, Stella S, ''et al'' |title=The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression |journal=Blood |volume=101 |issue=4 |pages=1262-9 |year=2003 |pmid=12406914 |doi=10.1182/blood-2002-06-1801}}</ref> prognostic groups of CLL exist based on the maturational state of the cell. This distinction is based on the maturity of the lymphocytes as discerned by the immunoglobulin variable-region [[heavy chain]] (IgVH) gene mutation status.<ref name="pmid16983131">{{cite journal |author=Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE |title=Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia |journal=Ann. Intern. Med. |volume=145 |issue=6 |pages=435-47 |year=2006 |pmid=16983131 |doi=|url=http://www.annals.org/cgi/content/full/145/6/435}}</ref> High risk patients have an immature cell pattern with few mutations in the DNA in the IgVH antibody gene region whereas low risk patients show considerable mutations of the DNA in the antibody gene region indicating mature lymphocytes.

Since assessment of the IgVH antibody DNA changes is difficult to perform, the presence of either [[cluster of differentiation]] [[CD38|38]] ([[CD38]]) or Z-chain–associated protein kinase-70 ([[ZAP-70]]) may be surrogate markers of high risk subtype of CLL.<ref name="pmid16983131"/> Their expression correlates with a more immature cellular state and a more rapid disease course. Unmutated IGVH survive worse than mutated and are associated with aggressive CLL. The ZAP70 (AKA Zeta-Associated Protein) presence on the CLL cell correlates with unmutated immunoglobulin genes and a poor prognosis. Conversely, its absence indicates the presence of mutated genes and a good clinical outcome. Patients positive for ZAP70 have a CLL more aggressive in nature and mor refractory to treatment. They are more likely to evolve to more unfavorable cytogenetic abnormalitites.

===Fluorescence in situ hybridization (FISH)===
In addition to the maturational state, the prognosis of patients with CLL is dependent on the genetic changes within the neoplastic cell population. These genetic changes can be identified by fluorescent probes to chromosomal parts using a technique referred to as [[fluorescent in situ hybridization]] (FISH).<ref name="pmid16983131"/> Compared with fluorescence in-situ hybridization (FISH), conventional metaphase cytogenetics play ONLY a MINOR prognostic role in CLL, so far, due to technical problems resulting from a limited proliferation of CLL cells in-vitro. Therefore conventional cytogenetics may define subgroups with a high risk of progression. FISH can be done (in CLL) on dividing and non-dividing cells. FISH doesn't tell about IgVH mutations nor does it define the presence of trisomy either. FISH is useful as long as there are CLL cells to test; you can't do it in a complete response (CR).The application of FISH to study interphase nuclei gives important prognostic information with B-cell CLL, especially for patients with 11q-, trisomy 12, 13q- and 17q-. PCR has extreme sensitivity as well as being quite specific.
The procedure of FISH involves cell cultures which are prepared after which metaphase and prometaphase chromosomes are fixed to a glass slide. A DNA probe is then hybridized onto the chromosome; the probe is labeled with fluorochrome which can be detected with fluorescent microscopy. FISH can be done on dividing and non-dividing cells. Inversions will be missed as probes detect sequences not precise locations. Small mutations, such as small deletions and insertions, will also be missed. FISH is a cytogenetic technology that looks at 200-500 blood cells (obtained with a bone marrow biopsy). Because of the small size it is not as sensitive as PCR.
PCR amplifies a fragment of DNA. It is at least 2-3 logs more sensitive than cytogenetic technology like FISH. PCR measurement requires a sample blood draw which is less invasive and intense than a bone marrow biopsy (with FISH).
Four main genetic aberrations are recognized in CLL cells that have a major impact on disease behavior.
# Deletions of part of the short arm of chromosome 17 (del 17p13) which target the cell cycle regulating protein p53 (a tumore suppressor gene) are particularly deleterious. Patients with this abnormality have significantly short interval before they require therapy and a shorter survival. This abnormality is found in 5-10% of patients with CLL.
# Deletions of the long arm on chromosome 11 (del 11q22-q23) are also unfavorable although not to the degree seen with del 17p. The abnormality targets the ATM gene and occurs infrequently in CLL (5-10%).
# Trisomy 12, an additional chromosome 12, is a relatively frequent finding occurring in 20-25% of patients and imparts an intermediate prognosis. It has a higher frequency of DNA aneuploidy.
# Deletion of the long arm of chromosome 13 (del 13q14) is the most common abnormality in CLL with roughly 50% of patients with cells containing this defect. These patients (along with those of normal karyotype)have the best prognosis and most will live many years, even decades, without the need for therapy. The gene targeted by this deletion is a segment that likely produces small inhibitory RNA molecules that affect expression of important death inhibiting genes.

The presence of 17p- typifies cells that are resistant to fludarabine, alkylators and rituxumab.
11q- portends a decreased RR to fludrabine as well as an early relapse after bone marrow transplant (BMT).
Both the 17p- and the 11q- have a decreased progression-free survival (PFS) and overall survival (OS).

==Symptoms and signs==
Most people are diagnosed without symptoms as the result of a routine blood test that returns a high white blood cell count, but as it advances CLL results in swollen lymph nodes, spleen, and liver, and eventually anemia and infections.

Uncommonly, CLL presents as enlargement of the lymph nodes without a high white blood cell count or no evidence of the disease in the blood. This is referred to as [[small lymphocytic lymphoma]].

The increase in lymphocytes and precursors in the bone marrow impairs the production of other [[leucocytes]] causing a decrease in such cell types.

A high beta-2-microglobulin level may be seen and is an independent adverse prognostic factor for CR and OS.

==Diagnosis==
CLL is usually first suspected by the presence of a [[lymphocytosis]], an increase in one type of the white blood cell, on a complete blood count (CBC) test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 4000 cells per mm3 (microliter) of blood but can be much higher.

===Pathology===
<div align="left">
<gallery heights="175" widths="175">
Image:CLL.jpg|CLL (more cytoplasmic space)<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
Image:CLL Smudge Cell.jpg|CLL Smudge Cell<ref>http://picasaweb.google.com/mcmumbi/USMLEIIImages</ref>
</gallery>
</div>

===Determining clonality===

The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the co-expression of cells surface markers [[cluster of differentiation]] [[CD5 (protein)|5]] ([[CD5 (protein)|CD5]]) and [[cluster of differentiation]] [[CD23|23]] ([[CD23]]). In addition, all the CLL cells within one individual are functionally inert and clonal, that is genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive [[Light_chain#In_humans|antibody light chains]], kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody producing cells resulting in a mixture of both kappa and lambda expressing cells. The lack of the normal distribution of kappa and lambda producing B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell Non-Hodgkin lymphoma).

Clonality is confirmed by the combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by [[flow cytometry]]. The later is easily accomplished on a small amount of blood. A [[flow cytometer]] is an instrument that can examine the marker molecule expression on individual cells in fluids. This is accomplished using antibodies with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (express marker molecules [[cluster of differentiation]] [[CD19|19]] ([[CD19]]) and [[CD20]]), and characteristically express the marker molecules [[CD5 (protein)|CD5]] and [[CD23]]. Morphologically, the cells resemble normal lymphocytes under the microscope, although slightly larger, and are fragile when smeared onto a glass slide giving rise to many broken cells (smudge cells).

===Differential diagnosis===
Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.
* [[B cell prolymphocytic leukemia]] (B PLL), which is a related but more aggressive disorder, has cells with similar phenotype but that are signficantly larger than normal lymphocytes and have a prominent nucleolus suggests a related.
* [[Hairy cell leukemia]] is also a neoplasm of B lymphocytes but differs significantly from CLL by its morphology under the microscope ([[hairy cell leukemia]] cells have delicate, hair-like projections on their surface) and marker molecule expression.

All the B cell malignancies of the blood and [[bone marrow]] can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow and occasionally lymph node cells by a [[pathologist]] with specific training in blood disorders. A sophisticated instrument called a [[flow cytometer]] is necessary for cell marker analysis and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by [[fluorescent in situ hybridization]] (FISH).

==Treatment==
While generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years - in some cases for decades. Because of its slow onset, early-stage CLL is generally not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time.

The decision to start CLL treatment is taken when the patient's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may affect the patient's quality of life.

CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by [[chemotherapy]], [[radiation therapy]], [[biological therapy]], or [[bone marrow transplantation]]. Symptoms are sometimes treated surgically ([[splenectomy]] removal of enlarged spleen) or by [[radiation therapy]] ("de-bulking" swollen lymph nodes).

Clinical "staging systems" such as the Rai 4-stage system and the Binet classification can help to determine when and how to treat the patient.<ref name="NCI-CLL-page2"/>

Determining when to start treatment and by what means is often difficult; studies have shown there is no survival advantage to treating the disease too early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.<ref name="pmid8652811">{{cite journal |author=Cheson BD, Bennett JM, Grever M, ''et al'' |title=National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment |journal=Blood |volume=87 |issue=12 |pages=4990-7 |year=1996 |pmid=8652811 |doi=}}</ref>

Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. There are dozens of agents used for CLL therapy, and there is considerable research activity studying them individually or in combination with each other.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page5 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Stage I, II, III, and IV Chronic Lymphocytic Leukemia|author=National Cancer Institute |accessdate=2007-09-04 |format= |work=}}</ref>

===Purine analogues===
Although the purine analogue [[fludarabine]] was shown to give superior response rates than [[chlorambucil]] as primary therapy,<ref name="pmid11114313">{{cite journal |author=Rai KR, Peterson BL, Appelbaum FR, ''et al'' |title=Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=24 |pages=1750-7 |year=2000 |pmid=11114313 |doi=}}</ref><ref name="pmid16856041">{{cite journal |author=Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R |title=Purine antagonists for chronic lymphocytic leukaemia |journal=Cochrane database of systematic reviews (Online) |volume=3 |issue= |pages=CD004270 |year=2006 |pmid=16856041 |doi=10.1002/14651858.CD004270.pub2}}</ref>
there is no evidence that early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.

===Monoclonal antibodies===
[[Monoclonal antibodies]] are [[alemtuzumab]] (directed against [[CD52]]) and [[rituximab]] (directed against [[CD20]]).

===Combination chemotherapy===

Combination chemotherapy options are effective in both newly-diagnosed and relapsed CLL. Recently, randomized trials have shown that combinations of purine analogues (fludarabine) with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:

* [[fludarabine]] with [[cyclophosphamide]] <ref name="pmid16219797"> {{cite journal |author=Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M, German CLL Study Group. |title=Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia |journal=Blood |year=2006 |volume=107 |pages=885-91.|pmid16219797}} </ref>
* [[fludarabine]] with [[rituximab]]<ref name="pmid12393429">{{cite journal |author=Byrd JC, Peterson BL, Morrison VA, ''et al'' |title=Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712) |journal=Blood |volume=101 |issue=1 |pages=6-14 |year=2003 |pmid=12393429 |doi=10.1182/blood-2002-04-1258}}</ref>
* FCR ([[fludarabine]], [[cyclophosphamide]], and [[rituximab]])<ref name="pmid15767648">{{cite journal |author=Keating MJ, O'Brien S, Albitar M, ''et al'' |title=Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia |journal=J. Clin. Oncol. |volume=23 |issue=18 |pages=4079-88 |year=2005 |pmid=15767648 |doi=10.1200/JCO.2005.12.051}}</ref>
* CHOP ([[cyclophosphamide]], [[doxorubicin]], [[vincristine]] and [[prednisolone]])

===Stem cell transplantion===
Allogeneic [[Stem cell transplantation|bone marrow (stem cell) transplantation]] is rarely used as a first-line treatment for CLL due to its risk. There is increasing interest in the use of reduced intensity allogeneic stem cell transplantation, which offers the prospect of cure for selected patients with a suitable donor.<ref name="Dreger">{{cite journal | author=Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D; Chronic Leukemia Working Party of the EBMT | title=Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning | journal=Leukemia | year=2003 | pages=841-8 | volume=17 | issue=5 | id=PMID 12750695}}</ref>

===Refractory CLL===
"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case more aggressive therapies, including [[lenalidomide]], flavopiridol, and bone marrow (stem cell) transplantation, are considered.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional/page6 |title=Chronic Lymphocytic Leukemia (PDQ®) Treatment: Refractory Chronic Lymphocytic Leukemia|author=National Cancer Institute|accessdate=2007-09-04 |format= |work=}}</ref> The monoclonal antibody, [[alemtuzumab]] (directed against [[CD52]]), may be used in patients with refractory, bone marrow-based disease.<ref name="Keating">{{cite journal | author=Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR | title=Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study | journal=Blood | year=2002 | pages=3554-61 | volume=99 | issue=10 | id=PMID 11986207}}</ref>

==Epidemiology==
CLL is a disease of the elderly and is rarely encountered in individuals under the age of 40. Thereafter the disease incidence increases with age. Of note, subclinical "disease" can be identified in up to 7-8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.

==References==
{{Reflist|2}}

==External links==

Forums:
*[http://www.ukcllforum.org.uk UK CLL Forum] - The UK's only specific forum for the patients, families, friends and carers of those diagnosed with Chronic Lymphocytic Leukaemia (CLL).
*[http://www.CLLForum.com CLL Forum] - Member supported, moderated, forum-based global community that provides friendly support, information and resources to people living with CLL and their caregivers.
*[http://www.cllsupport.org.uk UK CLL Support Association] - Registered charity that provides UK specific support to patients and caregivers.
Information Resources:
*[http://www.clltopics.org CLL Topics] - Non-profit educational and patient-advocacy organization (excellent resource.)
*[http://cll.ucsd.edu CLL Research Consortium] - NCI funded program project of leading clinician and scientists trying to cure CLL.
*[http://cllcanada.ca CLL Canada] - Repository of CLL research in laymen's terms.

*[http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=3221&cat_id=1209 Leukemia & Lymphoma Society] - General CLL information.
*[http://www.lymphomation.org/type-CLL.htm Lymphomation.org] - Lymphoma website with a CLL resource page.
*[http://www.cancer.gov/cancerinfo/pdq/treatment/CLL/patient/ US National Cancer Institute] - General information about CLL.
Listservs and Groups:
*[http://www.acor.org/index.html ACOR Homepage] - Non-profit ACOR (Association of Cancer Online Resources) mailing list. Sign-up and receive email messages from other members of the mailing list.

{{Hematology}}
{{Hematological malignancy histology}}
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[[Category:Oncology]]

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[[de:Chronische lymphatische Leukämie]]
[[es:Leucemia linfoide crónica]]
[[fr:Leucémie lymphoïde chronique]]
[[ms:Leukemia limfosit kronik]]
[[nl:Chronische lymfatische leukemie]]
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[[pt:Leucemia linfóide crônica]]
[[ru:Хронический лимфолейкоз]]
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Idiopathic thrombocytopenic purpura

2010-10-27T01:57:27Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 6673 |
ICD10 = {{ICD10|D|69|3|d|65}} |
ICD9 = {{ICD9|287.31}} |
ICDO = |
OMIM = 188030 |
MedlinePlus = |
eMedicineSubj = emerg |
eMedicineTopic = 282 |
MeshID = D016553 |
}}
{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==

'''Idiopathic thrombocytopenic purpura''' (ITP) is the condition of having a low [[platelet]] count ([[thrombocytopenia]]) of no known cause ([[idiopathic]]). As most causes appear to be related to [[antibody|antibodies]] against platelets, it is also known as '''immune thrombocytopenic purpura'''. Although most cases are [[asymptomatic]], very low platelet counts can lead to a [[bleeding diathesis]] and [[purpura]].

==Synonyms==
ITP knows many synonyms, but idiopathic or immunological thrombocytopenic purpura are the most common names. There's also an [[eponym]], [[Paul Gottlieb Werlhof|Werlhof]]'s disease,<ref>{{WhoNamedIt|synd|3349}}</ref> but this is used infrequently.

Other synonyms include: essential thrombocytopenia, haemogenia, haemogenic syndrome, haemorrhagic purpura, idiopathic thrombopenic purpura, morbus haemorrhagicus maculosus, morbus maculosis haemorrhagicus, morbus maculosus werlhofii, peliosis werlhofi, primary splenic thrombocytopenia, primary thrombocytopenia, primary thrombocytopenic purpura, purpura haemorrhagica, purpura thrombocytopenica, purpura werlhofii, splenic thrombocytopenic purpura, thrombocytolytic purpura.

==Signs and symptoms==
The incidence of ITP is 50–100 new cases per million per year, with children accounting for half of that amount.

More than 70% of the cases in children end up in remission within 6 months whether treated or not.<ref name="pmid15494875">{{cite journal |author=Watts RG |title=Idiopathic thrombocytopenic purpura: a 10-year natural history study at the children's hospital of alabama |journal=Clinical pediatrics |volume=43 |issue=8 |pages=691-702 |year=2004 |pmid=15494875 |doi=}}</ref><ref name="pmid17460024">{{cite journal |author=Treutiger I, Rajantie J, Zeller B, Henter JI, Elinder G, Rosthøj S |title=Does treatment of newly diagnosed idiopathic thrombocytopenic purpura reduce morbidity? |journal=Arch. Dis. Child. |volume=92 |issue=8 |pages=704-7 |year=2007 |pmid=17460024 |doi=10.1136/adc.2006.098442}}</ref><ref name="pmid17352309">{{cite journal |author=Ou CY, Hsieh KS, Chiou YH, Chang YH, Ger LP |title=A comparative study of initial use of intravenous immunoglobulin and prednisolone treatments in childhood idiopathic thrombocytopenic purpur |journal=Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za zhi |volume=47 |issue=5 |pages=226-31 |year=2006 |pmid=17352309 |doi=}}</ref> Moreover, a third of the remaining chronic cases remitted during the follow-up observation, and another third ended up with only mild thrombocytopenia (>50,000 platelets per μL).<ref name="pmid15494875"/> ITP is usually chronic in adults<ref name="pmid11919310">{{cite journal |author=Cines DB, Blanchette VS |title=Immune thrombocytopenic purpura |journal=N. Engl. J. Med. |volume=346 |issue=13 |pages=995-1008 |year=2002 |pmid=11919310 |doi=10.1056/NEJMra010501}}</ref> and the probability of durable remission is 20–40%.<ref name="pmid17122451">{{cite journal |author=Stevens W, Koene H, Zwaginga JJ, Vreugdenhil G |title=Chronic idiopathic thrombocytopenic purpura: present strategy, guidelines and new insights |journal=The Netherlands journal of medicine |volume=64 |issue=10 |pages=356-63 |year=2006 |pmid=17122451 |doi=}}</ref> The male:female ratio in the adult group is 1:1.2–1.7 (for children it is 1:1) and the median age of adults at the diagnosis is 56–60.<ref name="pmid15941913">{{cite journal |author=Cines DB, Bussel JB |title=How I treat idiopathic thrombocytopenic purpura (ITP) |journal=Blood |volume=106 |issue=7 |pages=2244-51 |year=2005 |pmid=15941913 |doi=10.1182/blood-2004-12-4598}}</ref> Usually, ITP patients suffer from [[bruising]]; [[petechia]]e, [[nosebleed]]s and bleeding [[gums]] may occur if the platelet count is below 20,000,<ref name="pmid15660520">{{cite journal |author=Cines DB, McMillan R |title=Management of adult idiopathic thrombocytopenic purpura |journal=Annu. Rev. Med. |volume=56 |issue= |pages=425-42 |year=2005 |pmid=15660520 |doi=10.1146/annurev.med.56.082103.104644}}</ref> compared to a normal range of 150,000–400,000 per mm3.[[Subarachnoid hemorrhage|Subarachnoid]], [[intracerebral hemorrhage]] or other internal bleeding are very serious possible complications of this disease. Fortunately, these are unlikely in patients with the platelets count above 20,000.

Evan's syndrome can occur in ~1% of cases and is manifest by an autoimmune (Coombs +)hemolytic anemia with ITP.
The bone marrow biopsy in ITP can show increased (thought not always) megakaryocytes, bizarre giant platelets and platelet fragments. (Large platelets are often seen in the peripheral blood smear though this can be seen in other diseases.) When the spleen is removed it may show increased lymphatic nodularity. Platelet-associated antibody (IgG), which was the standard test of past years, is not now considered mandatory to diagnose ITP. Test for platelet antibody are not helpful as both their sensitivity and specificity are limited.

==Pathogenesis==
In many cases, the cause is not actually [[idiopathic]] but [[autoimmune]],<ref>{{cite journal |author=Coopamah M, Garvey M, Freedman J, Semple J |title=Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update |journal=Transfus Med Rev |volume=17 |issue=1 |pages=69–80 |year=2003 |pmid=12522773}}</ref> with [[antibodies]] against platelets being detected in approximately 60% of patients. Most often these antibodies are against platelet membrane [[glycoprotein]]s IIb-IIIa or Ib-IX, and are of the [[IgG]] type. The famous [[Harrington–Hollingsworth Experiment]] established the immune [[pathogenesis]] of ITP.<ref name="pmid18046034">{{cite journal |author=Schwartz RS |title=Immune thrombocytopenic purpura--from agony to agonist |journal=N. Engl. J. Med. |volume=357 |issue=22 |pages=2299–301 |year=2007 |pmid=18046034 |doi=10.1056/NEJMe0707126}}</ref>

The cause of ITP is thought to be related to chronic infections such as HIV, hepatitis C and H. Pylori. The mechanism involved is thought to be MOLECULAR MIMICRY, that is, antibody is formed against the infection and this cross-reacts with platelets. Autoantibodies in ITP react with platelet IIb/IIIa glycoprotein, less commonly with GPIb/IX. Lymphocytes in the spleen make the antiplatelet antibody; this is why splenectomy works so well. There is a correlation between a platelet's short survival and high turnover rate and the subsequent excellent response to splenectomy.

The antibodies also appear to damage megakaryocytes, preventing them from releasing platelets. Autoantibody-mediated phagocytosis of platelets has long been thought to be the primary mechanism of the disease. Platelet kinetic studies show that platelet production is normal or reduced rather than increased in about two thirds of ITP patients. Also, autoantibodies from patients with ITP inhibit megakaryocyte growth in vitro. IgG from ITP-plasma inhibits megakaryocyte production.
Ultrastructural studies of the bone marrow in ITP show increased signs of megakaryocyte apoptosis and reduced platelet shedding.

ITP has a strong association with immune thyroid disease.

Recent evidence suggests that the stimulus for autoantibody production in ITP is due to abnormal [[T helper cell]]s reacting with platelet antigens on the surface of antigen presenting cells.<ref>{{cite journal |author=Semple JW, Freedman J |title=Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia |journal=Blood |volume=78 |issue=10 |pages=2619-25 |year=1991 |pmid=1840468 |doi=}}</ref> This important finding suggests that therapies directed towards T cells may be effective in treating ITP.

==Diagnosis==
The diagnosis of ITP is a diagnosis of exclusion. First, one has to make sure that there are no other blood abnormalities except for low platelet count and no physical signs except for signs of bleeding. Then, the secondary causes (usually 5-10% of suspected ITP cases) should be excluded. Secondary causes could be [[leukemia]], medications (e.g. [[quinine]], [[heparin]]), [[lupus erythematosus]], [[cirrhosis]], [[HIV]], [[hepatitis]] C, congenital causes, [[antiphospholipid syndrome]], [[von Willebrand factor]] deficiency and others.<ref name="pmid15941913"/><ref name="pmid15660520"/>

Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead a clinician to investigate other possible causes for the thrombocytopenia.

Bleeding time is prolonged in ITP patients; however, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines<ref name="pmid9036806">{{cite journal |author= |title=Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology ITP Practice Guideline Panel |journal=Ann. Intern. Med. |volume=126 |issue=4 |pages=319-26 |year=1997 |pmid=9036806 |doi=}}</ref> as useless. For example the [[BMJ]] review of the basics of hematology states: "The bleeding time may or may not be prolonged in congenital or acquired platelet dysfunction, and therefore a normal bleeding time does not exclude these conditions."<ref name="pmid9081003">{{cite journal |author=Liesner RJ, Machin SJ |title=ABC of clinical haematology. Platelet disorders |journal=BMJ |volume=314 |issue=7083 |pages=809-12 |year=1997 |pmid=9081003 |doi=}}</ref>

A [[bone marrow examination]] may be performed on patients over the age of 60 and people who do not respond to treatment, or when the diagnosis is in doubt.<ref name="pmid15941913"/> The blood analysis for the antiplatelet antibodies is a matter of clinician's preference, as there is a disagreement whether the 80% specificity of this test is sufficient.<ref name="pmid15941913"/> In conditions associated with bone marrow failure (aplastic anemia) thrombopoietin (TPO)levels are high whereas in ITP thrombopoietin levels are low. Thus TPO could distinguish between decreased platelets due to bone marrow failure or increased due to their destruction. The bone marrow in ITP contains normal or high numbers of megakaryocytes but they may be small or immature (& may have been damaged by antibodies).

The ITP in AIDS has a thrombocytopenia that is multifactorial involving both TPO and platelet problems. Mechanisms may involve portal hypertension that leads to splenomegaly causing platelet sequestration. Hepatits C (HCV) causes decreased TPO production leading to decreased platelet production. Steroids may be helpful but, with their taper, the count usually decreases again. Intravenous immunoglobulin's effect is transient. For ITP-HIV the primary treatment should be directed at HIV suppression with HAART. HIV patients whose platelet count fails to increase to > 50,000 with HAART can be treated with steroids. Splenectomy is safe and effective in ~80% of patients with refractory HIV-related thrombocytopenia and treated with interferon (IFN) may be effective in refractory cases of patients coinfected with HCV. A decrease in platelets in HIV can arise secondary to both HCV and hepatitis B (HBV).

Pregnant patients with ITP and platelet counts < 30,000 can be treated with intravenous immunoglobulin (IV-IgG) or steroids at the lowest dose possible to avoid hypertension, eclampsia and adrenal suppression of the fetus. ~10-30% of pregnant females with ITP have an infant with platelets <50,000, however, intracranial hemorrhage is rare. For these females administer prednisone during the last month of pregnancy to decrease the likelihood of thrombocytopenia in the fetus.
Mothers with ITP who have previously given birth to infants without thrombocytopenia tend not to be thrombocytopenic. The maternal platelet count doesn't correlate with fetal and females with a prior history of ITP with ITP in remission (eg after splenectomy) may still deliver severely thrombocytopenic infants. This likely occurs because asplenic patients in clinical remission may not necessarily be in immunologic remission and circulating platelet-reactive IgG may still be present in their plasma.

==Treatment==

Mechanism-based Approach to Treatment;
1) Inhibit phagocyte-mediated clearance of antibody-coated platelets; Steroids; Splenectomy; Anti-D; IV-IgG
2) Decreased autoantibody production; Rituximab; Steroids; Azathioprine & other immunosuppressants (eg cytoxan, cyclosporine, etc)
3) Impair T & B cell interactions.; Steroids; Rituximab
4) Enhance platelet production.; Thrombopoietic agents; IL-11.

===Observation===
Most children with ITP will recover even without specific treatment. Among adults ITP is typically a chronic disease. It is insidious in onset and, in some patients, refractory to treatment. 90% of childhood ITP cases are an acute, self-limited disease, developing several weeks after a viral illness, lasting for 4-6 weeks, then spontaneously remitting. The bleeding risk is low and treatment is reserved only for the most severely affected patients. Because spontaneous recovery is expected in children wit ITP some pediatric hematologists recommend supportive care only, no drugs. In less than 20% of children thrombocytopenia may persist for >6-12 months and even many of these kids can experience a spontaneous remission.

===Steroids/IVIgG===
[[Platelet count]] below 20,000 is an indication for treatment; the patients with 20,000–50,000 platelets/μL are considered on a case by case basis, and there is generally no need to treat the patients with above 50,000 platelets/μL.<ref name="pmid15941913"/> Hospitalization is recommended in the cases of significant internal or mucocutaneous bleeding. The treatment begins with intravenous steroids (methylprednisolone or prednisone), [[intravenous immunoglobulin]] (IVIg) or their combination and sometimes platelet infusions in order to raise the count quickly. After the platelet count stabilized and in the less severe cases oral prednisone (1–2 mg/kg) is used. Most cases respond during the first week of treatment (RR ~70%). After several weeks of prednisone therapy, the dose is gradually reduced. However, 60–90% of patients relapse after the dose decreased below 0.25 mg/kg and stopped.<ref name="pmid15941913"/><ref name="pmid17122451"/> Pulsed high-dose dexamethasone shows (in untreated patients) a high RR of ~90% with a long-term RR of ~80% when several cycles of treatment are given. However long term high dose steroids have a myriad of toxicities and should be avoided if possible.

===Splenectomy===
Splenectomy offers a 2nd line treatment for those who fail steroids. The criteria for surgery are severe thrombocytopenia (<10,000), high risk of bleeding or the requirement of frequent steroids/IVIgG/anti-D treatment to maintain an adequate platelet count. Of the ~15% of children with persistent thrombocytopenia bleeding symptoms are uncommon and splenectomy is rarely required. However splenectomy is an effective treatment option for children with severe / symptomatic thrombocytopenia with a CR of ~75%. Because of the risk for overwhelming sepsis after splenectomy it should be deferred until after 5 years of age. Remember to give immunizations before splenectomy and perioperative antibiotics. Response to IV-IgG often predicts a response to splenectomy (increasing the platelet count to >50,000 with IgG means a >90% RR to splenectomy).

===Anti-D===
A relatively new strategy is treatment with [[Rho(D) Immune Globulin|anti-D]], an agent also used in mothers who have been sensitized to [[rhesus]] antigen by a Rh+ baby, but the patient must be Rh+.
IV anti-D (WinRhoSD) can also increase the platelet count especially at a higher dose of 75 mcg / kg. IV anti-D is effective in patients who are Rh-positive and non-splenectomized with a RR equal to 70%. Its toxicities include mild hemolysis, fever, chills, headache, nausea and vomiting.

===Steroid-sparing agents===
Immunosuppresants like [[mycophenolic acid|mycophenolate mofetil]] and [[azathioprine]] are becoming more popular for their effectiveness. [[Rituximab]] has also been used successfully for some patients. <ref>Braendstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB, Andersen I, Schmidt K, Andersen TM, Peterslund NA, Birgens HS, Plesner T, Pedersen BB, Hasselbalch HC. ''Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura.'' Am J Hematol 2005;78:275-80. PMID 15795920.</ref><ref>
Patel V, Mihatov N, Cooper N, Stasi R,
Cunningham-Rundles S, Bussel JB,''Long-term responses seen with rituximab in patients with ITP'', Community Oncology Vol. 4 No. 2, February 2007:107 [http://www.communityoncology.net/journal/articles/0402107.pdf PDF]</ref> Rituximab is used in refractory ITP with success; circulating B-cells become undetectable after a single dose of Rituximab but recover after 3-6 months. Rituximab can be detected in the serum of patients 3-6 months after treatment. The duration of Rituximab correlates with the stability of hte platelet response. However, although the short-term CR = 46% the long-term CR is only 18%. The typical schedule is 375 mg / m2 qwk x4 wks. Rituximab (375 mg / m2 d7, 14, 21, 28) / Dexamethasone was compared to Dexamethasone alone (40 mg QD, d1 through 4, given in qmonthly cycles. Initial and sustained response rates were better with the combination therapy (reference; Zaja R et al ASH 2008).

Extreme cases (very rare, especially rare in children) may require [[vincristine]], a [[chemotherapy]] agent, to stop the immune system from destroying platelets. For the most part this and other agents such as cytoxan, cyclosporine and danazol have fallen into disuse.

[[Intravenous immunoglobulin]], while sometimes effective, is expensive and the improvement is temporary (generally lasting less than a month). However, in the case of a pre-splenectomy ITP patient with dangerously low platelet counts, and a poor response to other treatments, IVIgG treatment can increase platelet counts, making the splenectomy operation less dangerous. It is also commonly used as a long-term (though monthly) treatment. The administration of IV-IgG is safe for maternal and fetal platelet counts during pregnancy, delivery and in the neonatal period.
IV-IgG is administered at 400-1000 mg/kg/day over 1 to 5 days and gives a better RR than prednisone. The duration of action is only 2 to 4 weeks. Its toxicities are nausea, headache, chills and occasional vascular events (eg MI, CVA) in older patients. The possible mechanmism of action is a transient impairment of the reticulendothelial clearance or macrophage blockade, inhibition of complement binding to platelets and interference of immune complexes binding to platelets. IV-IgG and WinRho essentially are the same type of treatment.

===Splenic Radiation===
Splenic radiation (RT) is usually given for steroid-resistant ITP. One to six weeks of 75-1370 cGy with or without concomittant post-RT steroids. Patients can respond for >1 year. It is a safe alternative for patients too old for splenectomy.

===Platelet transfusion===
Platelet transfusion is not normally recommended and is usually unsuccessful in raising a patient's platelet count. This is because the underlying autoimmune mechanism that destroyed the patient's platelets to begin with will also destroy donor platelets. An exception to this rule is when a patient is bleeding profusely, when transfusion of platelets can quickly form a platelet plug to stop bleeding, a life-threatening hemorrhage. Intravenous immunoglobulin administration, with the platelet transfusion, may improve their survival.

===Experimental/novel agents===
*AMG 531 (Romiplostum; Nplate) is an experimental treatment for stimulating platelet production. It is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody), a TPO peptide mimetic. Initial clinical trials show it to be effective in chronic ITP.<ref>{{cite journal |author=Bussel JB, Kuter DJ, George JN, ''et al'' |title=AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP |journal=N. Engl. J. Med. |volume=355 |issue=16 |pages=1672–81 |year=2006 |pmid=17050891 |doi=10.1056/NEJMoa054626}}</ref>

*The novel agent [[eltrombopag]] (AKA Promacta) has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.<ref>{{cite journal|author=Bussel JB, Cheng G, Saleh MN, ''et al'' |year=2007|title=Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura|journal=N. Engl. J. Med. |volume=357|pages=2237-2247|id=PMID 18046028}}</ref> It is indicated for the treatment of thrombocytopenia in patients with chronic ITP refractory to steroids, immunoglobulins or splenectomy. It is NOT indicated for the treatment of thrombocytopenia due to any cause other than ITP (eg NOT MDS). It is a thrombopoietin receptor agonist. It is of note that UGT type enzymes (eg UGT1A1 / UDP-glucoronosyltransferase) are inhibited by Promacta. UGT1A1 polymorphisms, under exposure from Promacta, have a decrease in glucoronidation which means to increased susceptibility to toxicity from some chemotherapy agents such as Irinotecan, for example. Promacta has a rapid onset of action and neither the presence of a spleen nor coadministration of steroids affects its efficacy. Greater than 70% of patients treated had an increase of the platelet count to greater than or equal to 50,000 after 6 weeks. Promacta should ONLY be given to patients with decreased platelets that have an increased risk of bleeding. It should NOT be given to simply normalize the counts. The goal is to increase the platelet count to greater than 50,000. The usual dose of Promacta is 50 mg; given 25 mg for asian patients or those with hepatic impairment. It must be given on an empty stomach and not with multivitamins (containing cations). Decrease the dose to 25 mg if the platelet count exceeds 200,000; increase the dose to 75 mg if the platelet count decreases to less than 50,000. If the count exceeds 400,000 discontinue the medication; if the count then decreases to less than 150,000 restart the drug at 25 mg QD. Monitor the CBC weekly and the liver function studies q2 weeks.
Toxicities.
1) Hepatotoxicity is manifest as an increase in the SGOT / SGPT to 3-4xnormal but no liver failure has been reported. Rarely does the bilirubin increase. It is recommended to discontinue the medication just the same.
2) Promacta can cause the development and progression of reticulin fiber deposition in the bone marrow. Also excessive Promacta will cause thrombotic or thromboembolic problems.
3) Cataracts.
4) Approximately 5% of patients on Promacta will have a "rebound thrombocytopenia" on discontinuation of the medication. This thrombocytpenia is usually worse that that which was treated initially and it occurs very quickly. This can lead to bleeding especially if the patient is on anticoagulants or antiplatelet agents. Patients must be monitored with qwk CBC / platelet checks for at least 4 weeks after the discontinuation of Promacta.
5) Promacta may increase the risk of progression of underlying MDS or hematologic malignancies. There are thrombopoietin receptors on malignant cells of hematologic malignancies and they can POTENTIALLY be stimulated by Promacta.

*[[Dapsone]] (also called Diphenylsulfone, DDS, or Avlosulfon) is an anti-infective sulfone drug. In recent years Dapsone has also proved helpful in treating lupus, rheumatoid arthritis and as a second-line treatment for ITP. The exact mechanism by which Dapsone assists in ITP is unclear. However, limited studies report successful increases in platelet counts of around 40–50% of patients taking the drug. <ref name="pmid9163598">{{cite journal |author=Godeau B, Durand JM, Roudot-Thoraval F, ''et al'' |title=Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases |journal=Br. J. Haematol. |volume=97 |issue=2 |pages=336–9 |year=1997 |pmid=9163598 |doi=}}</ref><ref>http://www.itppeople.com/dapsone.htm</ref>

* TPO is normally produced at a steady rate in the liver. TPO improves the platelet production rate in the bone marrow. Patients can form antibodies against recombinant TPO (rHuTPO) (ref Li et al Blood 2001;98:3241). Pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) has activity but, like rHuTPO, antibody formation has prohibited its usefullness.

===H. pylori eradication===
Researchers in Japan (including Ryugo Sato, Oita University) and Italy (including Massimo Franchini, University of Verona) have found a possible connection between [[Helicobacter Pylori|H. Pylori]] ([[Helicobacter Pylori]]) infection and ITP. Some patients given antibiotic treatment to eradicate the bacterial infection have had their platelet count increase dramatically.

==References==
{{Reflist|2}}

==External links==
* {{cite web | url = http://www.itpsupport.org.uk/childhooditp.htm | title = Childhood ITP | accessdate = 2007-02-14 | publisher = ITP Support Association}}
* {{cite web | url = http://www.itppeople.com/warnings.htm | title = Drug Induced Thrombocytopenia | accessdate = 2007-02-14 | publisher = Platelet Disorder Support Association}}

{{Hematology}}
{{SIB}}

[[Category:Blood disorders]]
[[Category:Hematology]]

[[bn:স্বয়ম্ভূত অণুচক্রিকাস্বল্পতাজনিত পারপ্যুরা]]
[[da:ITP]]
[[de:Idiopathische thrombozytopenische Purpura]]
[[it:Porpora trombocitopenica idiopatica]]
[[he:CITP]]
[[ja:特発性血小板減少性紫斑病]]
[[pl:Małopłytkowość samoistna]]
[[pt:Púrpura trombocitopênica idiopática]]

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Idiopathic thrombocytopenic purpura

2010-10-23T23:50:31Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 6673 |
ICD10 = {{ICD10|D|69|3|d|65}} |
ICD9 = {{ICD9|287.31}} |
ICDO = |
OMIM = 188030 |
MedlinePlus = |
eMedicineSubj = emerg |
eMedicineTopic = 282 |
MeshID = D016553 |
}}
{{SI}}
{{CMG}}

{{Editor Help}}

==Overview==

'''Idiopathic thrombocytopenic purpura''' (ITP) is the condition of having a low [[platelet]] count ([[thrombocytopenia]]) of no known cause ([[idiopathic]]). As most causes appear to be related to [[antibody|antibodies]] against platelets, it is also known as '''immune thrombocytopenic purpura'''. Although most cases are [[asymptomatic]], very low platelet counts can lead to a [[bleeding diathesis]] and [[purpura]].

==Synonyms==
ITP knows many synonyms, but idiopathic or immunological thrombocytopenic purpura are the most common names. There's also an [[eponym]], [[Paul Gottlieb Werlhof|Werlhof]]'s disease,<ref>{{WhoNamedIt|synd|3349}}</ref> but this is used infrequently.

Other synonyms include: essential thrombocytopenia, haemogenia, haemogenic syndrome, haemorrhagic purpura, idiopathic thrombopenic purpura, morbus haemorrhagicus maculosus, morbus maculosis haemorrhagicus, morbus maculosus werlhofii, peliosis werlhofi, primary splenic thrombocytopenia, primary thrombocytopenia, primary thrombocytopenic purpura, purpura haemorrhagica, purpura thrombocytopenica, purpura werlhofii, splenic thrombocytopenic purpura, thrombocytolytic purpura.

==Signs and symptoms==
The incidence of ITP is 50–100 new cases per million per year, with children accounting for half of that amount.

More than 70% of the cases in children end up in remission within 6 months whether treated or not.<ref name="pmid15494875">{{cite journal |author=Watts RG |title=Idiopathic thrombocytopenic purpura: a 10-year natural history study at the children's hospital of alabama |journal=Clinical pediatrics |volume=43 |issue=8 |pages=691-702 |year=2004 |pmid=15494875 |doi=}}</ref><ref name="pmid17460024">{{cite journal |author=Treutiger I, Rajantie J, Zeller B, Henter JI, Elinder G, Rosthøj S |title=Does treatment of newly diagnosed idiopathic thrombocytopenic purpura reduce morbidity? |journal=Arch. Dis. Child. |volume=92 |issue=8 |pages=704-7 |year=2007 |pmid=17460024 |doi=10.1136/adc.2006.098442}}</ref><ref name="pmid17352309">{{cite journal |author=Ou CY, Hsieh KS, Chiou YH, Chang YH, Ger LP |title=A comparative study of initial use of intravenous immunoglobulin and prednisolone treatments in childhood idiopathic thrombocytopenic purpur |journal=Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za zhi |volume=47 |issue=5 |pages=226-31 |year=2006 |pmid=17352309 |doi=}}</ref> Moreover, a third of the remaining chronic cases remitted during the follow-up observation, and another third ended up with only mild thrombocytopenia (>50,000 platelets per μL).<ref name="pmid15494875"/> ITP is usually chronic in adults<ref name="pmid11919310">{{cite journal |author=Cines DB, Blanchette VS |title=Immune thrombocytopenic purpura |journal=N. Engl. J. Med. |volume=346 |issue=13 |pages=995-1008 |year=2002 |pmid=11919310 |doi=10.1056/NEJMra010501}}</ref> and the probability of durable remission is 20–40%.<ref name="pmid17122451">{{cite journal |author=Stevens W, Koene H, Zwaginga JJ, Vreugdenhil G |title=Chronic idiopathic thrombocytopenic purpura: present strategy, guidelines and new insights |journal=The Netherlands journal of medicine |volume=64 |issue=10 |pages=356-63 |year=2006 |pmid=17122451 |doi=}}</ref> The male:female ratio in the adult group is 1:1.2–1.7 (for children it is 1:1) and the median age of adults at the diagnosis is 56–60.<ref name="pmid15941913">{{cite journal |author=Cines DB, Bussel JB |title=How I treat idiopathic thrombocytopenic purpura (ITP) |journal=Blood |volume=106 |issue=7 |pages=2244-51 |year=2005 |pmid=15941913 |doi=10.1182/blood-2004-12-4598}}</ref> Usually, ITP patients suffer from [[bruising]]; [[petechia]]e, [[nosebleed]]s and bleeding [[gums]] may occur if the platelet count is below 20,000,<ref name="pmid15660520">{{cite journal |author=Cines DB, McMillan R |title=Management of adult idiopathic thrombocytopenic purpura |journal=Annu. Rev. Med. |volume=56 |issue= |pages=425-42 |year=2005 |pmid=15660520 |doi=10.1146/annurev.med.56.082103.104644}}</ref> compared to a normal range of 150,000–400,000 per mm3.[[Subarachnoid hemorrhage|Subarachnoid]], [[intracerebral hemorrhage]] or other internal bleeding are very serious possible complications of this disease. Fortunately, these are unlikely in patients with the platelets count above 20,000.

Evan's syndrome can occur in ~1% of cases and is manifest by an autoimmune (Coombs +)hemolytic anemia with ITP.
The bone marrow biopsy in ITP can show increased (thought not always) megakaryocytes, bizarre giant platelets and platelet fragments. (Large platelets are often seen in the peripheral blood smear though this can be seen in other diseases.) When the spleen is removed it may show increased lymphatic nodularity. Platelet-associated antibody (IgG), which was the standard test of past years, is not now considered mandatory to diagnose ITP. Test for platelet antibody are not helpful as both their sensitivity and specificity are limited.

==Pathogenesis==
In many cases, the cause is not actually [[idiopathic]] but [[autoimmune]],<ref>{{cite journal |author=Coopamah M, Garvey M, Freedman J, Semple J |title=Cellular immune mechanisms in autoimmune thrombocytopenic purpura: An update |journal=Transfus Med Rev |volume=17 |issue=1 |pages=69–80 |year=2003 |pmid=12522773}}</ref> with [[antibodies]] against platelets being detected in approximately 60% of patients. Most often these antibodies are against platelet membrane [[glycoprotein]]s IIb-IIIa or Ib-IX, and are of the [[IgG]] type. The famous [[Harrington–Hollingsworth Experiment]] established the immune [[pathogenesis]] of ITP.<ref name="pmid18046034">{{cite journal |author=Schwartz RS |title=Immune thrombocytopenic purpura--from agony to agonist |journal=N. Engl. J. Med. |volume=357 |issue=22 |pages=2299–301 |year=2007 |pmid=18046034 |doi=10.1056/NEJMe0707126}}</ref>

The cause of ITP is thought to be related to chronic infections such as HIV, hepatitis C and H. Pylori. The mechanism involved is thought to be MOLECULAR MIMICRY, that is, antibody is formed against the infection and this cross-reacts with platelets. Autoantibodies in ITP react with platelet IIb/IIIa glycoprotein, less commonly with GPIb/IX. Lymphocytes in the spleen make the antiplatelet antibody; this is why splenectomy works so well. There is a correlation between a platelet's short survival and high turnover rate and the subsequent excellent response to splenectomy.

The antibodies also appear to damage megakaryocytes, preventing them from releasing platelets. Autoantibody-mediated phagocytosis of platelets has long been thought to be the primary mechanism of the disease. Platelet kinetic studies show that platelet production is normal or reduced rather than increased in about two thirds of ITP patients. Also, autoantibodies from patients with ITP inhibit megakaryocyte growth in vitro. IgG from ITP-plasma inhibits megakaryocyte production.
Ultrastructural studies of the bone marrow in ITP show increased signs of megakaryocyte apoptosis and reduced platelet shedding.

ITP has a strong association with immune thyroid disease.

Recent evidence suggests that the stimulus for autoantibody production in ITP is due to abnormal [[T helper cell]]s reacting with platelet antigens on the surface of antigen presenting cells.<ref>{{cite journal |author=Semple JW, Freedman J |title=Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia |journal=Blood |volume=78 |issue=10 |pages=2619-25 |year=1991 |pmid=1840468 |doi=}}</ref> This important finding suggests that therapies directed towards T cells may be effective in treating ITP.

==Diagnosis==
The diagnosis of ITP is a diagnosis of exclusion. First, one has to make sure that there are no other blood abnormalities except for low platelet count and no physical signs except for signs of bleeding. Then, the secondary causes (usually 5-10% of suspected ITP cases) should be excluded. Secondary causes could be [[leukemia]], medications (e.g. [[quinine]], [[heparin]]), [[lupus erythematosus]], [[cirrhosis]], [[HIV]], [[hepatitis]] C, congenital causes, [[antiphospholipid syndrome]], [[von Willebrand factor]] deficiency and others.<ref name="pmid15941913"/><ref name="pmid15660520"/>

Despite the destruction of platelets by splenic macrophages, the spleen is normally not enlarged. In fact, an enlarged spleen should lead a clinician to investigate other possible causes for the thrombocytopenia.

Bleeding time is prolonged in ITP patients; however, the use of bleeding time in diagnosis is discouraged by the American Society of Hematology practice guidelines<ref name="pmid9036806">{{cite journal |author= |title=Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology ITP Practice Guideline Panel |journal=Ann. Intern. Med. |volume=126 |issue=4 |pages=319-26 |year=1997 |pmid=9036806 |doi=}}</ref> as useless. For example the [[BMJ]] review of the basics of hematology states: "The bleeding time may or may not be prolonged in congenital or acquired platelet dysfunction, and therefore a normal bleeding time does not exclude these conditions."<ref name="pmid9081003">{{cite journal |author=Liesner RJ, Machin SJ |title=ABC of clinical haematology. Platelet disorders |journal=BMJ |volume=314 |issue=7083 |pages=809-12 |year=1997 |pmid=9081003 |doi=}}</ref>

A [[bone marrow examination]] may be performed on patients over the age of 60 and people who do not respond to treatment, or when the diagnosis is in doubt.<ref name="pmid15941913"/> The blood analysis for the antiplatelet antibodies is a matter of clinician's preference, as there is a disagreement whether the 80% specificity of this test is sufficient.<ref name="pmid15941913"/> In conditions associated with bone marrow failure (aplastic anemia) thrombopoietin (TPO)levels are high whereas in ITP thrombopoietin levels are low. Thus TPO could distinguish between decreased platelets due to bone marrow failure or increased due to their destruction. The bone marrow in ITP contains normal or high numbers of megakaryocytes but they may be small or immature (& may have been damaged by antibodies).

The ITP in AIDS has a thrombocytopenia that is multifactorial involving both TPO and platelet problems. Mechanisms may involve portal hypertension that leads to splenomegaly causing platelet sequestration. Hepatits C (HCV) causes decreased TPO production leading to decreased platelet production. Steroids may be helpful but, with their taper, the count usually decreases again. Intravenous immunoglobulin's effect is transient. For ITP-HIV the primary treatment should be directed at HIV suppression with HAART. HIV patients whose platelet count fails to increase to > 50,000 with HAART can be treated with steroids. Splenectomy is safe and effective in ~80% of patients with refractory HIV-related thrombocytopenia and treated with interferon (IFN) may be effective in refractory cases of patients coinfected with HCV. A decrease in platelets in HIV can arise secondary to both HCV and hepatitis B (HBV).

Pregnant patients with ITP and platelet counts < 30,000 can be treated with intravenous immunoglobulin (IV-IgG) or steroids at the lowest dose possible to avoid hypertension, eclampsia and adrenal suppression of the fetus. ~10-30% of pregnant females with ITP have an infant with platelets <50,000, however, intracranial hemorrhage is rare. For these females administer prednisone during the last month of pregnancy to decrease the likelihood of thrombocytopenia in the fetus.
Mothers with ITP who have previously given birth to infants without thrombocytopenia tend not to be thrombocytopenic. The maternal platelet count doesn't correlate with fetal and females with a prior history of ITP with ITP in remission (eg after splenectomy) may still deliver severely thrombocytopenic infants. This likely occurs because asplenic patients in clinical remission may not necessarily be in immunologic remission and circulating platelet-reactive IgG may still be present in their plasma.

==Treatment==

Mechanism-based Approach to Treatment;
1) Inhibit phagocyte-mediated clearance of antibody-coated platelets.
Steroids
Splenectomy
Anti-D
IV-IgG
2) Decreased autoantibody production
Rituximab
Steroids
Azathioprine & other immunosuppressants (eg cytoxan, cyclosporine, etc)
3) Impair T & B cell interactions.
Steroids
Rituximab
4) Enhance platelet production.
Thrombopoietic agents
IL-11

===Observation===
Most children with ITP will recover even without specific treatment. Among adults ITP is typically a chronic disease. It is insidious in onset and, in some patients, refractory to treatment. 90% of childhood ITP cases are an acute, self-limited disease, developing several weeks after a viral illness, lasting for 4-6 weeks, then spontaneously remitting. The bleeding risk is low and treatment is reserved only for the most severely affected patients. Because spontaneous recovery is expected in children wit ITP some pediatric hematologists recommend supportive care only, no drugs. In less than 20% of children thrombocytopenia may persist for >6-12 months and even many of these kids can experience a spontaneous remission.

===Steroids/IVIgG===
[[Platelet count]] below 20,000 is an indication for treatment; the patients with 20,000–50,000 platelets/μL are considered on a case by case basis, and there is generally no need to treat the patients with above 50,000 platelets/μL.<ref name="pmid15941913"/> Hospitalization is recommended in the cases of significant internal or mucocutaneous bleeding. The treatment begins with intravenous steroids (methylprednisolone or prednisone), [[intravenous immunoglobulin]] (IVIg) or their combination and sometimes platelet infusions in order to raise the count quickly. After the platelet count stabilized and in the less severe cases oral prednisone (1–2 mg/kg) is used. Most cases respond during the first week of treatment (RR ~70%). After several weeks of prednisone therapy, the dose is gradually reduced. However, 60–90% of patients relapse after the dose decreased below 0.25 mg/kg and stopped.<ref name="pmid15941913"/><ref name="pmid17122451"/> Pulsed high-dose dexamethasone shows (in untreated patients) a high RR of ~90% with a long-term RR of ~80% when several cycles of treatment are given. However long term high dose steroids have a myriad of toxicities and should be avoided if possible.

===Splenectomy===
Splenectomy offers a 2nd line treatment for those who fail steroids. The criteria for surgery are severe thrombocytopenia (<10,000), high risk of bleeding or the requirement of frequent steroids/IVIgG/anti-D treatment to maintain an adequate platelet count. Of the ~15% of children with persistent thrombocytopenia bleeding symptoms are uncommon and splenectomy is rarely required. However splenectomy is an effective treatment option for children with severe / symptomatic thrombocytopenia with a CR of ~75%. Because of the risk for overwhelming sepsis after splenectomy it should be deferred until after 5 years of age. Remember to give immunizations before splenectomy and perioperative antibiotics. Response to IV-IgG often predicts a response to splenectomy (increasing the platelet count to >50,000 with IgG means a >90% RR to splenectomy).

===Anti-D===
A relatively new strategy is treatment with [[Rho(D) Immune Globulin|anti-D]], an agent also used in mothers who have been sensitized to [[rhesus]] antigen by a Rh+ baby, but the patient must be Rh+.
IV anti-D (WinRhoSD) can also increase the platelet count especially at a higher dose of 75 mcg / kg. IV anti-D is effective in patients who are Rh-positive and non-splenectomized with a RR equal to 70%. Its toxicities include mild hemolysis, fever, chills, headache, nausea and vomiting.

===Steroid-sparing agents===
Immunosuppresants like [[mycophenolic acid|mycophenolate mofetil]] and [[azathioprine]] are becoming more popular for their effectiveness. [[Rituximab]] has also been used successfully for some patients. <ref>Braendstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB, Andersen I, Schmidt K, Andersen TM, Peterslund NA, Birgens HS, Plesner T, Pedersen BB, Hasselbalch HC. ''Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura.'' Am J Hematol 2005;78:275-80. PMID 15795920.</ref><ref>
Patel V, Mihatov N, Cooper N, Stasi R,
Cunningham-Rundles S, Bussel JB,''Long-term responses seen with rituximab in patients with ITP'', Community Oncology Vol. 4 No. 2, February 2007:107 [http://www.communityoncology.net/journal/articles/0402107.pdf PDF]</ref> Rituximab is used in refractory ITP with success; circulating B-cells become undetectable after a single dose of Rituximab but recover after 3-6 months. Rituximab can be detected in the serum of patients 3-6 months after treatment. The duration of Rituximab correlates with the stability of hte platelet response. However, although the short-term CR = 46% the long-term CR is only 18%. The typical schedule is 375 mg / m2 qwk x4 wks. Rituximab (375 mg / m2 d7, 14, 21, 28) / Dexamethasone was compared to Dexamethasone alone (40 mg QD, d1 through 4, given in qmonthly cycles. Initial and sustained response rates were better with the combination therapy (reference; Zaja R et al ASH 2008).

Extreme cases (very rare, especially rare in children) may require [[vincristine]], a [[chemotherapy]] agent, to stop the immune system from destroying platelets. For the most part this and other agents such as cytoxan, cyclosporine and danazol have fallen into disuse.

[[Intravenous immunoglobulin]], while sometimes effective, is expensive and the improvement is temporary (generally lasting less than a month). However, in the case of a pre-splenectomy ITP patient with dangerously low platelet counts, and a poor response to other treatments, IVIgG treatment can increase platelet counts, making the splenectomy operation less dangerous. It is also commonly used as a long-term (though monthly) treatment. The administration of IV-IgG is safe for maternal and fetal platelet counts during pregnancy, delivery and in the neonatal period.
IV-IgG is administered at 400-1000 mg/kg/day over 1 to 5 days and gives a better RR than prednisone. The duration of action is only 2 to 4 weeks. Its toxicities are nausea, headache, chills and occasional vascular events (eg MI, CVA) in older patients. The possible mechanmism of action is a transient impairment of the reticulendothelial clearance or macrophage blockade, inhibition of complement binding to platelets and interference of immune complexes binding to platelets. IV-IgG and WinRho essentially are the same type of treatment.

===Splenic Radiation===
Splenic radiation (RT) is usually given for steroid-resistant ITP. One to six weeks of 75-1370 cGy with or without concomittant post-RT steroids. Patients can respond for >1 year. It is a safe alternative for patients too old for splenectomy.

===Platelet transfusion===
Platelet transfusion is not normally recommended and is usually unsuccessful in raising a patient's platelet count. This is because the underlying autoimmune mechanism that destroyed the patient's platelets to begin with will also destroy donor platelets. An exception to this rule is when a patient is bleeding profusely, when transfusion of platelets can quickly form a platelet plug to stop bleeding, a life-threatening hemorrhage. Intravenous immunoglobulin administration, with the platelet transfusion, may improve their survival.

===Experimental/novel agents===
*AMG 531 (Romiplostum; Nplate) is an experimental treatment for stimulating platelet production. It is a thrombopoiesis stimulating Fc-peptide fusion protein (peptibody), a TPO peptide mimetic. Initial clinical trials show it to be effective in chronic ITP.<ref>{{cite journal |author=Bussel JB, Kuter DJ, George JN, ''et al'' |title=AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP |journal=N. Engl. J. Med. |volume=355 |issue=16 |pages=1672–81 |year=2006 |pmid=17050891 |doi=10.1056/NEJMoa054626}}</ref>

*The novel agent [[eltrombopag]] has been demonstrated to increase platelet counts and decrease bleeding in a dose-dependent manner.<ref>{{cite journal|author=Bussel JB, Cheng G, Saleh MN, ''et al'' |year=2007|title=Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura|journal=N. Engl. J. Med. |volume=357|pages=2237-2247|id=PMID 18046028}}</ref> It is NOT indicated for the treatment of thrombocytopenia due to any other cause other than ITP (eg NOT MDS). This is a therapeutic protein and therefore the patient may develop antibodies to it. Toxicities include bone marrow reticulin deposition.

*[[Dapsone]] (also called Diphenylsulfone, DDS, or Avlosulfon) is an anti-infective sulfone drug. In recent years Dapsone has also proved helpful in treating lupus, rheumatoid arthritis and as a second-line treatment for ITP. The exact mechanism by which Dapsone assists in ITP is unclear. However, limited studies report successful increases in platelet counts of around 40–50% of patients taking the drug. <ref name="pmid9163598">{{cite journal |author=Godeau B, Durand JM, Roudot-Thoraval F, ''et al'' |title=Dapsone for chronic autoimmune thrombocytopenic purpura: a report of 66 cases |journal=Br. J. Haematol. |volume=97 |issue=2 |pages=336–9 |year=1997 |pmid=9163598 |doi=}}</ref><ref>http://www.itppeople.com/dapsone.htm</ref>

===H. pylori eradication===
Researchers in Japan (including Ryugo Sato, Oita University) and Italy (including Massimo Franchini, University of Verona) have found a possible connection between [[Helicobacter Pylori|H. Pylori]] ([[Helicobacter Pylori]]) infection and ITP. Some patients given antibiotic treatment to eradicate the bacterial infection have had their platelet count increase dramatically.

==References==
{{Reflist|2}}

==External links==
* {{cite web | url = http://www.itpsupport.org.uk/childhooditp.htm | title = Childhood ITP | accessdate = 2007-02-14 | publisher = ITP Support Association}}
* {{cite web | url = http://www.itppeople.com/warnings.htm | title = Drug Induced Thrombocytopenia | accessdate = 2007-02-14 | publisher = Platelet Disorder Support Association}}

{{Hematology}}
{{SIB}}

[[Category:Blood disorders]]
[[Category:Hematology]]

[[bn:স্বয়ম্ভূত অণুচক্রিকাস্বল্পতাজনিত পারপ্যুরা]]
[[da:ITP]]
[[de:Idiopathische thrombozytopenische Purpura]]
[[it:Porpora trombocitopenica idiopatica]]
[[he:CITP]]
[[ja:特発性血小板減少性紫斑病]]
[[pl:Małopłytkowość samoistna]]
[[pt:Púrpura trombocitopênica idiopática]]

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Thrombotic thrombocytopenic purpura

2010-10-17T23:48:11Z

Robert Killeen:

{{Infobox_Disease
| Name = Thrombotic thrombocytopenic purpura
| Image = Thrombotic thrombocytopenic purpura 1.jpg
| Caption = Thrombotic Thrombocytopenic Purpura: Micro H&E low mag; myocardial cells: an excellent example of this condition. [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] 
| DiseasesDB = 13052
| ICD10 = {{ICD10|M|31|1|m|31}}
| ICD9 = {{ICD9|446.6}}
| ICDO =
| OMIM =
| MedlinePlus = 000552
| eMedicineSubj = emerg
| eMedicineTopic = 579
| eMedicine_mult = {{eMedicine2|neuro|499}} {{eMedicine2|med|2265}}
| MeshID = D011697
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

'''Thrombotic thrombocytopenic purpura''' ('''TTP''' or ''Moschcowitz disease'') is a [[rare disease|rare]] disorder of the [[coagulation|blood-coagulation]] system, causing multiple blood clots to form in blood vessels around the body.<ref name="MedPlus">
"MedlinePlus: Thrombotic thrombocytopenic purpura",
''MedlinePlus Medical Encyclopedia'', 2007, webpage:
[http://www.nlm.nih.gov/medlineplus/ency/article/000552.htm NLM-552].
</ref>
Most cases of TTP arise from deficiency or inhibition of the [[enzyme]] [[ADAMTS13]], which is responsible for cleaving large multimers of [[von Willebrand factor]].<ref>{{cite journal |author=Moake JL |title=von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura |journal=Semin. Hematol. |volume=41 |issue=1 |pages=4–14 |year=2004 |pmid=14727254 |doi=}}</ref> This leads to [[hemolysis]] and end-organ damage, and may require [[plasmapheresis]] therapy.

==Signs and symptoms==
Classically, the following five symptoms are indicative of this elusive disease. The full 'pentad' is not seen in all cases and clinical suspicion and acumen are the foremost necessity.
* Fluctuating [[neurology|neurological]] symptoms, such as bizarre behavior, altered mental status, [[stroke]] or [[headache]]s (65%);
* [[Acute renal failure|Kidney failure]] (46%);
* [[Fever]] (33%);
* [[Thrombocytopenia]] (low [[platelet]] count; most < 50,000), leading to [[bruising]] or [[purpura]];
* [[Microangiopathic hemolytic anemia]] ([[anemia]], [[jaundice]], elevated LDH and a characteristic [[blood film]] showing schistocytes or fragmented erythrocytes).

A patient may notice dark urine from the hemolytic anemia. Because of the many small areas of ischemia produced by clots in the microvasculature, symptoms may be diffuse and fluctuating, including the classical bruising, confusion, or headache, but also nausea and vomiting (from ischemia in the GI tract or from central nervous system involvement), chest pain from cardiac ischemia, seizures, muscle and joint pain, etc.

==Causes==
ADAMTS13 is a zinc-requiring and calcium-requiring 190,000 Dalton glycosylated protein that is encoded on chromosome 9q34. It is a disintegrin and a metalloprotease with 8 thrombospondin 1-like domains composed of an aminoterminal metalloprotease followed by a disintegrin domain; a thrombospondin 1-like domain; a cysteine-rich domain and an adjacent spacer portion; seven additional thrombospondin 1-like domains and 2 other different types of domains that resemble each other at the carboxyl-terminal end of the molecule. It cleaves a tyrosine 1605-1606 methionine peptide bond of VWF. This protease is #13 in a family of 19 distinct ADAMTS-type metalloprotease enzymes. It is produced predominantly in endothelial cells for slow, constitutive release into the circulation. Endothelial cells can be stimulated to secrete long VWF strings by inflammatory cytokines (TNF, IL8 & IL6, shiga toxins or estrogen). ADAMTS13 is inhibited by EDTA and therefore functional assays of the enzyme are usually performed using plasma anticoagulated with citrate (a weaker divalent cation binder than EDTA).

TTP, as with other [[microangiopathic hemolytic anemia]]s (MAHAs), is caused by a spontaneous [[aggregation]] of [[platelet]]s and activation of [[coagulation]] in the small [[blood vessel]]s. When stimulated, endothelial cells secrete the ultra-large VWF multimers in long strips that remain anchored to the cell membrane. The long VWF multimeric strings are EXTREMELY "sticky" to the glycoprotein Iba components of platelet GPIb-IX-V surface receptors. The initial adherence of platelets via the GPIb receptors to the long VWF strings and the subsequent coherence of additional platelets to each other (aggregation) via activated GPIIb/IIIa receptors produces potentially occlusive platelet thrombi. Platelets are consumed in the coagulation process, and bind [[fibrin]], the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of [[red blood cell]]s, resulting in [[hemolysis]].

Roughly, there are two forms of TTP: ''idiopathic'' and ''secondary'' TTP. A special case is the inherited deficiency of ADAMTS13, known as the ''Upshaw-Schulman syndrome''.

The differential diagnosis of TTP includes hemolytic-uremic syndrome (HUS; which has neurosymptoms, renal failure, hypertension and fever). Note that ADAMTS13 activity is normal in HUS.

===Idiopathic TTP===
The ''[[idiopathic]]'' form of TTP was recently linked to the inhibition of the [[enzyme]] ADAMTS13 by [[antibody|antibodies]], rendering TTP as an [[autoimmune disease]]. [[von Willebrand factor]] (vWF) is a protein that links platelets, [[blood clot]]s, and the blood vessel wall in the process of blood [[coagulation]]. ADAMTS13 is a proteinase responsible for the breakdown of VWF; very large VWF molecules are prone to coagulation. Without proper cleavage of VWF by ADAMTS13, these unusually large VWF cause coagulation at a higher rate, especially in the part of the circulatory system where VWF is most active due to high shear stress - in the microvascualture, thereby causing thrombi.

In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients, and inhibitors are often found in this subgroup (44-56%). The relationship of reduced [[ADAMTS13]] to the pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent researchers who published their research in the same issue of the [[New England Journal of Medicine]] in 1998.<ref name="pmid9828253">{{cite journal |author=Moake JL |title=Moschcowitz, multimers, and metalloprotease |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1629–31 |year=1998 |pmid=9828253 |doi=}}</ref><ref name="pmid9828245">{{cite journal |author=Furlan M, Robles R, Galbusera M, ''et al'' |title=von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1578–84 |year=1998 |pmid=9828245 |doi=}}</ref><ref name="pmid9828246">{{cite journal |author=Tsai HM, Lian EC |title=Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1585–94 |year=1998 |pmid=9828246 |doi=}}</ref> This theory is seen as insufficient to explain the etiology of TTP, since many patients with a hereditary lack of [[ADAMTS13]] activity do not manifest clinical symptoms of TTP.

Congenital or acquired ADAMTS13 deficiency causes TTP; acute TTP in adults is usually due to an acquired atuoantibody to ADAMTS13. However, as stated before, cases of plasma exchange-responsive acute TTP have been reported in patients who have no evidence of an autoantibody to ADAMTS13 and patients with congenital ADAMTS13 deficiency may not manifest TTP until adulthood. Autoantibodies against ADAMTS13 present in a majority of patients with idiopathic TTP and, additionally, ticlopidine and clopidogrel associated TTP. Severe deficiency of ADAMTS13 activity (<5%) is a specific feature of TTP. Normal levels of ADAMTS13 do NOT rule out the diagnosis of TTP. Normally there is only a slight increase in D-dimers, FDP and thrombin-antithrombin complexes in acute TTP. Secondary DIC may arise due to prolonged tissue ischemia and is an ominous prognostic sign.

===Secondary TTP===
''Secondary TTP'' is diagnosed when the patient's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:
* [[Cancer]]
* [[Bone marrow transplantation]]; (TBI is a risk factor).
* [[Pregnancy]]; rare.
* [[Medication]] use:
** Platelet aggregation inhibitors ([[ticlopidine]] and [[clopidogrel]])
** Immunosuppressants ([[cyclosporine]], [[mitomycin]], [[tacrolimus]]/FK506, [[interferon|interferon-α]])
* [[HIV-1]] infection

The mechanism of ''secondary'' TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. The probable etiology may involve, at least in some cases, endothelial damage.
A small fraction of patients treated for arterial thrombosis with the platelet P2Y12 adenosine diphosphate receptor inhibiting thienopyridine drugs ticopidine (Ticlid) or clopidogrel (Plavix) develop TTP within a few weeks after the initiation of treatment. Autoantibodies that inhibit plasma ADAMTS13 have been demonstrated in a few patients with Ticlid-associated or Plavix-associated TTP, indicating a possible immune dysregulation induced by these similar thienpyridine compounds. Ticlodipine-associated TTP may respond to drug withdrawal and plasma exchange whereas TTP-like syndromes occuring after transplantation (often in associated with cyclosporine or FK506) are less likely to be responsive to plasma exchange treatment.

===Upshaw-Schulman syndrome===
A hereditary form of TTP is called the ''Upshaw-Schulman syndrome''; this is generally due to inherited deficiency of ADAMTS13 (frameshift and point mutations). Patients with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased [[von Willebrand factor]] levels, e.g. infection. Reportedly, 5-10% of all TTP cases are due to Upshaw-Schulman syndrome.

==Treatment==
Since the early 1990s, [[plasmapheresis]] has become the treatment of choice for TTP.<ref>{{cite journal |author=Zheng XL, Kaufman RM, Goodnough LT, Sadler JE |title=Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura |journal=Blood |volume=103 |issue=11 |pages=4043–9 |year=2004 |pmid=14982878 |doi=10.1182/blood-2003-11-4035}}</ref> This is an [[exchange transfusion]] involving removal of the patient's [[blood plasma]] through [[apheresis]] and replacement with donor plasma ([[fresh frozen plasma]] or cryosupernatant); the procedure has to be repeated daily to eliminate the inhibitor and ablate the symptoms. Plasma infusion may be necessary and preferred if plasma exchange is not readily available. Exchange tranfusion has a complete response rate of 76%; plasma exchange allows ~80% of acquired ADAMTS13 autoantibody mediated TTP patients to survive an episode(compared to ~80% mortality without it), usually with minimal organ damage. FFP is the replacement fluid of choice in TTP and an exchange of a single plasma volume is the standard initial treatment. All patients should receive folate. [[Lactate dehydrogenase]] levels are generally used to monitor disease activity. The serum level increases as erythrocytes are destroyed. Plasmapheresis may need to be continued for 1-8 weeks before patients with idiopathic TTP cease to consume platelets and begin to normalize their hemoglobin. No single laboratory test (platelet count, LDH, ADAMTS13 level, or inhibitory factor) is indicative of recovery; research protocols have used improvement or normalization of LDH as a measure for ending plasmapheresis. Although patients may be critically ill with failure of multiple organ systems during the acute illness, including renal failure, myocardial ischemia, and neurologic symptoms, recovery over several months may be complete in the absence of a frank myocardial infarct, stroke, or CNS hemorrhage. Platelet transfusions are contraindicated unless there is life-threatening hemorrhage.

Many TTP patients need additional [[immunosuppressive]] therapy, with [[glucocorticoid]] [[steroid]]s (e.g. [[prednisolone]] or [[prednisone]]), [[vincristine]], [[cyclophosphamide]], [[splenectomy]] or a combination of the above. [[Rituximab]], a [[monoclonal antibody]] targeting CD20 on [[B cell]]s, has been successfully used to treat patients with refractory disease.

Children with Upshaw-Schulman syndrome receive plasma every three weeks prophylactically; this maintains adequate levels of functioning ADAMTS13.

==Epidemiology==
The incidence of TTP is about 4-6 per million people per year. As with most other [[autoimmune disorder]]s, idiopathic TTP occurs more often in women and blacks, while the secondary forms do not show this distribution.

==Prognosis==
The mortality rate is approximately 95% for untreated cases, but the prognosis is reasonably favorable (80-90%) for patients with idiopathic TTP diagnosed and treated early with plasmapheresis.

Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.

Secondary TTP still has a dismal prognosis, with mortality rates despite treatment being reported as 59% to 100%.

==History==
TTP was initially described in a 16-year old girl by Dr Eli Moschcowitz of New York City in 1924.<ref>{{cite journal |author=Moschcowitz E |title=An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. |journal=Proc NY Pathol Soc |volume=24 |pages=21-4 |year=1924}} Reprinted in ''Mt Sinai J Med'' 2003;70(5):322-5, PMID 14631522.</ref> Moschcowitz ascribed the disease (incorrectly) to a toxic cause. Moschcowitz noted that his 16 year-old patient had anemia; petechiae; microscopic hematuria; and at autopsy, disseminated microvascular thrombi. Since that time, the pathophysiology, etiology, and medical management of TTP has expanded.

==See also==
* [[Plasmapheresis]]
* [[Exchange transfusion]]
* [[ADAMTS13]]

==Notes==
<references/>

==References==
* {{cite journal |author=Moake JL |title=Thrombotic microangiopathies |journal=N. Engl. J. Med. |volume=347 |issue=8 |pages=589–600 |year=2002 |pmid=12192020 |doi=10.1056/NEJMra020528}}

== External links ==
* [http://www.netdoctor.co.uk/diseases/facts/ttp.htm Thrombotic thrombocytopenic purpura]
* [http://www.ttpnetwork.org.uk TTPNetwork Patient Support Group]

{{Hematology}}
{{SIB}}

[[Category:Autoimmune diseases]]
[[Category:Hematology]]
[[Category:Rare diseases]]

[[bn:তঞ্চনসংক্রান্ত অণুচক্রিকাস্বল্পতাজনিত পারপ্যুরা]]
[[de:Thrombotisch-thrombozytopenische Purpura]]
[[es:Púrpura trombocitopénica trombótica]]
[[fr:Purpura thrombotique thrombocytopénique]]
[[it:Porpora trombotica trombocitopenica]]
[[nl:Thrombotische thrombocytopenische purpura]]
[[ja:血栓性血小板減少性紫斑病]]
[[pl:Zakrzepowa plamica małopłytkowa]]

{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

Thrombotic thrombocytopenic purpura

2010-10-17T03:13:13Z

Robert Killeen:

{{Infobox_Disease
| Name = Thrombotic thrombocytopenic purpura
| Image = Thrombotic thrombocytopenic purpura 1.jpg
| Caption = Thrombotic Thrombocytopenic Purpura: Micro H&E low mag; myocardial cells: an excellent example of this condition. [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] 
| DiseasesDB = 13052
| ICD10 = {{ICD10|M|31|1|m|31}}
| ICD9 = {{ICD9|446.6}}
| ICDO =
| OMIM =
| MedlinePlus = 000552
| eMedicineSubj = emerg
| eMedicineTopic = 579
| eMedicine_mult = {{eMedicine2|neuro|499}} {{eMedicine2|med|2265}}
| MeshID = D011697
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

'''Thrombotic thrombocytopenic purpura''' ('''TTP''' or ''Moschcowitz disease'') is a [[rare disease|rare]] disorder of the [[coagulation|blood-coagulation]] system, causing multiple blood clots to form in blood vessels around the body.<ref name="MedPlus">
"MedlinePlus: Thrombotic thrombocytopenic purpura",
''MedlinePlus Medical Encyclopedia'', 2007, webpage:
[http://www.nlm.nih.gov/medlineplus/ency/article/000552.htm NLM-552].
</ref>
Most cases of TTP arise from deficiency or inhibition of the [[enzyme]] [[ADAMTS13]], which is responsible for cleaving large multimers of [[von Willebrand factor]].<ref>{{cite journal |author=Moake JL |title=von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura |journal=Semin. Hematol. |volume=41 |issue=1 |pages=4–14 |year=2004 |pmid=14727254 |doi=}}</ref> This leads to [[hemolysis]] and end-organ damage, and may require [[plasmapheresis]] therapy.

==Signs and symptoms==
Classically, the following five symptoms are indicative of this elusive disease. The full 'pentad' is not seen in all cases and clinical suspicion and acumen are the foremost necessity.
* Fluctuating [[neurology|neurological]] symptoms, such as bizarre behavior, altered mental status, [[stroke]] or [[headache]]s (65%);
* [[Acute renal failure|Kidney failure]] (46%);
* [[Fever]] (33%);
* [[Thrombocytopenia]] (low [[platelet]] count; most < 50,000), leading to [[bruising]] or [[purpura]];
* [[Microangiopathic hemolytic anemia]] ([[anemia]], [[jaundice]], elevated LDH and a characteristic [[blood film]]showing schistocytes or fragmented erythrocytes).

A patient may notice dark urine from the hemolytic anemia. Because of the many small areas of ischemia produced by clots in the microvasculature, symptoms may be diffuse and fluctuating, including the classical bruising, confusion, or headache, but also nausea and vomiting (from ischemia in the GI tract or from central nervous system involvement), chest pain from cardiac ischemia, seizures, muscle and joint pain, etc.

==Causes==
ADAMTS13 is a zinc-requiring and calcium-requiring 190,000 Dalton glycosylated protein that is encoded on chromosome 9q34. It is a disintegrin and a metalloprotease with 8 thrombospondin 1-like domains composed of a aminoterminal metalloprotease followed by a disintegrin domain; a thrombospondin 1-like domain; a cysteine-rich domain and an adjacent spacer portion; seven additional thrombospondin 1-like domains and 2 other different types of domains that resemble each other at the carboxyl-terminal end of the molecule. It cleases a tyrosine 1605-1606 methionine peptide bond of VWF. This protease is #13 in a family of 19 distinct ADAMTS-type metalloprotease enzymes. It is produced predominantly in endothelial cells for slow, constitutive release into the circulation. Endothelial cells can be stimulated to secrete long VWF strings by inflammatory cytokines (TNF, IL8 & IL6, shiga toxins or estrogen). ADAMTS13 is inhibited by EDTA and therefore functional assays of the enzyme are usually performed using plasma anticoagulated with citrate (a weaker divalent cation binder than EDTA).

TTP, as with other [[microangiopathic hemolytic anemia]]s (MAHAs), is caused by spontaneous [[aggregation]] of [[platelet]]s and activation of [[coagulation]] in the small [[blood vessel]]s. When stimulated, endothelial cells secrete the ultra-large VWF multimers in long strips that remain anchored to the cell membrane. The long VWF multimeric strings are EXTREMELY "sticky" to the glycoprotein Iba components of platelet GPIb-IX-V surface receptors. The initial adherence of platelets via the GPIb receptors to the long VWF strings and the subsequent coherence of additional platelets to each other (aggregation) via activated GPIIb/IIIa receptors produces potentially occulsive platelet thrombi. Platelets are consumed in the coagulation process, and bind [[fibrin]], the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of [[red blood cell]]s, resulting in [[hemolysis]].

Roughly, there are two forms of TTP: ''idiopathic'' and ''secondary'' TTP. A special case is the inherited deficiency of ADAMTS13, known as the ''Upshaw-Schulman syndrome''.

The differential diagnosis of TTP includes hemolytic-uremic syndrome (HUS; which has neurosymptoms, renal failure, hypertension and fever). Note that ADAMTS13 activity is normal in HUS.

===Idiopathic TTP===
The ''[[idiopathic]]'' form of TTP was recently linked to the inhibition of the [[enzyme]] ADAMTS13 by [[antibody|antibodies]], rendering TTP an [[autoimmune disease]]. [[von Willebrand factor]] (vWF) is a protein that links platelets, [[blood clot]]s, and the blood vessel wall in the process of blood [[coagulation]]. ADAMTS13 is a proteinase responsible for the breakdown of VWF; very large VWF molecules are prone to coagulation. Without proper cleavage of VWF by ADAMTS13, these unusually large VWF cause coagulation at a higher rate, especially in the part of the circulatory system where VWF is most active due to high shear stress - in the microvascualture, thereby causing thrombi.

In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients, and inhibitors are often found in this subgroup (44-56%). The relationship of reduced [[ADAMTS13]] to the pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent researchers who published their research in the same issue of the [[New England Journal of Medicine]] in 1998.<ref name="pmid9828253">{{cite journal |author=Moake JL |title=Moschcowitz, multimers, and metalloprotease |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1629–31 |year=1998 |pmid=9828253 |doi=}}</ref><ref name="pmid9828245">{{cite journal |author=Furlan M, Robles R, Galbusera M, ''et al'' |title=von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1578–84 |year=1998 |pmid=9828245 |doi=}}</ref><ref name="pmid9828246">{{cite journal |author=Tsai HM, Lian EC |title=Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura |journal=N. Engl. J. Med. |volume=339 |issue=22 |pages=1585–94 |year=1998 |pmid=9828246 |doi=}}</ref> This theory is seen as insufficient to explain the etiology of TTP, since many patients with hereditary lack of [[ADAMTS13]] activity do not manifest clinical symptoms of TTP.

Congenital or acquired ADAMTS13 deficiency causes TTP; acute TTP in adults is usually due to an acquired atuoantibody to ADAMTS13. However, as stated before, cases of plasma exchange-responsive acute TTP have been reported in patients who have no evidence of an autoantibody to ADAMTS13 and patients with congenital ADAMTS13 deficiency may not manifest TTP until adulthood. Autoantibodies against ADAMTS13 present in a majority of patients with idiopathic TTP and, additionally, ticlopidine and clopidogrel associated TTP. Severe deficiency of ADAMTS13 activity (<5%) is a specific feature of TTP. Normal levels of ADAMTS13 do NOT rule out the diagnosis of TTP. Normally there is only a slight increase in D-dimers, FDP and thrombin-antithrombin complexes in acute TTP. Secondary DIC may arise due to prolonged tissue ischemia and is an ominous prognostic sign.

===Secondary TTP===
''Secondary TTP'' is diagnosed when the patient's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:
* [[Cancer]]
* [[Bone marrow transplantation]]; (TBI is a risk factor).
* [[Pregnancy]]; rare.
* [[Medication]] use:
** Platelet aggregation inhibitors ([[ticlopidine]] and [[clopidogrel]])
** Immunosuppressants ([[cyclosporine]], [[mitomycin]], [[tacrolimus]]/FK506, [[interferon|interferon-α]])
* [[HIV-1]] infection

The mechanism of ''secondary'' TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inhibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage.
A small fraction of patients treated for arterial thrombosis with the platelet P2Y12 adenosine diphosphate receptor inhibiting thienopyridine drugs ticopidine (Ticlid) or clopidogrel (Plavix) develop TTP within a few weeks after the initiation of treatment. Autoantibodies that inhibit plasma ADAMTS13 have been demonstrated in a few patients with Ticlid-associated or Plavix-associated TTP, indicating a possible immune dysregulation induced by these similar thienpyridine compounds. Ticlodipine-associated TTP may respond to drug withdrawal and plasma exchange whereas TTP-like syndromes occuring after transplantation (often in associated with cyclosporine or FK506) are less likely to be responsive to plasma exchange treatment.

===Upshaw-Schulman syndrome===
A hereditary form of TTP is called the ''Upshaw-Schulman syndrome''; this is generally due to inherited deficiency of ADAMTS13 (frameshift and point mutations). Patients with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased [[von Willebrand factor]] levels, e.g. infection. Reportedly, 5-10% of all TTP cases are due to Upshaw-Schulman syndrome.

==Treatment==
Since the early 1990s, [[plasmapheresis]] has become the treatment of choice for TTP.<ref>{{cite journal |author=Zheng XL, Kaufman RM, Goodnough LT, Sadler JE |title=Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura |journal=Blood |volume=103 |issue=11 |pages=4043–9 |year=2004 |pmid=14982878 |doi=10.1182/blood-2003-11-4035}}</ref> This is an [[exchange transfusion]] involving removal of the patient's [[blood plasma]] through [[apheresis]] and replacement with donor plasma ([[fresh frozen plasma]] or cryosupernatant); the procedure has to be repeated daily to eliminate the inhibitor and ablate the symptoms. Plasma infusion may be necessary and preferred if plasma exchange is not readily available. Exhange tranfusion has a complete response rate of 76%; plasma exchange allows ~80% of acquired ADAMTS13 autoantibody mediated TTP patients to survive an episode(compared to ~80 mortality without it), usually with minimal organ damage. FFP is the replacement fluid of choice in TTP and an exchange of a single plasma volume is the standard initial treatment. All patients should receive folate. [[Lactate dehydrogenase]] levels are generally used to monitor disease activity. The serum level increases as erythrocytes are destroyed. Plasmapheresis may need to be continued for 1-8 weeks before patients with idiopathic TTP cease to consume platelets and begin to normalize their hemoglobin. No single laboratory test (platelet count, LDH, ADAMTS13 level, or inhibitory factor) is indicative of recovery; research protocols have used improvement or normalization of LDH as a measure for ending plasmapheresis. Although patients may be critically ill with failure of multiple organ systems during the acute illness, including renal failure, myocardial ischemia, and neurologic symptoms, recovery over several months may be complete in the absence of a frank myocardial infarct, stroke, or CNS hemorrhage. Platelet transfusions are contraindicated unless there is life-threatening hemorrhage.

Many TTP patients need additional [[immunosuppressive]] therapy, with [[glucocorticoid]] [[steroid]]s (e.g. [[prednisolone]] or [[prednisone]]), [[vincristine]], [[cyclophosphamide]], [[splenectomy]] or a combination of the above. [[Rituximab]], a [[monoclonal antibody]] targeting CD20 on [[B cell]]s, has been successfully used to treat patients with refractory disease.

Children with Upshaw-Schulman syndrome receive plasma every three weeks prophylactically; this maintains adequate levels of functioning ADAMTS13.

==Epidemiology==
The incidence of TTP is about 4-6 per million people per year. As with most other [[autoimmune disorder]]s, idiopathic TTP occurs more often in women and blacks, while the secondary forms do not show this distribution.

==Prognosis==
The mortality rate is approximately 95% for untreated cases, but the prognosis is reasonably favorable (80-90%) for patients with idiopathic TTP diagnosed and treated early with plasmapheresis.

Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.

Secondary TTP still has a dismal prognosis, with mortality rates despite treatment being reported as 59% to 100%.

==History==
TTP was initially described in a 16-year old girl by Dr Eli Moschcowitz of New York City in 1924.<ref>{{cite journal |author=Moschcowitz E |title=An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries: an undescribed disease. |journal=Proc NY Pathol Soc |volume=24 |pages=21-4 |year=1924}} Reprinted in ''Mt Sinai J Med'' 2003;70(5):322-5, PMID 14631522.</ref> Moschcowitz ascribed the disease (incorrectly) to a toxic cause. Moschcowitz noted that his 16 year-old patient had anemia; petechiae; microscopic hematuria; and at autopsy, disseminated microvascular thrombi. Since that time, the pathophysiology, etiology, and medical management of TTP has expanded.

==See also==
* [[Plasmapheresis]]
* [[Exchange transfusion]]
* [[ADAMTS13]]

==Notes==
<references/>

==References==
* {{cite journal |author=Moake JL |title=Thrombotic microangiopathies |journal=N. Engl. J. Med. |volume=347 |issue=8 |pages=589–600 |year=2002 |pmid=12192020 |doi=10.1056/NEJMra020528}}

== External links ==
* [http://www.netdoctor.co.uk/diseases/facts/ttp.htm Thrombotic thrombocytopenic purpura]
* [http://www.ttpnetwork.org.uk TTPNetwork Patient Support Group]

{{Hematology}}
{{SIB}}

[[Category:Autoimmune diseases]]
[[Category:Hematology]]
[[Category:Rare diseases]]

[[bn:তঞ্চনসংক্রান্ত অণুচক্রিকাস্বল্পতাজনিত পারপ্যুরা]]
[[de:Thrombotisch-thrombozytopenische Purpura]]
[[es:Púrpura trombocitopénica trombótica]]
[[fr:Purpura thrombotique thrombocytopénique]]
[[it:Porpora trombotica trombocitopenica]]
[[nl:Thrombotische thrombocytopenische purpura]]
[[ja:血栓性血小板減少性紫斑病]]
[[pl:Zakrzepowa plamica małopłytkowa]]

{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

NPM1

2010-10-11T22:19:22Z

Robert Killeen:

{{PBB_Controls
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


{{GNF_Protein_box
| image = PBB_Protein_NPM1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2p1b.
| PDB = {{PDB2|2p1b}}
| Name = Nucleophosmin (nucleolar phosphoprotein B23, numatrin)
| HGNCid = 7910
| Symbol = NPM1
| AltSymbols =; B23; MGC104254; NPM
| OMIM = 164040
| ECnumber =
| Homologene = 87629
| MGIid = 3647121
| GeneAtlas_image1 = PBB_GE_NPM1_221691_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0003723 |text = RNA binding}} {{GNF_GO|id=GO:0030957 |text = Tat protein binding}} {{GNF_GO|id=GO:0042803 |text = protein homodimerization activity}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}} {{GNF_GO|id=GO:0051059 |text = NF-kappaB binding}} {{GNF_GO|id=GO:0051082 |text = unfolded protein binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005813 |text = centrosome}}
| Process = {{GNF_GO|id=GO:0006886 |text = intracellular protein transport}} {{GNF_GO|id=GO:0006913 |text = nucleocytoplasmic transport}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006950 |text = response to stress}} {{GNF_GO|id=GO:0007098 |text = centrosome cycle}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007569 |text = cell aging}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0042255 |text = ribosome assembly}} {{GNF_GO|id=GO:0051092 |text = activation of NF-kappaB transcription factor}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 4869
| Hs_Ensembl = ENSG00000181163
| Hs_RefseqProtein = NP_001032827
| Hs_RefseqmRNA = NM_001037738
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 5
| Hs_GenLoc_start = 170746725
| Hs_GenLoc_end = 170770492
| Hs_Uniprot = P06748
| Mm_EntrezGene = 434373
| Mm_Ensembl =
| Mm_RefseqmRNA = XM_486188
| Mm_RefseqProtein = XP_486188
| Mm_GenLoc_db =
| Mm_GenLoc_chr =
| Mm_GenLoc_start =
| Mm_GenLoc_end =
| Mm_Uniprot =
}}
}}
'''Nucleophosmin (nucleolar phosphoprotein B23, numatrin)''', also known as '''NPM1''', is a human protein and [[gene]]. It has attracted recent attention as a prognostic indicator in cytogenetically normal Acute Myelocytic Leukemia (CN-AML). The NPM1-mutated AML encompasses all FAB / WHO catagories except FAB M3 (APL). NPM1 gene mutations are found only in primary AML and not in AML arising from myelodysplasia (MDS; secondary AML).
NPM1 gene mutations are most common in AMLs with monocytic differentiation (FAB M4/M5). NPM1 mutations have a distinctive gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.
NPM1 mutated AML is preferentially associated with AML with monocytic differentiation (inparticular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations and a trend toward a favorable clinical outcome especially in patients without the FLT3 gene mutation. NOM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM.

'''Genetics;'''
The prevalence of cytogenetically-normal AML (CN-AML) varies between 40-49% of adults with de novo AML. Over half of the CN-AML patients can have the NPM1 mutation. The NPM1 gene is mapped to chromosome 5q15. NPM1 mutations cause alterations in the encoded protein that lead to its aberrant cytoplasmic localization. Mutations in nucleophosmin NPM1 are the most frequently ACQUIRED molecular abnormality in AML. NPM1 mutations positively correlate with AML with a high WBC count, normal karyotype and fms-tyrosine kinase 3 gene (FLT3) internal tandem duplication (ITD)mutations. FLT3ITD is a secondary genetic alteration that is not stable over the course of the disease. It is thoguht that the FLT3 "nullifies" the increased survival brought on by the presence of the NPM1. These mutations may contribute to leukemogenesis at least in part through disruption of the MDM2-p53 pathway and centrosome duplication.

CN-AML can be divided into two subsets; one is a molecular low risk group (ie CN-AML with NPM1 and NO FLT3ITD) which has a better outcome and the other is the molecular high risk group (ie patients with FLT3ITD or those without FLT3ITD and WITH wild-type, non-mutated NPM1). The event free survival (EFS) at 5 years is ~50% in patients with FLT3ITD negative / NPM1 mutated and only ~25% in patients with FLT3ITD positive / NPM1 wild-type (wt). The former have been considered to be a molecular low risk group and the latter a molecular high risk group. It has been shown that intermediate cytogenetic risk AML patient without FLT3ITD mutations but with NPM1 mutations have a significant better overall survival (OS) and EFS than those without NPM1 mutations. In multivariate analyses NPM1 mutations express an independent prognostic value with regeard to OS, EFS and disease free survival (DFS). In CN-AML patients older than 60 years the NPM1 mutation showed a higher complete response rate (CR) and had a significant increase in the OS compared with wild-type patients (84% versus 48%).

Patients who have NPM1 and lack FLT3ITD also have a high expression of a gene called ERG and have a negative outcome similar to molecular high risk patients. In contrast, patients who have NPM1+ and lack FLT3ITD would have a very favorable outcome if they express low levels of ERG.

'''Mechanism;'''
The various NPM1 mutations identified in AML are heterozygous and involve the C-terminal region encoded by exon 12. These not only disrupt key tryptophan residues that are required for localization to the nucleolus, but also generate a nuclear export signal leading to delocalization of mutant NPM1 to the cytoplasm where it sequesters residual wild-type protein from the nucleus. It is also thought to play an important role in centrosome assembly and has RNA binding and chaperone activity. NPM1-mutated AMLs frequently have CD34-negative blasts, normal karyotype and have a good response to induction treatment. NPM1 is predominantly localized in the nucleolus and is thought to function as a molecular chaperone of proteins, facilitating the transport of ribosomal proteins through the nuclear membrane. Disruption of NPM1, either by chromosomal translocation or b mutation, results in the cytoplasmic dislocation of NPM1. The high frequency of NPM1 mutations in AML with normal karyotypes and the observation that cytoplasmic NPM1 cannot exert its normal function as binding partner and transporter protein leads to the notion that NPM1 mutation may be an early event in leukemogenesis.
Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor suppressor pathway. Tranlocations involving the NPM gene cause cytoplasmic dislocation of the NPM protien.

The granulocytic, monocytic, erythroid and megakaryocytic series were found to be involved and these findings are consistent with the NPM1 mutation arising in myeloid or multipotent progenitors and raise the distinct possibility that this may be a primary lesion in AML, present in the leukemic stem cell population. NPM1-mutated / FLT3-ITD negative cases show a better prognosis (overall response and better response to induction treatment) reinforcing the concept that NPM1 mutation is a founder genetic lesion. Moreover, in cases where NPM1 and FLT3 are both mutated, multiple FLT3 internal tandem duplications (ITDs) can be detected within the leukemic subpopulations on the background of a single NPM1 mutation, implying that the latter was the first lesion to arise. A high frequency of NPM1 gene mutations are found in blasts that have a prominent nuclear invagination, a so-called 'cup-like' nuclei.

Chimeric oncoproteins generated as a result of the recurrent cytogenetic abnoramlities include t(8;21) / AML1-ETO, inv(16) / CBFB-MYH11 and t(11;23) / MLL rearrangements. The internal tandem duplication (ITD) in the fms-like tyrosine kinase-3 gene (FLT3) and the partial tandem duplication (PTD) of the mixed lineage leukemia gene (MLL) are indicative of a poor prognosis.

Immunopehnotypic analysis by flow cytometry has shown frequent absence of hematopoietic stem cell markers (CD34 and CD133) in NPM1-mutated AML (~80% versus 40% of cases lacking CD34 in NPM1-unmutated AML) while retaining other myeloid antigen markers such as CD13 and CD33. NPM1 mutations are a sensitive marker for minimal residual disease.

With regards to bone marrow transplantation if a patient had mutant NPM1 without FLT3ITD then there was no apparent advantage for transplantation in the first remission because, by analysis, for patients with NPM1-mutated / FLT3 wild-type, the relapse free survival (RFS) was the same regardless of whether or not a donor was available. If the patient had any genotype other than NPM1-mutated / FLT-wild type there was a definite benefit to receiving the allogeneic transplantation or at least having the donor and the potential for transplantation while in first remission.

==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Li L, Li HS, Pauza CD, ''et al.'' |title=Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions. |journal=Cell Res. |volume=15 |issue= 11-12 |pages= 923-34 |year= 2006 |pmid= 16354571 |doi= 10.1038/sj.cr.7290370 }}
*{{cite journal | author=Gjerset RA |title=DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer. |journal=J. Mol. Histol. |volume=37 |issue= 5-7 |pages= 239-51 |year= 2007 |pmid= 16855788 |doi= 10.1007/s10735-006-9040-y }}
*{{cite journal | author=Chen W, Rassidakis GZ, Medeiros LJ |title=Nucleophosmin gene mutations in acute myeloid leukemia. |journal=Arch. Pathol. Lab. Med. |volume=130 |issue= 11 |pages= 1687-92 |year= 2006 |pmid= 17076533 |doi= }}
*{{cite journal | author=Falini B, Nicoletti I, Bolli N, ''et al.'' |title=Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. |journal=Haematologica |volume=92 |issue= 4 |pages= 519-32 |year= 2007 |pmid= 17488663 |doi= }}
*{{cite journal | author=Fankhauser C, Izaurralde E, Adachi Y, ''et al.'' |title=Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. |journal=Mol. Cell. Biol. |volume=11 |issue= 5 |pages= 2567-75 |year= 1991 |pmid= 2017166 |doi= }}
*{{cite journal | author=Venkatesh LK, Mohammed S, Chinnadurai G |title=Functional domains of the HIV-1 rev gene required for trans-regulation and subcellular localization. |journal=Virology |volume=176 |issue= 1 |pages= 39-47 |year= 1990 |pmid= 2109912 |doi= }}
*{{cite journal | author=Cochrane AW, Perkins A, Rosen CA |title=Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function. |journal=J. Virol. |volume=64 |issue= 2 |pages= 881-5 |year= 1990 |pmid= 2404140 |doi= }}
*{{cite journal | author=Chan PK, Chan WY, Yung BY, ''et al.'' |title=Amino acid sequence of a specific antigenic peptide of protein B23. |journal=J. Biol. Chem. |volume=261 |issue= 30 |pages= 14335-41 |year= 1986 |pmid= 2429957 |doi= }}
*{{cite journal | author=Zhang XX, Thomis DC, Samuel CE |title=Isolation and characterization of a molecular cDNA clone of a human mRNA from interferon-treated cells encoding nucleolar protein B23, numatrin. |journal=Biochem. Biophys. Res. Commun. |volume=164 |issue= 1 |pages= 176-84 |year= 1989 |pmid= 2478125 |doi= }}
*{{cite journal | author=Hale TK, Mansfield BC |title=Nucleotide sequence of a cDNA clone representing a third allele of human protein B23. |journal=Nucleic Acids Res. |volume=17 |issue= 23 |pages= 10112 |year= 1990 |pmid= 2602120 |doi= }}
*{{cite journal | author=Chan WY, Liu QR, Borjigin J, ''et al.'' |title=Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. |journal=Biochemistry |volume=28 |issue= 3 |pages= 1033-9 |year= 1989 |pmid= 2713355 |doi= }}
*{{cite journal | author=Li XZ, McNeilage LJ, Whittingham S |title=The nucleotide sequence of a human cDNA encoding the highly conserved nucleolar phosphoprotein B23. |journal=Biochem. Biophys. Res. Commun. |volume=163 |issue= 1 |pages= 72-8 |year= 1989 |pmid= 2775293 |doi= }}
*{{cite journal | author=Chan PK, Aldrich M, Cook RG, Busch H |title=Amino acid sequence of protein B23 phosphorylation site. |journal=J. Biol. Chem. |volume=261 |issue= 4 |pages= 1868-72 |year= 1986 |pmid= 3944116 |doi= }}
*{{cite journal | author=Bocker T, Bittinger A, Wieland W, ''et al.'' |title=In vitro and ex vivo expression of nucleolar proteins B23 and p120 in benign and malignant epithelial lesions of the prostate. |journal=Mod. Pathol. |volume=8 |issue= 3 |pages= 226-31 |year= 1995 |pmid= 7542384 |doi= }}
*{{cite journal | author=Dundr M, Leno GH, Hammarskjöld ML, ''et al.'' |title=The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein. |journal=J. Cell. Sci. |volume=108 ( Pt 8) |issue= |pages= 2811-23 |year= 1995 |pmid= 7593322 |doi= }}
*{{cite journal | author=Miyazaki Y, Takamatsu T, Nosaka T, ''et al.'' |title=The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23. |journal=Exp. Cell Res. |volume=219 |issue= 1 |pages= 93-101 |year= 1995 |pmid= 7628555 |doi= 10.1006/excr.1995.1209 }}
*{{cite journal | author=Szebeni A, Herrera JE, Olson MO |title=Interaction of nucleolar protein B23 with peptides related to nuclear localization signals. |journal=Biochemistry |volume=34 |issue= 25 |pages= 8037-42 |year= 1995 |pmid= 7794916 |doi= }}
*{{cite journal | author=Kato S, Sekine S, Oh SW, ''et al.'' |title=Construction of a human full-length cDNA bank. |journal=Gene |volume=150 |issue= 2 |pages= 243-50 |year= 1995 |pmid= 7821789 |doi= }}
*{{cite journal | author=Marasco WA, Szilvay AM, Kalland KH, ''et al.'' |title=Spatial association of HIV-1 tat protein and the nucleolar transport protein B23 in stably transfected Jurkat T-cells. |journal=Arch. Virol. |volume=139 |issue= 1-2 |pages= 133-54 |year= 1995 |pmid= 7826206 |doi= }}
*{{cite journal | author=Valdez BC, Perlaky L, Henning D, ''et al.'' |title=Identification of the nuclear and nucleolar localization signals of the protein p120. Interaction with translocation protein B23. |journal=J. Biol. Chem. |volume=269 |issue= 38 |pages= 23776-83 |year= 1994 |pmid= 8089149 |doi= }}
}}
{{refend}}

{{protein-stub}}
{{WikiDoc Sources}}

NPM1

2010-10-09T14:58:22Z

Robert Killeen:

{{PBB_Controls
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


{{GNF_Protein_box
| image = PBB_Protein_NPM1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2p1b.
| PDB = {{PDB2|2p1b}}
| Name = Nucleophosmin (nucleolar phosphoprotein B23, numatrin)
| HGNCid = 7910
| Symbol = NPM1
| AltSymbols =; B23; MGC104254; NPM
| OMIM = 164040
| ECnumber =
| Homologene = 87629
| MGIid = 3647121
| GeneAtlas_image1 = PBB_GE_NPM1_221691_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0003723 |text = RNA binding}} {{GNF_GO|id=GO:0030957 |text = Tat protein binding}} {{GNF_GO|id=GO:0042803 |text = protein homodimerization activity}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}} {{GNF_GO|id=GO:0051059 |text = NF-kappaB binding}} {{GNF_GO|id=GO:0051082 |text = unfolded protein binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005813 |text = centrosome}}
| Process = {{GNF_GO|id=GO:0006886 |text = intracellular protein transport}} {{GNF_GO|id=GO:0006913 |text = nucleocytoplasmic transport}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006950 |text = response to stress}} {{GNF_GO|id=GO:0007098 |text = centrosome cycle}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007569 |text = cell aging}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0042255 |text = ribosome assembly}} {{GNF_GO|id=GO:0051092 |text = activation of NF-kappaB transcription factor}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 4869
| Hs_Ensembl = ENSG00000181163
| Hs_RefseqProtein = NP_001032827
| Hs_RefseqmRNA = NM_001037738
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 5
| Hs_GenLoc_start = 170746725
| Hs_GenLoc_end = 170770492
| Hs_Uniprot = P06748
| Mm_EntrezGene = 434373
| Mm_Ensembl =
| Mm_RefseqmRNA = XM_486188
| Mm_RefseqProtein = XP_486188
| Mm_GenLoc_db =
| Mm_GenLoc_chr =
| Mm_GenLoc_start =
| Mm_GenLoc_end =
| Mm_Uniprot =
}}
}}
'''Nucleophosmin (nucleolar phosphoprotein B23, numatrin)''', also known as '''NPM1''', is a human protein and [[gene]]. It has attracted recent attention as a prognostic indicator in cytogenetically normal Acute Myelocytic Leukemia (CN-AML). The NPM1-mutated AML encompasses all FAB / WHO catagories except FAB M3 (APL). NPM1 gene mutations are found only in primary AML and not in AML arising from myelodysplasia (MDS; secondary AML).
NPM1 gene mutations are most common in AMLs with monocytic differentiation (FAB M4/M5). NPM1 mutations have a distinctive gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.
NPM1 mutated AML is preferentially associated with AML with monocytic differentiation (inparticular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations and a trend toward a favorable clinical outcome especially in patients without the FLT3 gene mutation. NOM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM.

'''Genetics;'''
The prevalence of cytogenetically-normal AML (CN-AML) varies between 40-49% of adults with de novo AML. Over half of the CN-AML patients can have the NPM1 mutation. The NPM1 gene is mapped to chromosome 5q15. NPM1 mutations cause alterations in the encoded protein that lead to its aberrant cytoplasmic localization. Mutations in nucleophosmin NPM1 are the most frequently ACQUIRED molecular abnormality in AML. NPM1 mutations positively correlate with AML with a high WBC count, normal karyotype and fms-tyrosine kinase 3 gene (FLT3) internal tandem duplication (ITD)mutations. FLT3ITD is a secondary genetic alteration that is not stable over the course of the disease. It is thoguht that the FLT3 "nullifies" the increased survival brought on by the presence of the NPM1. These mutations may contribute to leukemogenesis at least in part through disruption of the MDM2-p53 pathway and centrosome duplication.

CN-AML can be divided into two subsets; one is a molecular low risk group (ie CN-AML with NPM1 and NO FLT3ITD) which has a better outcome and the other is the molecular high risk group (ie patients with FLT3ITD or those without FLT3ITD and WITH wild-type, non-mutated NPM1). The event free survival (EFS) at 5 years is ~50% in patients with FLT3ITD negative / NPM1 mutated and only ~25% in patients with FLT3ITD positive / NPM1 wild-type (wt). The former have been consiedered to be a molecular low risk group and the latter a molecular high risk group. It has been shown that intermediate cytogenetic risk AML patient without FLT3ITD mutations but with NPM1 mutations have a significant better overall survival (OS) and EFS than those without NPM1 mutations. In multivariate analyses NPM1 mutations express an independent prognostic value with regeard to OS, EFS and disease free survival (DFS). In patients older than 60 years the NPM1 mutation showed a higher complete response rate (CR) and had a significant increase in the OS compared with wild type patients (84% versus 48%).

Patients who have NPM1 and lack FLT3ITD also have a high expression of a gene called ERG and have a negative outcome similar to molecular high risk patients. In contrast, patients who have NPM1+ and lack FLT3ITD would have a very favorable outcome if they express low levels of ERG.

'''Mechanism;'''
The various NPM1 mutations identified in AML are heterozygous and involve the C-terminal region encoded by exon 12. These not only disrupt key tryptophan residues that are required for localization to the nucleolus, but also generate a nuclear export signal leading to delocalization of mutant NPM1 to the cytoplasm where it sequesters residual wild-type protein from the nucleus. It is also thought to play an important role in centrosome assembly and has RNA binding and chaperone activity. NPM1-mutated AMLs frequently have CD34-negative blasts, normal karyotype and have a good response to induction treatment. NPM1 is predominantly localized in the nucleolus and is thought to function as a molecular chaperone of proteins, facilitating the transport of ribosomal proteins through the nuclear membrane. Disruption of NPM1, either by chromosomal translocation or b mutation, results in the cytoplasmic dislocation of NPM1. The high frequency of NPM1 mutations in AML with normal karyotypes and the observation that cytoplasmic NPM1 cannot exert its normal function as binding partner and transporter protein leads to the notion that NPM1 mutation may be an early event in leukemogenesis.
Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor suppressor pathway. Tranlocations involving the NPM gene cause cytoplasmic dislocation of the NPM protien.

The granulocytic, monocytic, erythroid and megakaryocytic series were found to be involved and these findings are consistent with the NPM1 mutation arising in myeloid or multipotent progenitors and raise the distinct possibility that this may be a primary lesion in AML, present in the leukemic stem cell population. NPM1-mutated / FLT3-ITD negative cases show a better prognosis (overall response and better response to induction treatment) reinforcing the concept that NPM1 mutation is a founder genetic lesion. Moreover, in cases where NPM1 and FLT3 are both mutated, multiple FLT3 internal tandem duplications (ITDs) can be detected within the leukemic subpopulations on the background of a single NPM1 mutation, implying that the latter was the first lesion to arise. A high frequency of NPM1 gene mutations are found in blasts that have a prominent nuclear invagination, a so-called 'cup-like' nuclei.

Chimeric oncoproteins generated as a result of the recurrent cytogenetic abnoramlities include t(8;21) / AML1-ETO, inv(16) / CBFB-MYH11 and t(11;23) / MLL rearrangements. The internal tandem duplication (ITD) in the fms-like tyrosine kinase-3 gene (FLT3) and the partial tandem duplication (PTD) of the mixed lineage leukemia gene (MLL) are indicative of a poor prognosis.

Immunopehnotypic analysis by flow cytometry has shown frequent absence of hematopoietic stem cell markers (CD34 and CD133) in NPM1-mutated AML (~80% versus 40% of cases lacking CD34 in NPM1-unmutated AML) while retaining other myeloid antigen markers such as CD13 and CD33. NPM1 mutations are a sensitive marker for minimal residual disease.

'''Prognosis;'''
Older patients with cytogenetically normal AML and NPM1 mutations, particularly those aged 70 years or older, had more favorable outcomes than did patients with wild-type NPM1. In the older age group (>70 yrs) 87% of the patients with the mutated gene had complete remissions with treatment compared to 15% with the wild-type gene. The overall survival was 45% for patients greater than 70 years with NPM1 mutations versus 5% for those without the mutation. Mutations in the NPM1 gene are known to signal a favorable prognosis in younger patients with AML.

With regards to bone marrow transplantation if a patient had mutant NPM1 without FLT3ITD then there was no apparent advantage for transplantation in the first remission because, by analysis, for patients with NPM1-mutated / FLT3 wild-type, the relapse free survival (RFS) was the same regardless of whether or not a donor was available. If the patient had any genotype other than NPM1-mutated / FLT-wild type there was a definite benefit to receiving the allogeneic transplantation or at least having the donor and the potential for transplantation while in first remission.

==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Li L, Li HS, Pauza CD, ''et al.'' |title=Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions. |journal=Cell Res. |volume=15 |issue= 11-12 |pages= 923-34 |year= 2006 |pmid= 16354571 |doi= 10.1038/sj.cr.7290370 }}
*{{cite journal | author=Gjerset RA |title=DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer. |journal=J. Mol. Histol. |volume=37 |issue= 5-7 |pages= 239-51 |year= 2007 |pmid= 16855788 |doi= 10.1007/s10735-006-9040-y }}
*{{cite journal | author=Chen W, Rassidakis GZ, Medeiros LJ |title=Nucleophosmin gene mutations in acute myeloid leukemia. |journal=Arch. Pathol. Lab. Med. |volume=130 |issue= 11 |pages= 1687-92 |year= 2006 |pmid= 17076533 |doi= }}
*{{cite journal | author=Falini B, Nicoletti I, Bolli N, ''et al.'' |title=Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. |journal=Haematologica |volume=92 |issue= 4 |pages= 519-32 |year= 2007 |pmid= 17488663 |doi= }}
*{{cite journal | author=Fankhauser C, Izaurralde E, Adachi Y, ''et al.'' |title=Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. |journal=Mol. Cell. Biol. |volume=11 |issue= 5 |pages= 2567-75 |year= 1991 |pmid= 2017166 |doi= }}
*{{cite journal | author=Venkatesh LK, Mohammed S, Chinnadurai G |title=Functional domains of the HIV-1 rev gene required for trans-regulation and subcellular localization. |journal=Virology |volume=176 |issue= 1 |pages= 39-47 |year= 1990 |pmid= 2109912 |doi= }}
*{{cite journal | author=Cochrane AW, Perkins A, Rosen CA |title=Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function. |journal=J. Virol. |volume=64 |issue= 2 |pages= 881-5 |year= 1990 |pmid= 2404140 |doi= }}
*{{cite journal | author=Chan PK, Chan WY, Yung BY, ''et al.'' |title=Amino acid sequence of a specific antigenic peptide of protein B23. |journal=J. Biol. Chem. |volume=261 |issue= 30 |pages= 14335-41 |year= 1986 |pmid= 2429957 |doi= }}
*{{cite journal | author=Zhang XX, Thomis DC, Samuel CE |title=Isolation and characterization of a molecular cDNA clone of a human mRNA from interferon-treated cells encoding nucleolar protein B23, numatrin. |journal=Biochem. Biophys. Res. Commun. |volume=164 |issue= 1 |pages= 176-84 |year= 1989 |pmid= 2478125 |doi= }}
*{{cite journal | author=Hale TK, Mansfield BC |title=Nucleotide sequence of a cDNA clone representing a third allele of human protein B23. |journal=Nucleic Acids Res. |volume=17 |issue= 23 |pages= 10112 |year= 1990 |pmid= 2602120 |doi= }}
*{{cite journal | author=Chan WY, Liu QR, Borjigin J, ''et al.'' |title=Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. |journal=Biochemistry |volume=28 |issue= 3 |pages= 1033-9 |year= 1989 |pmid= 2713355 |doi= }}
*{{cite journal | author=Li XZ, McNeilage LJ, Whittingham S |title=The nucleotide sequence of a human cDNA encoding the highly conserved nucleolar phosphoprotein B23. |journal=Biochem. Biophys. Res. Commun. |volume=163 |issue= 1 |pages= 72-8 |year= 1989 |pmid= 2775293 |doi= }}
*{{cite journal | author=Chan PK, Aldrich M, Cook RG, Busch H |title=Amino acid sequence of protein B23 phosphorylation site. |journal=J. Biol. Chem. |volume=261 |issue= 4 |pages= 1868-72 |year= 1986 |pmid= 3944116 |doi= }}
*{{cite journal | author=Bocker T, Bittinger A, Wieland W, ''et al.'' |title=In vitro and ex vivo expression of nucleolar proteins B23 and p120 in benign and malignant epithelial lesions of the prostate. |journal=Mod. Pathol. |volume=8 |issue= 3 |pages= 226-31 |year= 1995 |pmid= 7542384 |doi= }}
*{{cite journal | author=Dundr M, Leno GH, Hammarskjöld ML, ''et al.'' |title=The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein. |journal=J. Cell. Sci. |volume=108 ( Pt 8) |issue= |pages= 2811-23 |year= 1995 |pmid= 7593322 |doi= }}
*{{cite journal | author=Miyazaki Y, Takamatsu T, Nosaka T, ''et al.'' |title=The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23. |journal=Exp. Cell Res. |volume=219 |issue= 1 |pages= 93-101 |year= 1995 |pmid= 7628555 |doi= 10.1006/excr.1995.1209 }}
*{{cite journal | author=Szebeni A, Herrera JE, Olson MO |title=Interaction of nucleolar protein B23 with peptides related to nuclear localization signals. |journal=Biochemistry |volume=34 |issue= 25 |pages= 8037-42 |year= 1995 |pmid= 7794916 |doi= }}
*{{cite journal | author=Kato S, Sekine S, Oh SW, ''et al.'' |title=Construction of a human full-length cDNA bank. |journal=Gene |volume=150 |issue= 2 |pages= 243-50 |year= 1995 |pmid= 7821789 |doi= }}
*{{cite journal | author=Marasco WA, Szilvay AM, Kalland KH, ''et al.'' |title=Spatial association of HIV-1 tat protein and the nucleolar transport protein B23 in stably transfected Jurkat T-cells. |journal=Arch. Virol. |volume=139 |issue= 1-2 |pages= 133-54 |year= 1995 |pmid= 7826206 |doi= }}
*{{cite journal | author=Valdez BC, Perlaky L, Henning D, ''et al.'' |title=Identification of the nuclear and nucleolar localization signals of the protein p120. Interaction with translocation protein B23. |journal=J. Biol. Chem. |volume=269 |issue= 38 |pages= 23776-83 |year= 1994 |pmid= 8089149 |doi= }}
}}
{{refend}}

{{protein-stub}}
{{WikiDoc Sources}}

NPM1

2010-10-05T02:18:06Z

Robert Killeen:

{{PBB_Controls
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


{{GNF_Protein_box
| image = PBB_Protein_NPM1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2p1b.
| PDB = {{PDB2|2p1b}}
| Name = Nucleophosmin (nucleolar phosphoprotein B23, numatrin)
| HGNCid = 7910
| Symbol = NPM1
| AltSymbols =; B23; MGC104254; NPM
| OMIM = 164040
| ECnumber =
| Homologene = 87629
| MGIid = 3647121
| GeneAtlas_image1 = PBB_GE_NPM1_221691_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0003723 |text = RNA binding}} {{GNF_GO|id=GO:0030957 |text = Tat protein binding}} {{GNF_GO|id=GO:0042803 |text = protein homodimerization activity}} {{GNF_GO|id=GO:0046982 |text = protein heterodimerization activity}} {{GNF_GO|id=GO:0051059 |text = NF-kappaB binding}} {{GNF_GO|id=GO:0051082 |text = unfolded protein binding}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}} {{GNF_GO|id=GO:0005813 |text = centrosome}}
| Process = {{GNF_GO|id=GO:0006886 |text = intracellular protein transport}} {{GNF_GO|id=GO:0006913 |text = nucleocytoplasmic transport}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006950 |text = response to stress}} {{GNF_GO|id=GO:0007098 |text = centrosome cycle}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007569 |text = cell aging}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0042255 |text = ribosome assembly}} {{GNF_GO|id=GO:0051092 |text = activation of NF-kappaB transcription factor}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 4869
| Hs_Ensembl = ENSG00000181163
| Hs_RefseqProtein = NP_001032827
| Hs_RefseqmRNA = NM_001037738
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 5
| Hs_GenLoc_start = 170746725
| Hs_GenLoc_end = 170770492
| Hs_Uniprot = P06748
| Mm_EntrezGene = 434373
| Mm_Ensembl =
| Mm_RefseqmRNA = XM_486188
| Mm_RefseqProtein = XP_486188
| Mm_GenLoc_db =
| Mm_GenLoc_chr =
| Mm_GenLoc_start =
| Mm_GenLoc_end =
| Mm_Uniprot =
}}
}}
'''Nucleophosmin (nucleolar phosphoprotein B23, numatrin)''', also known as '''NPM1''', is a human protein and [[gene]]. It has attracted recent attention as a prognostic indicator in cytogenetically normal Acute Myelocytic Leukemia (CN-AML). The NPM1-mutated AML encompasses all FAB / WHO catagories except FAB M3 (APL). NPM1 gene mutations are found only in primary AML and not in AML arising from myelodysplasia (MDS; secondary AML).
NPM1 gene mutations are most common in AMLs with monocytic differentiation (FAB M4/M5). NPM1 mutations have a distinctive gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance.
NPM1 mutated AML is preferentially associated with AML with monocytic differentiation (inparticular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations and a trend toward a favorable clinical outcome especially in patients without the FLT3 gene mutation. NOM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM.

'''Genetics;'''
The prevalence of cytogenetically-normal AML (CN-AML) varies between 40-49% of adults with de novo AML. Over half of the CN-AML patients can have the NPM1 mutation. The NPM1 gene is mapped to chromosome 5q15. NPM1 mutations cause alterations in the encoded protein that lead to its aberrant cytoplasmic localization. Mutations in nucleophosmin NPM1 are the most frequently ACQUIRED molecular abnormality in AML. NPM1 mutations positively correlate with AML with a high WBC count, normal karyotype and fms-tyrosine kinase 3 gene (FLT3) internal tandem duplication (ITD)mutations. FLT3ITD is a secondary genetic alteration that is not stable over the course of the disease. It is thoguht that the FLT3 "nullifies" the increased survival brought on by the presence of the NPM1. These mutations may contribute to leukemogenesis at least in part through disruption of the MDM2-p53 pathway and centrosome duplication.

CN-AML can be divided into two subsets; one is a molecular low risk group (ie CN-AML with NPM1 and NO FLT3ITD) which has a better outcome and the other is the molecular high risk group (ie patients with FLT3ITD or those without FLT3ITD and WITH wild-type, non-mutated NPM1). The event free survival (EFS) at 5 years is ~50% in patients with FLT3ITD negative / NPM1 mutated and only ~25% in patients with FLT3ITD positive / NPM1 wild-type (wt). The former have been consiedered to be a molecular low risk group and the latter a molecular high risk group. It has been shown that intermediate cytogenetic risk AML patient without FLT3ITD mutations but with NPM1 mutations have a significant better overall survival (OS) and EFS than those without NPM1 mutations. In multivariate analyses NPM1 mutations express an independent prognostic value with regeard to OS, EFS and disease free survival (DFS). In patients older than 60 years the NPM1 mutation showed a higher complete response rate (CR) and had a significant increase in the OS compared with wild type patients (84% versus 48%).

Patients who have NPM1 and lack FLT3ITD also have a high expression of a gene called ERG and have a negative outcome similar to molecular high risk patients. In contrast, patients who have NPM1+ and lack FLT3ITD would have a very favorable outcome if they express low levels of ERG.

==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Li L, Li HS, Pauza CD, ''et al.'' |title=Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions. |journal=Cell Res. |volume=15 |issue= 11-12 |pages= 923-34 |year= 2006 |pmid= 16354571 |doi= 10.1038/sj.cr.7290370 }}
*{{cite journal | author=Gjerset RA |title=DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer. |journal=J. Mol. Histol. |volume=37 |issue= 5-7 |pages= 239-51 |year= 2007 |pmid= 16855788 |doi= 10.1007/s10735-006-9040-y }}
*{{cite journal | author=Chen W, Rassidakis GZ, Medeiros LJ |title=Nucleophosmin gene mutations in acute myeloid leukemia. |journal=Arch. Pathol. Lab. Med. |volume=130 |issue= 11 |pages= 1687-92 |year= 2006 |pmid= 17076533 |doi= }}
*{{cite journal | author=Falini B, Nicoletti I, Bolli N, ''et al.'' |title=Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. |journal=Haematologica |volume=92 |issue= 4 |pages= 519-32 |year= 2007 |pmid= 17488663 |doi= }}
*{{cite journal | author=Fankhauser C, Izaurralde E, Adachi Y, ''et al.'' |title=Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. |journal=Mol. Cell. Biol. |volume=11 |issue= 5 |pages= 2567-75 |year= 1991 |pmid= 2017166 |doi= }}
*{{cite journal | author=Venkatesh LK, Mohammed S, Chinnadurai G |title=Functional domains of the HIV-1 rev gene required for trans-regulation and subcellular localization. |journal=Virology |volume=176 |issue= 1 |pages= 39-47 |year= 1990 |pmid= 2109912 |doi= }}
*{{cite journal | author=Cochrane AW, Perkins A, Rosen CA |title=Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function. |journal=J. Virol. |volume=64 |issue= 2 |pages= 881-5 |year= 1990 |pmid= 2404140 |doi= }}
*{{cite journal | author=Chan PK, Chan WY, Yung BY, ''et al.'' |title=Amino acid sequence of a specific antigenic peptide of protein B23. |journal=J. Biol. Chem. |volume=261 |issue= 30 |pages= 14335-41 |year= 1986 |pmid= 2429957 |doi= }}
*{{cite journal | author=Zhang XX, Thomis DC, Samuel CE |title=Isolation and characterization of a molecular cDNA clone of a human mRNA from interferon-treated cells encoding nucleolar protein B23, numatrin. |journal=Biochem. Biophys. Res. Commun. |volume=164 |issue= 1 |pages= 176-84 |year= 1989 |pmid= 2478125 |doi= }}
*{{cite journal | author=Hale TK, Mansfield BC |title=Nucleotide sequence of a cDNA clone representing a third allele of human protein B23. |journal=Nucleic Acids Res. |volume=17 |issue= 23 |pages= 10112 |year= 1990 |pmid= 2602120 |doi= }}
*{{cite journal | author=Chan WY, Liu QR, Borjigin J, ''et al.'' |title=Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. |journal=Biochemistry |volume=28 |issue= 3 |pages= 1033-9 |year= 1989 |pmid= 2713355 |doi= }}
*{{cite journal | author=Li XZ, McNeilage LJ, Whittingham S |title=The nucleotide sequence of a human cDNA encoding the highly conserved nucleolar phosphoprotein B23. |journal=Biochem. Biophys. Res. Commun. |volume=163 |issue= 1 |pages= 72-8 |year= 1989 |pmid= 2775293 |doi= }}
*{{cite journal | author=Chan PK, Aldrich M, Cook RG, Busch H |title=Amino acid sequence of protein B23 phosphorylation site. |journal=J. Biol. Chem. |volume=261 |issue= 4 |pages= 1868-72 |year= 1986 |pmid= 3944116 |doi= }}
*{{cite journal | author=Bocker T, Bittinger A, Wieland W, ''et al.'' |title=In vitro and ex vivo expression of nucleolar proteins B23 and p120 in benign and malignant epithelial lesions of the prostate. |journal=Mod. Pathol. |volume=8 |issue= 3 |pages= 226-31 |year= 1995 |pmid= 7542384 |doi= }}
*{{cite journal | author=Dundr M, Leno GH, Hammarskjöld ML, ''et al.'' |title=The roles of nucleolar structure and function in the subcellular location of the HIV-1 Rev protein. |journal=J. Cell. Sci. |volume=108 ( Pt 8) |issue= |pages= 2811-23 |year= 1995 |pmid= 7593322 |doi= }}
*{{cite journal | author=Miyazaki Y, Takamatsu T, Nosaka T, ''et al.'' |title=The cytotoxicity of human immunodeficiency virus type 1 Rev: implications for its interaction with the nucleolar protein B23. |journal=Exp. Cell Res. |volume=219 |issue= 1 |pages= 93-101 |year= 1995 |pmid= 7628555 |doi= 10.1006/excr.1995.1209 }}
*{{cite journal | author=Szebeni A, Herrera JE, Olson MO |title=Interaction of nucleolar protein B23 with peptides related to nuclear localization signals. |journal=Biochemistry |volume=34 |issue= 25 |pages= 8037-42 |year= 1995 |pmid= 7794916 |doi= }}
*{{cite journal | author=Kato S, Sekine S, Oh SW, ''et al.'' |title=Construction of a human full-length cDNA bank. |journal=Gene |volume=150 |issue= 2 |pages= 243-50 |year= 1995 |pmid= 7821789 |doi= }}
*{{cite journal | author=Marasco WA, Szilvay AM, Kalland KH, ''et al.'' |title=Spatial association of HIV-1 tat protein and the nucleolar transport protein B23 in stably transfected Jurkat T-cells. |journal=Arch. Virol. |volume=139 |issue= 1-2 |pages= 133-54 |year= 1995 |pmid= 7826206 |doi= }}
*{{cite journal | author=Valdez BC, Perlaky L, Henning D, ''et al.'' |title=Identification of the nuclear and nucleolar localization signals of the protein p120. Interaction with translocation protein B23. |journal=J. Biol. Chem. |volume=269 |issue= 38 |pages= 23776-83 |year= 1994 |pmid= 8089149 |doi= }}
}}
{{refend}}

{{protein-stub}}
{{WikiDoc Sources}}

CD135

2010-10-05T01:14:18Z

Robert Killeen:

Heparin-induced thrombocytopenia

2010-10-04T01:19:13Z

Robert Killeen:

{{SI}}
{{CMG}}
__NOTOC__
'''Associate Editor-In-Chief:''' {{CZ}}

'''Assistant Editor-In-Chief:''' Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [mailto:achall@bidmc.harvard.edu]

{{Editor Help}}

==Overview==

'''Heparin-induced thrombocytopenia''' (HIT) with or without '''thrombosis''' (HITT) is [[thrombocytopenia]] (low [[platelet]] counts) due to the administration of [[heparin]]. While it is mainly associated with [[unfractionated heparin]] ([[UFH]]), it can also occur with exposure to [[low-molecular weight heparin]] (LMWH), but at significantly lower rates. The development of mild to moderate thrombocytopenia (platelet counts of 50-70,000) in the context of heparin exposure is suggestive of a possible diagnosis of HIT while severe thrombocytopenia and platelet counts less than 20,000 are quite unusual for the syndrome.<ref name="pmid20059332">{{cite journal |author=Arepally GM, Ortel TL |title=Heparin-induced thrombocytopenia |journal=Annu. Rev. Med. |volume=61 |issue= |pages=77–90 |year=2010 |pmid=20059332 |doi=10.1146/annurev.med.042808.171814 |url=}}</ref> Given the nadirs in the platelet count, clinically significant bleeding associated with the thrombocoytopenia is quite rare. On the contrary, heparin induced thrombocytopenia is primarily a [[thrombosis|thrombotic]] disorder, with very high rates of [[thrombosis]], in the [[artery|arteries]] with or without [[vein|venous]] complications. Of note, the rate of [[DVT]] ([[Deep Vein Thrombosis]]) is roughly 4 times that of arterial thrombosis, and while [[thrombocytopenia]] is the most common "event" in HIT, DVT is in fact the most common complication.

HIT typically develops 4-14 days after the administration of [[heparin]]. The onset of thrombocytopenia in less than 4-5 days after the initiation of heparin treatment is extremely rare due to the time required for antibody production, and alternative explanations should be sought for the development of thrombocytopenia this early in therapy. The primary exception to this is in the case of recent heparin exposures (<100 days) where the patient may have pre-existing antibodies against the heparin-PF4 complex.<ref name="pmid16928996">{{cite journal |author=Arepally GM, Ortel TL |title=Clinical practice. Heparin-induced thrombocytopenia |journal=N. Engl. J. Med. |volume=355 |issue=8 |pages=809–17 |year=2006 |month=August |pmid=16928996 |doi=10.1056/NEJMcp052967 |url=}}</ref>

[[Heparin]] ([[UFH]]) is used in [[cardiovascular surgery]], as prevention or treatment for [[deep-vein thrombosis]] and [[pulmonary embolism]] and in various other clinical scenarios. [[LMWH]] is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

===Type I===
In this form patients characteristically have a transient decrease in platelet count (rarely <100,000) without any further symptoms. This thrombocytopenia recovers even if heparin is continued to be administered. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation. HIT-1 is due to heparin-induced platelet clumping; it is innocuous.

===Type II===
This form is due to an [[autoimmune disorder|autoimmune]] reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and [[IL-8|interleukin 8]] (IL8) which form complexes with heparin. The most common form is to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it [[antigen|antigenic]]. Antibodies bind to these complexes, activate the surrounding platelets and generate thrombin. The antibodies found are most commonly are of the [[IgG]] class with or without [[IgM]] and [[IgA]] class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II [[HIT]] develops in about 3% of all patients on UFH and in 0.1% of patients on [[LMWH]], and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of [[hemostasis|hemostasis]] that leads to thrombosis. Clot formation is mainly arterial and rich in [[platelets]] ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped [[red blood cells]]). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion. Rapid-onset HIT can result in life-threatening acute systemic reactions (eg rigors, fever, hypertension, tachycardia) and cardiopulmonary collapse.

Delayed-onset HIT occurs in ~3-5% of HIT cases; patients who develop delayed onset HIT have heparin/PF4 reactive antibodies that are able to activate platelets even in the absence of heparin. Single or trivial doses of heparin, such as catheter flushes, can cause HIT. In HIT2 the onset of thrombocytopenia is independent of the type of heparin, dose and route of administration. HIT antibodies can persist for 4-6 weeks but disappear after 3 months.

The presence of HIT antibodies, even at higher titer, doesn't predict an increase in complications. An increase in the titers of the antibodies do, however, give an increase in the in-vitro activaton of the coagulation system. The ELISA test, though not ideal, is the best predictive diagnostic test of HIT2. It has been suggested that HIT2 only occurs with high antibody titers and after persistent exposure to heparin; also it suggests that antigens different from the H-PF4 complex can be involved. There may be a HIT antibody active in a non-heparin dependent manner. Data exists suggesting that there are "superactive" HIT antibodies capable of activating platelets without heparin.

Genetic risk factors for thrombosis such as [[factor V Leiden]], [[prothrombin]] gene mutation, [[methylenetetrahydrofolate reductase]] ([[MTHFR]]) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

4 factors that affect the risk of developing HIT are noted as follows.<ref>Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. ''Blood'' 2006;108:2937-41. PMID 16857993.</ref>
1) Duration of heparin treatment; long duration, up to 2 weeks is associated with the greatest risk.
2) The type of heparin involved; UFH has a greater risk than LMWH.
3) The type of patient; surgical patients are at higher risk than medical; cardiac surgical patients have the highest risk of all.
4) Females have a higher risk.

CPB bypass: The management of cardiopulmonary bypass (CPB) patients with active HIT is controversial. Direct Thrombin Inhibitors such as agatroban and hirudin are used (and increase the aPTT in a dose dependent manner). However, in the large doses required for CPB hirudin's effects cannot be monitored well. Following CPB surgery the platelet count drops to about 40-60% of normal within the first 2-3 days postop due to hemodilution and platelet consumption. But there is also a risk of HIT. 20-50% of patients develop heparin antibodies during the first 5-10 days following CPB and some develop HIT (1-3% if UFH is continued through the postop period).

==Diagnosis==

The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests. <ref>{{cite journal |author=Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U |title=Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia |journal=Br J Haematol |volume=109 |issue=1 |pages=182-6 |year=2000 |pmid=10848798}}.</ref> <ref>Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992; 102:337S-351S. PMID 1327666</ref> <ref>Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am 1998; 82:635-58. PMID 9646784</ref> <ref>Fabris F, Luzzatto G, Stefani PM, Girolami B, Cella G, Girolami A. Heparin-induced thrombocytopenia. Haematologica 2000 Jan; 85:72-81. PMID 10629596</ref>

If HIT is suspected it may take hours to days to obtain the laboratory back.
In the meantime it may simply be a safer approach to substitute another agent (eg agatroban) for heparin. If there is a major diagnostic doubt then there is a "4T" system for identifying patients at risk for HIT. It is defined as follows;
0-3 points; low probability
4-5 points; intermediate probability
6-8 points; high probability
If the probability is high then discontinue the heparin and begin an alternative anticoagulant; some references recommend the same for those of intermediate risk too.

1) Thrombocytopenia;
0 points for <30% fall or a nadir <10,000
1 point for a 30-50% fall or a nadir of 10-19,000
2 points for a >50% fall or a nadir greater than or equal to 20,000
2) Timing of the decrease in platelet count;
0 points for less than a day
1 point for greater than day 10 or timing unclear or less than day 1 if heparin exposure was within the past 30-100 days.
2 points for day 5-10 or less than or equal to day 1 with recent heparin use (past 30 days)
3) Thrombosis or other sequelae;
0 points for no thrombosis
1 point for progressive, recurrent or silent thrombosis; erythematous skin lesions.
2 points for a proven thrombosis, skin necrosis or acute systemic reaction after heparin bolus.
4) Other causes of thrombocytopenia;
0 points if a definitive concurrent cause.
1 point if there is a possible other reason for thrombocytopenia.
2 points if there are no other possible reasons for thrombocytopenia.

Isolated HIT:
This entity occurs when there is a decreased platelet count but without evidence of thrombosis. It is recommended to stop the heparin and use alternative anticoagulation. It is also recommended to screen for subclinical deep venous thrombosis with a compression ultrasound (~50% of patients show a DVT with this check).
==Treatment==
Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, [[lepirudin]], [[fondaparinux]], [[bivalirudin]], [[argatroban]], [[danaparoid]] or other [[direct thrombin inhibitor]]s are used. [[Low molecular weight heparin]] is deemed contraindicated in HIT.

According to past reviews, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. <ref>{{cite journal |author=Hirsh J, Heddle N, Kelton J |title=Treatment of heparin-induced thrombocytopenia: a critical review |journal=Arch Intern Med |volume=164 |issue=4 |pages=361-9 |year=2004 |pmid=14980986}}
.</ref>

== Pharmacotherapy ==

=== Acute Pharmacotherapies ===
* Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis and should be reserved for patients with active bleeding. [[Warfarin]] therapy should be avoided for 3-5 days after [[heparin]] cessation and/or until [[thrombocytopenia]] resolves (>100,000).
* Use of direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention.

Danaproid (Orgaran) is a heparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% [[chondroitin sulphate]] that has approximately 10% cross reactivity with [[heparin]]. It has been shown to reduce mortality from thrombotic complications to 5% from 28%.
* The in vitro cross reactivity of LMWH with heparin dependent antibodies is approximately 60-100%. Some argue that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity. Nonetheless, a theoretical argument for the use of [[LMWH]] in therapy for HIT has been made. The theory is that the [[LMWH]] overall interaction of [[heparin]] with PF4 will diminish. Though there are reports of [[LMWH]] being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.

As stated before when HIT is suspected it is recommended to discontinue the heparin and initiate other agents such as direct thrombin inhibitors (DTIs; agatroban, hirudin & bivalirudin). Agatroban (AKA Novastan) doesn't resemble heparin and therefore won't cross-react with heparin antibodies. It is a medication specifically designed as a synthetic intravenous thrombin inhibitor, derived from arginine, to be an anticoagulant in patients with HIT. It is hepatically eliminated (t1/2 = 1 hour). It is contraindicated in patients with problems of hemorrhage and one should avoid intramuscular injections during its use. The infusion is initiated at 2 ug/kg/min; in patients with hepatic impairment it is recommended to reduce the dose to 0.5 ug/kg/min. Adjustment is made to a steady state aPTT of 1.5-3X the baseline. With this regimen greater than half of patients had platelet counts recover by day 3 (in HIT). Abrupt discontinuation of agatroban can lead to a hypercoagulable state. With administration its effects are immediate and a steady state can be achieved in 1-3 hours. When agatroban is given it is advised to begin coumadin. When the INR is >4 discontinue the agatroban and recheck the INR 4-6 hours later. If the INR is below the therapeutic range then resume agatroban. Avoid prothrombotic problems by overlapping the coumadin and agatroban. It has no cross-reactivity with HIT antibodies (to PF4). There is no antibody formation after repeated administration. It does not require dose adjustment in renal impairment.
Lepirudin is a DTI but, unlike agatroban, it is eliminated by the kidneys.
Hirudin binds to the active site of thrombin by exosite 1, the site at which thrombin binds to its substrates.
Bivalrirudin, like hirudin, binds to the active site of thrombin/exostie 1.

Coumadin (and vitamin K antagonists generally) are recommended for long-term anticoagulation however they should not be administered too early, unopposed or in excessive doses. It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene. Discontinuing the heparin and giving Coumadin doesn't prevent the onset of thrombosis in ~50% of patients. Once thrombocytopenia has resolved the coumadin can then be given at a low maintenance dose and alternative anticoagulation should be continued along with coumadin for at least 5 days. The alternative anticoagulant should not be discontinued until the platelet count has achieved a stable plateau and the INR has been the therapeutic range for at least 2 days. The optimal duration of the anticoagulation has not been established.

== Patients Undergoing Surgery or PCI ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support these procedures.

== Secondary Prevention ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support future procedures.

==Reference==
{{Reflist|2}}

==External links==
* [http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2001/thrombocytopenia.htm Cleveland clinic] page on HIT
* [http://www.clinicalschool.swan.ac.uk/wics/itugl/hit.htm HIT page]

==Additional Reading==
* Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1
* Aouifi A, Blanc P, Piriou V, Bastien OH, French P, Hanss M, Lehot JJ. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thoracic Surg 2001;71:678-683.
* Follis F, Filippone G, Montalbano G, Floriano M, LoBianco E, D'Ancona G, Follis M. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact CardioVas Thorac Surg 2010;10:592-596.
* Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytpenia patients. Artificial Organs. 2010;34(8):667-669.

{{SIB}}

[[Category:Hematology]]

[[de:Heparin-induzierte Thrombozytopenie]]
[[it:Trombocitopenia indotta da eparina]]

{{WH}}
{{WS}}

Heparin-induced thrombocytopenia

2010-10-03T01:12:38Z

Robert Killeen:

{{SI}}
{{CMG}}
__NOTOC__
'''Associate Editor-In-Chief:''' {{CZ}}

'''Assistant Editor-In-Chief:''' Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [mailto:achall@bidmc.harvard.edu]

{{Editor Help}}

==Overview==

'''Heparin-induced thrombocytopenia''' (HIT) with or without '''thrombosis''' (HITT) is [[thrombocytopenia]] (low [[platelet]] counts) due to the administration of [[heparin]]. While it is mainly associated with [[unfractionated heparin]] ([[UFH]]), it can also occur with exposure to [[low-molecular weight heparin]] (LMWH), but at significantly lower rates. The development of mild to moderate thrombocytopenia (platelet counts of 50-70,000) in the context of heparin exposure is suggestive of a possible diagnosis of HIT while severe thrombocytopenia and platelet counts less than 20,000 are quite unusual for the syndrome.<ref name="pmid20059332">{{cite journal |author=Arepally GM, Ortel TL |title=Heparin-induced thrombocytopenia |journal=Annu. Rev. Med. |volume=61 |issue= |pages=77–90 |year=2010 |pmid=20059332 |doi=10.1146/annurev.med.042808.171814 |url=}}</ref> Alternatively, a decrease of platelet count by 30-50% with heparin exposure in the absence of absolute thrombocytopenia is also consistent with heparin induced thrombocytopenia. Given these relatively high nadirs in platelet count, clinically significant bleeding associated with the thrombocoytopenia is quite rare. Heparin induced thrombocytopenia is primarily a [[thrombosis|thrombotic]] disorder, with very high rates of [[thrombosis]], in the [[artery|arteries]] with or without [[vein|venous]] complications. Of note, the rate of [[DVT]] ([[Deep Vein Thrombosis]]) is roughly 4 times that of arterial thrombosis, and while [[thrombocytopenia]] is the most common "event" in HIT, DVT is in fact the most common complication.

HIT typically develops 4-14 days after the administration of [[heparin]]. The onset of thrombocytopenia in less than 4-5 days after the initiation of heparin treatment is extremely rare due to the time required for antibody production, and alternative explanations should be sought for the development of thrombocytopenia earlier in therapy. The primary exception to this is in the case of recent heparin exposures (<100 days) where the patient may have pre-existing antibodies against the heparin-PF4 complex.<ref name="pmid16928996">{{cite journal |author=Arepally GM, Ortel TL |title=Clinical practice. Heparin-induced thrombocytopenia |journal=N. Engl. J. Med. |volume=355 |issue=8 |pages=809–17 |year=2006 |month=August |pmid=16928996 |doi=10.1056/NEJMcp052967 |url=}}</ref>

[[Heparin]] ([[UFH]]) is used in [[cardiovascular surgery]], as prevention or treatment for [[deep-vein thrombosis]] and [[pulmonary embolism]] and in various other clinical scenarios. [[LMWH]] is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

===Type I===
Patients characteristically have a transient decrease in platelet count (rarely <100,000) without any further symptoms. This recovers even if heparin is continued to be administered. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation. HIT-1 is due to heparin-induced platelet clumping; it is innocuous.

===Type II===
This form is due to an [[autoimmune disorder|autoimmune]] reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and [[IL-8|interleukin 8]] (IL8) which form complexes with heparin. The most common being to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it [[antigen|antigenic]]. The antibodies found are most commonly of the [[IgG]] class with or without [[IgM]] and [[IgA]] class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II [[HIT]] develops in about 3% of all patients on UFH and in 0.1% of patients on [[LMWH]], and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of [[hemostasis|hemostasis]] that leads to thrombosis. Clot formation is mainly arterial and rich in [[platelets]] ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped [[red blood cells]]). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion. Rapid-onset HIT can result in life-threatening acute systemic reactions (eg rigors, fever, hypertension, tachycardia) and cardiopulmonary collapse.

Delayed-onset HIT occurs in ~3-5% of HIT cases; patients who develop delayed onset HIT have heparin/PF4 reactive antibodies that are able to activate platelets even in the absence of heparin. Single or trivial doses of heparin, such as catheter flushes, can cause HIT. In HIT2 the onset of thrombocytopenia is independent of the type of heparin, dose and route of administration. Necrosis of the skin occurs at the injection site. HIT antibodies can persist for 4-6 weeks but disappear after 3 months.

The presence of HIT antibodies, even at higher titer, didn't predict an increase in complications. An increase in the titers of the antibodies did, however, give an increase in the in-vitro activaton of the coagulation system. The ELISA test, though not ideal, is the best predictive diagnostic test of HIT2. It has been suggested that HIT2 only occurs with high antibody titers and after persistent exposure to heparin; also it suggest that antigens different from the H-PF4 complex can be involved. There may be a HIT antibody active in a non-heparin dependent manner. Data exists suggesting that there are "superactive" HIT antibodies capable of activating platelets without heparin.

The most important enzyme in type II HIT is [[thrombin]], the generation of which is increased following platelet activation. Platelet activation follows the binding of heparin to PF4 and the cross linking of receptors on the platelet surface.

Genetic risk factors for thrombosis such as [[factor V Leiden]], [[prothrombin]] gene mutation, [[methylenetetrahydrofolate reductase]] ([[MTHFR]]) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

4 factors that affect the risk of developing HIT are noted as follows.<ref>Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. ''Blood'' 2006;108:2937-41. PMID 16857993.</ref>
1) Duration of heparin treatment; long duration, up to 2 weeks is associated with the greatest risk.
2) The type of heparin involved; UFH has a greater risk than LMWH.
3) The type of patient; Surgical patients are at higher risk than medical; cardiac surgical patients have the highest risk of all.
4) Females have a higher risk.

CPB bypass: The management of cardiopulmonary bypass (CPB) patients with active HIT is controversial. Direct Thrombin Inhibitors such as agatroban and hirudin are used (and increase the aPTT in a dose dependent manner). However, in the large doses required for CPB hirudin's effects cannot be monitored well. Following CPB surgery the platelet count drops to about 40-60% of normal within the first 2-3 days postop due to hemodilution and platelet consumption. But there is also a risk of HIT. 20-50% of patients develop heparin antibodies during the first 5-10 days following CPB and some develop HIT (1-3% if UFH is continued through the postop period).

==Diagnosis==

The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests. <ref>{{cite journal |author=Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U |title=Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia |journal=Br J Haematol |volume=109 |issue=1 |pages=182-6 |year=2000 |pmid=10848798}}.</ref> <ref>Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992; 102:337S-351S. PMID 1327666</ref> <ref>Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am 1998; 82:635-58. PMID 9646784</ref> <ref>Fabris F, Luzzatto G, Stefani PM, Girolami B, Cella G, Girolami A. Heparin-induced thrombocytopenia. Haematologica 2000 Jan; 85:72-81. PMID 10629596</ref>

If HIT is suspected it may take hours to days to obtain the laboratory back.
In the meantime it may simply be a safer approach to substitute another agent (eg agatroban) for heparin. If there is a major doubt then there is a "4T" system for identifying patients at risk for HIT. It is defined as follows;
0-3 points; low probability
4-5 points; intermediate probability
6-8 points; high probability
If the probability is high then discontinue the heparin and begin an alternative anticoagulant; some references recommend the same for those of intermediate risk too.

1) Thrombocytopenia;
0 points for <30% fall or a nadir <10,000
1 point for a 30-50% fall or a nadir of 10-19,000
2 points for a >50% fall or a nadir greater than or equal to 20,000
2) Timing of the decrease in platelet count;
0 points for less than a day
1 point for greater than day 10 or timing unclear or less than day 1 if heparin exposure was within the past 30-100 days.
2 points for day 5-10 or less than or equal to day 1 with recent heparin use (past 30 days)
3) Thrombosis or other sequelae;
0 points for no thrombosis
1 point for progressive, recurrent or silent thrombosis; erythematous skin lesions.
2 points for a proven thrombosis, skin necrosis or acute systemic reaction after heparin bolus.
4) Other causes of thrombocytopenia;
0 points if a definitive concurrent cause.
1 point if there is a possible other reason for thrombocytopenia.
2 points if there are no other possible reasons for thrombocytopenia.

Isolated HIT:
This entity occurs when there is a decreased platelet count but without evidence of thrombosis. It is recommended to stop the heparin and use alternative anticoagulation. It is also recommended to screen for subclinical deep venous thrombosis with a compression ultrasound (~50% of patients show a DVT with this check).
==Treatment==
Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, [[lepirudin]], [[fondaparinux]], [[bivalirudin]], [[argatroban]], [[danaparoid]] or other [[direct thrombin inhibitor]]s are used. [[Low molecular weight heparin]] is deemed contraindicated in HIT.

According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. <ref>{{cite journal |author=Hirsh J, Heddle N, Kelton J |title=Treatment of heparin-induced thrombocytopenia: a critical review |journal=Arch Intern Med |volume=164 |issue=4 |pages=361-9 |year=2004 |pmid=14980986}}
.</ref>

== Pharmacotherapy ==

=== Acute Pharmacotherapies ===
* Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis and should be reserved for patients with active bleeding. [[Warfarin]] therapy is should be avoided for 3-5 days after [[heparin]] cessation and/or until [[thrombocytopenia]] resolves (>100,000).
* Use of heparinoids and direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention.

Danaproid (Orgaran) is a heparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% [[chondroitin sulphate]] that has approximately 10% cross reactivity with [[heparin]]. It has been shown to reduce mortality from thrombotic complications to 5% from 28%.
* The in vitro cross reactivity of LMWH with heparin dependent antibodies is approximately 60-100%. Some argue that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity. Nonetheless, a theoretical argument for the use of [[LMWH]] in therapy for HIT has been made. The theory is that the [[LMWH]] overall interaction of [[heparin]] with PF4 will diminish. Though there are reports of [[LMWH]] being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.

As stated before when HIT is suspected it is recommended to discontinue the heparin and initiate other agents such as direct thrombin inhibitors (DTIs; agatroban, hirudin & bivalirudin). Agatroban (AKA Novastan) doesn't resemble heparin and therefore won't cross-react with heparin antibodies. Is is a medication specifically designed as a synthetic intravenous thrombin inhibitor, derived from arginine, to be an anticoagulant in patients with HIT. It is hepatically eliminated (t1/2 = 1 hour). It is contraindicated in patients with problems of hemorrhage and one should avoid intramuscular injections during its use. The infusion is initiated at 2 ug/kg/min; in patients with hepatic impairment it is recommended to reduce the dose to 0.5 ug/kg/min. Adjustment is made to a steady state aPTT of 1.5-3X the baseline. With this regimen greater than half of patients had platelet counts recover by day 3 (in HIT). Abrupt discontinuation of agatroban can lead to a hypercoagulable state. With administration its effects are immediate and a steady state can be achieved in 1-3 hours. When agatroban is given it is advised to begin coumadin. When the INR is >4 discontinue the agatroban and recheck the INR 4-6 hours later. If the INR is below the therapeutic range then resume agatroban. Avoid prothrombotic problems by overlapping the coumadin and agatroban. It has no cross-reactivity with HIT antibodies (to PF4). There is no antibody formation after repeated adminstration. It does not requrie dose adjustment in renal impariment.
Lepirudin is a DTI but, unlike agatroban, it is eliminated by the kidneys.
Hirudin binds to the active site of thrombin by exosite 1, the site at which thrombin binds to its substrates.
Bivalrirudin, like hirudin, binds to the active site of thrombin/exostie 1.

Coumadin (and vitamin K antagonists generally) are recommended for long-term anticoagulation however they should not be administered early, unopposed or in excessive doses. It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene. Discontinuing the heparin and giving Coumadin doesn't prevent the onset of thrombosis in ~50% of patients. Once thrombocytopenia has resolved coumadin can then be given at a low maintenance dose and alternative anticoagulation should be continued along with coumadin for at least 5 days. The alternative anticoagulant should not be discontinued until the platelet count has achieved a stable plateau and the INR has been the therapeutic range for at least 2 days. The optimal duration of the anticoagulation has not been established.

== Patients Undergoing Surgery or PCI ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support these procedures.

== Secondary Prevention ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support future procedures.

==Reference==
{{Reflist|2}}

==External links==
* [http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2001/thrombocytopenia.htm Cleveland clinic] page on HIT
* [http://www.clinicalschool.swan.ac.uk/wics/itugl/hit.htm HIT page]

==Additional Reading==
* Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1
* Aouifi A, Blanc P, Piriou V, Bastien OH, French P, Hanss M, Lehot JJ. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thoracic Surg 2001;71:678-683.
* Follis F, Filippone G, Montalbano G, Floriano M, LoBianco E, D'Ancona G, Follis M. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact CardioVas Thorac Surg 2010;10:592-596.
* Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytpenia patients. Artificial Organs. 2010;34(8):667-669.

{{SIB}}

[[Category:Hematology]]

[[de:Heparin-induzierte Thrombozytopenie]]
[[it:Trombocitopenia indotta da eparina]]

{{WH}}
{{WS}}

Heparin-induced thrombocytopenia

2010-10-03T00:43:41Z

Robert Killeen:

{{SI}}
{{CMG}}
__NOTOC__
'''Associate Editor-In-Chief:''' {{CZ}}

'''Assistant Editor-In-Chief:''' Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [mailto:achall@bidmc.harvard.edu]

{{Editor Help}}

==Overview==

'''Heparin-induced thrombocytopenia''' (HIT) with or without '''thrombosis''' (HITT) is [[thrombocytopenia]] (low [[platelet]] counts) due to the administration of [[heparin]]. While it is mainly associated with [[unfractionated heparin]] ([[UFH]]), it can also occur with exposure to [[low-molecular weight heparin]] (LMWH), but at significantly lower rates. The development of mild to moderate thrombocytopenia (platelet counts of 50-70,000) in the context of heparin exposure is suggestive of a possible diagnosis of HIT while severe thrombocytopenia and platelet counts less than 20,000 are quite unusual for the syndrome.<ref name="pmid20059332">{{cite journal |author=Arepally GM, Ortel TL |title=Heparin-induced thrombocytopenia |journal=Annu. Rev. Med. |volume=61 |issue= |pages=77–90 |year=2010 |pmid=20059332 |doi=10.1146/annurev.med.042808.171814 |url=}}</ref> Alternatively, a decrease of platelet count by 30-50% with heparin exposure in the absence of absolute thrombocytopenia is also consistent with heparin induced thrombocytopenia. Given these relatively high nadirs in platelet count, clinically significant bleeding associated with the thrombocoytopenia is quite rare. Heparin induced thrombocytopenia is primarily a [[thrombosis|thrombotic]] disorder, with very high rates of [[thrombosis]], in the [[artery|arteries]] with or without [[vein|venous]] complications. Of note, the rate of [[DVT]] ([[Deep Vein Thrombosis]]) is roughly 4 times that of arterial thrombosis, and while [[thrombocytopenia]] is the most common "event" in HIT, DVT is in fact the most common complication.

HIT typically develops 4-14 days after the administration of [[heparin]]. The onset of thrombocytopenia in less than 4-5 days after the initiation of heparin treatment is extremely rare due to the time required for antibody production, and alternative explanations should be sought for the development of thrombocytopenia earlier in therapy. The primary exception to this is in the case of recent heparin exposures (<100 days) where the patient may have pre-existing antibodies against the heparin-PF4 complex.<ref name="pmid16928996">{{cite journal |author=Arepally GM, Ortel TL |title=Clinical practice. Heparin-induced thrombocytopenia |journal=N. Engl. J. Med. |volume=355 |issue=8 |pages=809–17 |year=2006 |month=August |pmid=16928996 |doi=10.1056/NEJMcp052967 |url=}}</ref>

[[Heparin]] ([[UFH]]) is used in [[cardiovascular surgery]], as prevention or treatment for [[deep-vein thrombosis]] and [[pulmonary embolism]] and in various other clinical scenarios. [[LMWH]] is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

===Type I===
Patients characteristically have a transient decrease in platelet count (rarely <100,000) without any further symptoms. This recovers even if heparin is continued to be administered. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation. HIT-1 is due to heparin-induced platelet clumping; it is innocuous.

===Type II===
This form is due to an [[autoimmune disorder|autoimmune]] reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and [[IL-8|interleukin 8]] (IL8) which form complexes with heparin. The most common being to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it [[antigen|antigenic]]. The antibodies found are most commonly of the [[IgG]] class with or without [[IgM]] and [[IgA]] class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II [[HIT]] develops in about 3% of all patients on UFH and in 0.1% of patients on [[LMWH]], and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of [[hemostasis|hemostasis]] that leads to thrombosis. Clot formation is mainly arterial and rich in [[platelets]] ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped [[red blood cells]]). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion. Rapid-onset HIT can result in life-threatening acute systemic reactions (eg rigors, fever, hypertension, tachycardia) and cardiopulmonary collapse.

Delayed-onset HIT occurs in ~3-5% of HIT cases; patients who develop delayed onset HIT have heparin/PF4 reactive antibodies that are able to activate platelets even in the absence of heparin. Single or trivial doses of heparin, such as catheter flushes, can cause HIT. In HIT2 the onset of thrombocytopenia is independent of the type of heparin, dose and route of administration. Necrosis of the skin occurs at the injection site. HIT antibodies can persist for 4-6 weeks but disappear after 3 months.

The presence of HIT antibodies, even at higher titer, didn't predict an increase in complications. An increase in the titers of the antibodies did, however, give an increase in the in-vitro activaton of the coagulation system. The ELISA test, though not ideal, is the best predictive diagnostic test of HIT2. It has been suggested that HIT2 only occurs with high antibody titers and after persistent exposure to heparin; also it suggest that antigens different from the H-PF4 complex can be involved. There may be a HIT antibody active in a non-heparin dependent manner. Data exists suggesting that there are "superactive" HIT antibodies capable of activating platelets without heparin.

The most important enzyme in type II HIT is [[thrombin]], the generation of which is increased following platelet activation. Platelet activation follows the binding of heparin to PF4 and the cross linking of receptors on the platelet surface.

Genetic risk factors for thrombosis such as [[factor V Leiden]], [[prothrombin]] gene mutation, [[methylenetetrahydrofolate reductase]] ([[MTHFR]]) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

4 factors that affect the risk of developing HIT are noted as follows.<ref>Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. ''Blood'' 2006;108:2937-41. PMID 16857993.</ref>
1) Duration of heparin treatment; long duration, up to 2 weeks is associated with the greatest risk.
2) The type of heparin involved; UFH has a greater risk than LMWH.
3) The type of patient; Surgical patients are at higher risk than medical; cardiac surgical patients have the highest risk of all.
4) Females have a higher risk.

==Diagnosis==

The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests. <ref>{{cite journal |author=Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U |title=Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia |journal=Br J Haematol |volume=109 |issue=1 |pages=182-6 |year=2000 |pmid=10848798}}.</ref> <ref>Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992; 102:337S-351S. PMID 1327666</ref> <ref>Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am 1998; 82:635-58. PMID 9646784</ref> <ref>Fabris F, Luzzatto G, Stefani PM, Girolami B, Cella G, Girolami A. Heparin-induced thrombocytopenia. Haematologica 2000 Jan; 85:72-81. PMID 10629596</ref>

If HIT is suspected it may take hours to days to obtain the laboratory back.
In the meantime it may simply be a safer approach to substitute another agent (eg agatroban) for heparin. If there is a major doubt then there is a "4T" system for identifying patients at risk for HIT. It is defined as follows;
0-3 points; low probability
4-5 points; intermediate probability
6-8 points; high probability
If the probability is high then discontinue the heparin and begin an alternative anticoagulant; some references recommend the same for those of intermediate risk too.

1) Thrombocytopenia;
0 points for <30% fall or a nadir <10,000
1 point for a 30-50% fall or a nadir of 10-19,000
2 points for a >50% fall or a nadir greater than or equal to 20,000
2) Timing of the decrease in platelet count;
0 points for less than a day
1 point for greater than day 10 or timing unclear or less than day 1 if heparin exposure was within the past 30-100 days.
2 points for day 5-10 or less than or equal to day 1 with recent heparin use (past 30 days)
3) Thrombosis or other sequelae;
0 points for no thrombosis
1 point for progressive, recurrent or silent thrombosis; erythematous skin lesions.
2 points for a proven thrombosis, skin necrosis or acute systemic reaction after heparin bolus.
4) Other causes of thrombocytopenia;
0 points if a definitive concurrent cause.
1 point if there is a possible other reason for thrombocytopenia.
2 points if there are no other possible reasons for thrombocytopenia.

Isolated HIT:
This entity occurs when there is a decreased platelet count but without evidence of thrombosis. It is recommended to stop the heparin and use alternative anticoagulation. It is also recommended to screen for subclinical deep venous thrombosis with a compression ultrasound (~50% of patients show a DVT with this check).
==Treatment==
Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, [[lepirudin]], [[fondaparinux]], [[bivalirudin]], [[argatroban]], [[danaparoid]] or other [[direct thrombin inhibitor]]s are used. [[Low molecular weight heparin]] is deemed contraindicated in HIT.

According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. <ref>{{cite journal |author=Hirsh J, Heddle N, Kelton J |title=Treatment of heparin-induced thrombocytopenia: a critical review |journal=Arch Intern Med |volume=164 |issue=4 |pages=361-9 |year=2004 |pmid=14980986}}
.</ref>

== Pharmacotherapy ==

=== Acute Pharmacotherapies ===
* Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis and should be reserved for patients with active bleeding. [[Warfarin]] therapy is should be avoided for 3-5 days after [[heparin]] cessation and/or until [[thrombocytopenia]] resolves (>100,000).
* Use of heparinoids and direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention.

Danaproid (Orgaran) is a heparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% [[chondroitin sulphate]] that has approximately 10% cross reactivity with [[heparin]]. It has been shown to reduce mortality from thrombotic complications to 5% from 28%.
* The in vitro cross reactivity of LMWH with heparin dependent antibodies is approximately 60-100%. Some argue that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity. Nonetheless, a theoretical argument for the use of [[LMWH]] in therapy for HIT has been made. The theory is that the [[LMWH]] overall interaction of [[heparin]] with PF4 will diminish. Though there are reports of [[LMWH]] being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.

Coumadin (and vitamin K antagonists generally) are recommended for long-term anticoagulation however they should not be administered early, unopposed or in excessive doses. It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene. Discontinuing the heparin and giving Coumadin doesn't prevent the onset of thrombosis in ~50% of patients. Once thrombocytopenia has resolved coumadin can then be given at a low maintenance dose and alternative anticoagulation should be continued along with coumadin for at least 5 days. The alternative anticoagulant should not be discontinued until the platelet count has achieved a stable plateau and the INR has been the therapeutic range for at least 2 days. The optimal duration of the anticoagulation has not been established.

== Patients Undergoing Surgery or PCI ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support these procedures.

== Secondary Prevention ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support future procedures.

==Reference==
{{Reflist|2}}

==External links==
* [http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2001/thrombocytopenia.htm Cleveland clinic] page on HIT
* [http://www.clinicalschool.swan.ac.uk/wics/itugl/hit.htm HIT page]

==Additional Reading==
* Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1
* Aouifi A, Blanc P, Piriou V, Bastien OH, French P, Hanss M, Lehot JJ. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thoracic Surg 2001;71:678-683.
* Follis F, Filippone G, Montalbano G, Floriano M, LoBianco E, D'Ancona G, Follis M. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact CardioVas Thorac Surg 2010;10:592-596.
* Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytpenia patients. Artificial Organs. 2010;34(8):667-669.

{{SIB}}

[[Category:Hematology]]

[[de:Heparin-induzierte Thrombozytopenie]]
[[it:Trombocitopenia indotta da eparina]]

{{WH}}
{{WS}}

Heparin-induced thrombocytopenia

2010-10-02T22:19:03Z

Robert Killeen:

{{SI}}
{{CMG}}
__NOTOC__
'''Associate Editor-In-Chief:''' {{CZ}}

'''Assistant Editor-In-Chief:''' Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [mailto:achall@bidmc.harvard.edu]

{{Editor Help}}

==Overview==

'''Heparin-induced thrombocytopenia''' (HIT) with or without '''thrombosis''' (HITT) is [[thrombocytopenia]] (low [[platelet]] counts) due to the administration of [[heparin]]. While it is mainly associated with [[unfractionated heparin]] ([[UFH]]), it can also occur with exposure to [[low-molecular weight heparin]] (LMWH), but at significantly lower rates. The development of mild to moderate thrombocytopenia (platelet counts of 50-70,000) in the context of heparin exposure is suggestive of a possible diagnosis of HIT while severe thrombocytopenia and platelet counts less than 20,000 are quite unusual for the syndrome.<ref name="pmid20059332">{{cite journal |author=Arepally GM, Ortel TL |title=Heparin-induced thrombocytopenia |journal=Annu. Rev. Med. |volume=61 |issue= |pages=77–90 |year=2010 |pmid=20059332 |doi=10.1146/annurev.med.042808.171814 |url=}}</ref> Alternatively, a decrease of platelet count by 30-50% with heparin exposure in the absence of absolute thrombocytopenia is also consistent with heparin induced thrombocytopenia. Given these relatively high nadirs in platelet count, clinically significant bleeding associated with the thrombocoytopenia is quite rare. Heparin induced thrombocytopenia is primarily a [[thrombosis|thrombotic]] disorder, with very high rates of [[thrombosis]], in the [[artery|arteries]] with or without [[vein|venous]] complications. Of note, the rate of [[DVT]] ([[Deep Vein Thrombosis]]) is roughly 4 times that of arterial thrombosis, and while [[thrombocytopenia]] is the most common "event" in HIT, DVT is in fact the most common complication.

HIT typically develops 4-14 days after the administration of [[heparin]]. The onset of thrombocytopenia in less than 4-5 days after the initiation of heparin treatment is extremely rare due to the time required for antibody production, and alternative explanations should be sought for the development of thrombocytopenia earlier in therapy. The primary exception to this is in the case of recent heparin exposures (<100 days) where the patient may have pre-existing antibodies against the heparin-PF4 complex.<ref name="pmid16928996">{{cite journal |author=Arepally GM, Ortel TL |title=Clinical practice. Heparin-induced thrombocytopenia |journal=N. Engl. J. Med. |volume=355 |issue=8 |pages=809–17 |year=2006 |month=August |pmid=16928996 |doi=10.1056/NEJMcp052967 |url=}}</ref>

[[Heparin]] ([[UFH]]) is used in [[cardiovascular surgery]], as prevention or treatment for [[deep-vein thrombosis]] and [[pulmonary embolism]] and in various other clinical scenarios. [[LMWH]] is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

===Type I===
Patients characteristically have a transient decrease in platelet count (rarely <100,000) without any further symptoms. This recovers even if heparin is continued to be administered. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation. HIT-1 is due to heparin-induced platelet clumping; it is innocuous.

===Type II===
This form is due to an [[autoimmune disorder|autoimmune]] reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and [[IL-8|interleukin 8]] (IL8) which form complexes with heparin. The most common being to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it [[antigen|antigenic]]. The antibodies found are most commonly of the [[IgG]] class with or without [[IgM]] and [[IgA]] class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II [[HIT]] develops in about 3% of all patients on UFH and in 0.1% of patients on [[LMWH]], and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of [[hemostasis|hemostasis]] that leads to thrombosis. Clot formation is mainly arterial and rich in [[platelets]] ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped [[red blood cells]]). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion. Rapid-onset HIT can result in life-threatening acute systemic reactions (eg rigors, fever, hypertension, tachycardia) and cardiopulmonary collapse.

Delayed-onset HIT occurs in ~3-5% of HIT cases; patients who develop delayed onset HIT have heparin/PF4 reactive antibodies that are able to activate platelets even in the absence of heparin. Single or trivial doses of heparin, such as catheter flushes, can cause HIT. In HIT2 the onset of thrombocytopenia is independent of the type of heparin, dose and route of administration. Necrosis of the skin occurs at the injection site. HIT antibodies can persist for 4-6 weeks but disappear after 3 months.

The presence of HIT antibodies, even at higher titer, didn't predict an increase in complications. An increase in the titers of the antibodies did, however, give an increase in the in-vitro activaton of the coagulation system. The ELISA test, though not ideal, is the best predictive diagnostic test of HIT2. It has been suggested that HIT2 only occurs with high antibody titers and after persistent exposure to heparin; also it suggest that antigens different from the H-PF4 complex can be involved. There may be a HIT antibody active in a non-heparin dependent manner. Data exists suggesting that there are "superactive" HIT antibodies capable of activating platelets without heparin.

The most important enzyme in type II HIT is [[thrombin]], the generation of which is increased following platelet activation. Platelet activation follows the binding of heparin to PF4 and the cross linking of receptors on the platelet surface.

Genetic risk factors for thrombosis such as [[factor V Leiden]], [[prothrombin]] gene mutation, [[methylenetetrahydrofolate reductase]] ([[MTHFR]]) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

4 factors that affect the risk of developing HIT are noted as follows.<ref>Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. ''Blood'' 2006;108:2937-41. PMID 16857993.</ref>
1) Duration of heparin treatment; long duration, up to 2 weeks is associated with the greatest risk.
2) The type of heparin involved; UFH has a greater risk than LMWH.
3) The type of patient; Surgical patients are at higher risk than medical; cardiac surgical patients have the highest risk of all.
4) Females have a higher risk.

==Diagnosis==

The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests. <ref>{{cite journal |author=Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U |title=Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia |journal=Br J Haematol |volume=109 |issue=1 |pages=182-6 |year=2000 |pmid=10848798}}.</ref> <ref>Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992; 102:337S-351S. PMID 1327666</ref> <ref>Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am 1998; 82:635-58. PMID 9646784</ref> <ref>Fabris F, Luzzatto G, Stefani PM, Girolami B, Cella G, Girolami A. Heparin-induced thrombocytopenia. Haematologica 2000 Jan; 85:72-81. PMID 10629596</ref>

If HIT is suspected it may take hours to days to obtain the laboratory back.
In the meantime it may simply be a safer approach to substitute another agent (eg agatroban) for heparin. If there is a major doubt then there is a "4T" system for identifying patients at risk for HIT. It is defined as follows;
0-3 points; low probability
4-5 points; intermediate probability
6-8 points; high probability
If the probability is high then discontinue the heparin and begin an alternative anticoagulant; some references recommend the same for those of intermediate risk too.
1) Thrombocytopenia;
0 points for <30% fall or a nadir <10,000
1 point for a 30-50% fall or a nadir of 10-19,000
2 points for a >50% fall or a nadir greater than or equal to 20,000
2) Timing of the decrease in platelet count;
0 points for less than a day
1 point for greater than day 10 or timing unclear or less than day 1 if heparin exposure was within the past 30-100 days.
2 points for day 5-10 or less than or equal to day 1 with recent heparin use (past 30 days)
3) Thrombosis or other sequelae;
0 points for no thrombosis
1 point for progressive, recurrent or silent thrombosis; erythematous skin lesions.
2 points for a proven thrombosis, skin necrosis or acute systemic reaction after heparin bolus.
4) Other causes of thrombocytopenia;
0 points if a definitive concurrent cause.
1 point if there is a possible other reason for thrombocytopenia.
2 points if there are no other possible reasons for thrombocytopenia.

==Treatment==
Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, [[lepirudin]], [[fondaparinux]], [[bivalirudin]], [[argatroban]], [[danaparoid]] or other [[direct thrombin inhibitor]]s are used. [[Low molecular weight heparin]] is deemed contraindicated in HIT.

According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. <ref>{{cite journal |author=Hirsh J, Heddle N, Kelton J |title=Treatment of heparin-induced thrombocytopenia: a critical review |journal=Arch Intern Med |volume=164 |issue=4 |pages=361-9 |year=2004 |pmid=14980986}}
.</ref>

== Pharmacotherapy ==

=== Acute Pharmacotherapies ===
* Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis and should be reserved for patients with active bleeding. [[Warfarin]] therapy is should be avoided for 3-5 days after [[heparin]] cessation and/or until [[thrombocytopenia]] resolves (>100,000).
* Use of heparinoids and direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention.

Danaproid (Orgaran) is a heparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% [[chondroitin sulphate]] that has approximately 10% cross reactivity with [[heparin]]. It has been shown to reduce mortality from thrombotic complications to 5% from 28%.
* The in vitro cross reactivity of LMWH with heparin dependent antibodies is approximately 60-100%. Some argue that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity. Nonetheless, a theoretical argument for the use of [[LMWH]] in therapy for HIT has been made. The theory is that the [[LMWH]] overall interaction of [[heparin]] with PF4 will diminish. Though there are reports of [[LMWH]] being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.

Coumadin (and vitamin K antagonists generally) are recommended for long-term anticoagulation however they should not be administered early, unopposed or in excessive doses. It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene. Discontinuing the heparin and giving Coumadin doesn't prevent the onset of thrombosis in ~50% of patients. Once thrombocytopenia has resolved coumadin can then be given at a low maintenance dose and alternative anticoagulation should be continued along with coumadin for at least 5 days. The alternative anticoagulant should not be discontinued until the platelet count has achieved a stable plateau and the INR has been the therapeutic range for at least 2 days. The optimal duration of the anticoagulation has not been established.

== Patients Undergoing Surgery or PCI ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support these procedures.

== Secondary Prevention ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support future procedures.

==Reference==
{{Reflist|2}}

==External links==
* [http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2001/thrombocytopenia.htm Cleveland clinic] page on HIT
* [http://www.clinicalschool.swan.ac.uk/wics/itugl/hit.htm HIT page]

==Additional Reading==
* Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1
* Aouifi A, Blanc P, Piriou V, Bastien OH, French P, Hanss M, Lehot JJ. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thoracic Surg 2001;71:678-683.
* Follis F, Filippone G, Montalbano G, Floriano M, LoBianco E, D'Ancona G, Follis M. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact CardioVas Thorac Surg 2010;10:592-596.
* Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytpenia patients. Artificial Organs. 2010;34(8):667-669.

{{SIB}}

[[Category:Hematology]]

[[de:Heparin-induzierte Thrombozytopenie]]
[[it:Trombocitopenia indotta da eparina]]

{{WH}}
{{WS}}

Heparin-induced thrombocytopenia

2010-09-29T22:54:37Z

Robert Killeen:

{{SI}}
{{CMG}}
__NOTOC__
'''Associate Editor-In-Chief:''' {{CZ}}

'''Assistant Editor-In-Chief:''' Aric C. Hall, M.D. Beth Israel Deaconess Medical Center, Boston, MA [mailto:achall@bidmc.harvard.edu]

{{Editor Help}}

==Overview==

'''Heparin-induced thrombocytopenia''' (HIT) with or without '''thrombosis''' (HITT) is [[thrombocytopenia]] (low [[platelet]] counts) due to the administration of [[heparin]]. While it is mainly associated with [[unfractionated heparin]] ([[UFH]]), it can also occur with exposure to [[low-molecular weight heparin]] (LMWH), but at significantly lower rates. The development of mild to moderate thrombocytopenia (platelet counts of 50-70,000) in the context of heparin exposure is suggestive of a possible diagnosis of HIT while severe thrombocytopenia and platelet counts less than 20,000 are quite unusual for the syndrome.<ref name="pmid20059332">{{cite journal |author=Arepally GM, Ortel TL |title=Heparin-induced thrombocytopenia |journal=Annu. Rev. Med. |volume=61 |issue= |pages=77–90 |year=2010 |pmid=20059332 |doi=10.1146/annurev.med.042808.171814 |url=}}</ref> Alternatively, a decrease of platelet count by 30-50% with heparin exposure in the absence of absolute thrombocytopenia is also consistent with heparin induced thrombocytopenia. Given these relatively high nadirs in platelet count, clinically significant bleeding associated with the thrombocoytopenia is quite rare. Heparin induced thrombocytopenia is primarily a [[thrombosis|thrombotic]] disorder, with very high rates of [[thrombosis]], in the [[artery|arteries]] with or without [[vein|venous]] complications. Of note, the rate of [[DVT]] ([[Deep Vein Thrombosis]]) is roughly 4 times that of arterial thrombosis, and while [[thrombocytopenia]] is the most common "event" in HIT, DVT is in fact the most common complication.

HIT typically develops 4-14 days after the administration of [[heparin]]. The onset of thrombocytopenia in less than 4-5 days after the initiation of heparin treatment is extremely rare due to the time required for antibody production, and alternative explanations should be sought for the development of thrombocytopenia earlier in therapy. The primary exception to this is in the case of recent heparin exposures (<100 days) where the patient may have pre-existing antibodies against the heparin-PF4 complex.<ref name="pmid16928996">{{cite journal |author=Arepally GM, Ortel TL |title=Clinical practice. Heparin-induced thrombocytopenia |journal=N. Engl. J. Med. |volume=355 |issue=8 |pages=809–17 |year=2006 |month=August |pmid=16928996 |doi=10.1056/NEJMcp052967 |url=}}</ref>

[[Heparin]] ([[UFH]]) is used in [[cardiovascular surgery]], as prevention or treatment for [[deep-vein thrombosis]] and [[pulmonary embolism]] and in various other clinical scenarios. [[LMWH]] is increasingly used in outpatient prophylaxis regimes.

There are two forms of HIT. Type II HIT is the main adverse effect of heparin use.

===Type I===
Patients have a transient decrease in platelet count without any further symptoms. This recovers even if heparin is continued to be administered. Platelet counts rarely fall below 100,000. It occurs in 10-20% of all patients on heparin. It is not due to an immune reaction and antibodies are not found upon investigation.

===Type II===
This form is due to an [[autoimmune disorder|autoimmune]] reaction with antibodies formed against platelet factor 4 (PF4), neutrophil-activating peptide 2 (NAP-2) and [[IL-8|interleukin 8]] (IL8) which form complexes with heparin. The most common being to the heparin-PF4 complex. It appears that heparin binding to platelet factor 4 causes a conformational change in the protein, rendering it [[antigen|antigenic]]. The antibodies found are most commonly of the [[IgG]] class with or without [[IgM]] and [[IgA]] class antibodies. IgM and IgA are rarely found without IgG antibodies. Type II [[HIT]] develops in about 3% of all patients on UFH and in 0.1% of patients on [[LMWH]], and causes thrombosis in 30% to 40% of these patients. The other patients are able to compensate for the activation of [[hemostasis|hemostasis]] that leads to thrombosis. Clot formation is mainly arterial and rich in [[platelets]] ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped [[red blood cells]]). Most thrombotic events are in the lower limbs, skin lesions and necrosis may also occur at the site of the heparin infusion

The most important enzyme in type II HIT is [[thrombin]], the generation of which is increased following platelet activation. Platelet activation follows the binding of heparin to PF4 and the cross linking of receptors on the platelet surface.

Genetic risk factors for thrombosis such as [[factor V Leiden]], [[prothrombin]] gene mutation, [[methylenetetrahydrofolate reductase]] ([[MTHFR]]) polymorphism and platelet-receptor polymorphisms do not increase the risk of developing HIT associated thrombosis.

4 factors that affect the risk of developing HIT are noted as follows.<ref>Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. ''Blood'' 2006;108:2937-41. PMID 16857993.</ref>
1) Duration of heparin treatment; long duration, up to 2 weeks is associated with the greatest risk.
2) The type of heparin involved; UFH has a greater risk than LMWH.
3) The type of patient; Surgical patients are at higher risk than medical; cardiac surgical patients have the highest risk of all.
4) Females have a hgiher risk.

==Diagnosis==

The most specific tests are: the serotonin release assay (SRA), the heparin induce platelet aggregation (HIPA) assays and the solid-phase immunoassay (SPI). The sensitivity of these tests is 94% at best. The gold standard is the SRA where antibodies from the patient’s serum result in release of radiolabeled serotonin attached to platelets from a normal patient. The HIPA looks for platelet aggregation that is present with heparin, platelets and patient serum but does not occur in the absence of heparin. It has a >90% specificity but is limited by low sensitivity. The SPI is an enzyme-linked immunosorbent assay (ELISA) that tests for the presence or absence of heparin-PF4 complexes. Because it does not determine whether the antibodies are functionally significant, it is best used in conjunction with one of the two prior tests. <ref>{{cite journal |author=Harenberg J, Huhle G, Giese C, Wang L, Feuring M, Song X, Hoffmann U |title=Determination of serotonin release from platelets by enzyme immunoassay in the diagnosis of heparin-induced thrombocytopenia |journal=Br J Haematol |volume=109 |issue=1 |pages=182-6 |year=2000 |pmid=10848798}}.</ref> <ref>Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1992; 102:337S-351S. PMID 1327666</ref> <ref>Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy. Med Clin North Am 1998; 82:635-58. PMID 9646784</ref> <ref>Fabris F, Luzzatto G, Stefani PM, Girolami B, Cella G, Girolami A. Heparin-induced thrombocytopenia. Haematologica 2000 Jan; 85:72-81. PMID 10629596</ref>

If HIT is suspected it may take hours to days to obtain the laboratory back.
In the meantime it may simply be a safer approach to substitute another agent (eg agatroban) for heparin. If there is a major doubt then there is a "4T" system for identifying patients at risk for HIT. It is defined as follows;
0-3 points; low probability
4-5 points; intermediate probability
6-8 points; high probability
If the probability is high then discontinue the heparin and begin an alternative anticoagulant; some references recommend the same for those of intermediate risk too.
1) Thrombocytopenia;
0 points for <30% fall or a nadir <10,000
1 point for a 30-50% fall or a nadir of 10-19,000
2 points for a >50% fall or a nadir greater than or equal to 20,000
2) Timing of the decrease in platelet count;
0 points for less than a day
1 point for greater than day 10 or timing unclear or less than day 1 if heparin exposure was within the past 30-100 days.
2 points for day 5-10 or less than or equal to day 1 with recent heparin use (past 30 days)
3) Thrombosis or other sequelae;
0 points for no thrombosis
1 point for progressive, recurrent or silent thrombosis; erythematous skin lesions.
2 points for a proven thrombosis, skin necrosis or acute systemic reaction after heparin bolus.
4) Other causes of thrombocytopenia;
0 points if a definitive concurrent cause.
1 point if there is a possible other reason for thrombocytopenia.
2 points if there are no other possible reasons for thrombocytopenia.

==Treatment==
Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, [[lepirudin]], [[fondaparinux]], [[bivalirudin]], [[argatroban]], [[danaparoid]] or other [[direct thrombin inhibitor]]s are used. [[Low molecular weight heparin]] is deemed contraindicated in HIT.

According to systematic review, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. <ref>{{cite journal |author=Hirsh J, Heddle N, Kelton J |title=Treatment of heparin-induced thrombocytopenia: a critical review |journal=Arch Intern Med |volume=164 |issue=4 |pages=361-9 |year=2004 |pmid=14980986}}
.</ref>

== Pharmacotherapy ==

=== Acute Pharmacotherapies ===
* Check platelet counts twice weekly while on heparin. Withdrawal heparin immediately of HIT is suspected. Platelet transfusion worsens thrombosis and should be reserved for patients with active bleeding. [[Warfarin]] therapy is should be avoided for 3-5 days after [[heparin]] cessation and/or until [[thrombocytopenia]] resolves (>100,000).
* Use of heparinoids and direct thrombin inhibitors is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention.

Danaproid (Orgaran) is a heparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% [[chondroitin sulphate]] that has approximately 10% cross reactivity with [[heparin]]. It has been shown to reduce mortality from thrombotic complications to 5% from 28%.
* The in vitro cross reactivity of LMWH with heparin dependent antibodies is approximately 60-100%. Some argue that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity. Nonetheless, a theoretical argument for the use of [[LMWH]] in therapy for HIT has been made. The theory is that the [[LMWH]] overall interaction of [[heparin]] with PF4 will diminish. Though there are reports of [[LMWH]] being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.

Coumadin (and vitamin K antagonists generally) are recommended for long-term anticoagulation however they should not be administered early, unopposed or in excessive doses. It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene. Discontinuing the heparin and giving Coumadin doesn't prevent the onset of thrombosis in ~50% of patients. Once thrombocytopenia has resolved coumadin can then be given at a low maintenance dose and alternative anticoagulation should be continued along with coumadin for at least 5 days. The alternative anticoagulant should not be discontinued until the platelet count has achieved a stable plateau and the INR has been the therapeutic range for at least 2 days. The optimal duration of the anticoagulation has not been established.

== Patients Undergoing Surgery or PCI ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support these procedures.

== Secondary Prevention ==
Patients with HIT should be treated with [[Bivalirudin]], a direct thrombin inhibitor to support future procedures.

==Reference==
{{Reflist|2}}

==External links==
* [http://www.clevelandclinicmeded.com/medical_info/pharmacy/septoct2001/thrombocytopenia.htm Cleveland clinic] page on HIT
* [http://www.clinicalschool.swan.ac.uk/wics/itugl/hit.htm HIT page]

==Additional Reading==
* Kumar, Vinay, Abul Abbas, and Nelson Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. (2005). ISBN 0-7216-0187-1

{{SIB}}

[[Category:Hematology]]

[[de:Heparin-induzierte Thrombozytopenie]]
[[it:Trombocitopenia indotta da eparina]]

{{WH}}
{{WS}}

Paroxysmal nocturnal hemoglobinuria

2010-09-29T22:11:41Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 9688 |
ICD10 = {{ICD10|D|59|5|d|55}} |
ICD9 = {{ICD9|283.2}} |
ICDO = |
OMIM = 311770 |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2696 |
MeshID = D006457 |
}}
{{Search infobox}}
{{CMG}}

'''Editor-In-Chief:''' Robert Killeen, MD.[mailto:aak324@gmail.com]

{{EJ}}

==Overview==
'''Paroxysmal nocturnal hemoglobinuria''' ([[PNH]]) is a rare, acquired, potentially life-threatening disease of the blood characterised by [[hemolytic anemia]], [[thrombosis]] and red [[urine]] due to breakdown of [[red blood cell]]s. [[PNH]] is the only hemolytic anemia caused by an ''acquired'' intrinsic defect in the [[cell membrane]].

==History==
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852).<ref>Strübing P. Paroxysmale Hämoglobinurie. ''Dtsch Med Wochenschr'' 1882;8:1-3 and 17-21.</ref><ref>[http://www.whonamedit.com/synd.cfm/2918.html Whonamedit entry]</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>Marchiafava E, Nazari A. Nuovo contributo allo studio degli itteri cronici emolitici. ''Policlinico [Med]'' 1911;18:241-254.</ref> with further elaborations by Marchiafava in 1928<ref>Marchiafava E. Anemia emolitica con emosiderinuria perpetua. ''Policlinico [Med]'' 1928;35:105-117.</ref> and Dr Ferdinando Micheli in 1931.<ref>Micheli F. Uno caso di anemia emolitica con emosiderinuria perpetua. ''G Accad Med Torino'' 1931;13:148.</ref>

==Classification==
PNH is classified:
* ''Classic PNH''. Evidence of [[PNH]] in the absence of another bone marrow disorder.
* ''[[PNH]] in the setting of another specified bone marrow disorder''.
* ''Subclinical PNH''. [[PNH]] abnormalities on flow cytometry without signs of hemolysis.

==Pathophysiology==
All cells have proteins attached to their membranes that are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. [[PNH]] occurs as a result of a defect in one of these mechanisms.

It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.<ref>Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. ''PIG-A mutations in normal hematopoiesis.'' Blood 2005;105:3848-54. PMID 15687243.</ref> The gene that codes for PIG-A is inherited in an [[Sex linkage|X-linked]] fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation'). Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected). Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease. The complement system is the part of the immune system that helps to destroy invading microorganisms. The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement. CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.

The increased destruction of red blood cells results in [[anemia]]. The increased rate of thrombosis is due to dysfunction of [[platelet]]s. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

==Signs and symptoms==
Quite paradoxically, the destruction of red blood cells ([[hemolysis]]) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). Patients with PNH manifest the clinical and laboratory signs of chronic hemolytic anemia. Weakness, dyspnea and pallor are common. Splenomegaly may be present.

A common finding in [[PNH]] is the presence of breakdown products of [[RBC]]s, hemoglobin (26% pf patients) and hemosiderin, in the urine. Hemosiderinuria is a more constant feature of this disease and typically doesn't occur in other forms of anemia unless there is considerable intravascular erythrocyte destruction. Hemolysis is increased in the evening however, the (classic) passage of dark, hemoglobin-containing urine upon rising in the morning is seen in only a minority of cases. Haptoglobin is decreased and LDH can be increased to as much as 2-10 times normal. Neutropenia as well as thrombocytopenia may be evident. The leukocyte alkaline phosphatase (LAP) score is decreased.

An inconsistent, but potentially life-threatening, complication of PNH is the development of venous thrombosis (~40% of patients). These thrombi are often found in the [[hepatic vein|hepatic]] (causing [[Budd-Chiari syndrome]]; the most comon cause of mortality), [[Portal vein|portal]] (causing [[portal vein thrombosis]]), and cerebral veins (causing [[cerebral venous thrombosis]]). The risk of thrombosis has been directly linked to the size of the PNH clone. The thrombotic risk increases with pregnancy.

PNH can present with or as other disease entities such as aplastic anemia or myelodysplasia (MDS). Patients who present with pancytopenia or thrombosis compounding anemia should be suspected of having PNH. Many patients with bone marrow failure ([[aplastic anemia]]) develop [[PNH]] (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.<ref>Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."</ref> <ref>Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."</ref> A small percentage of PNH patients can have dysplasia that leads to Acute Myelocytic Leukemia. Interestingly, the blasts of the PNH-derived AML also lack leukocyte alkaline phosphatase (LAP) and decay accelerating factor (CD59;DAF).

Iron deficiency often occurs with PNH patients because of urinary loss and should be treated. The administration of oral iron is usually sufficient. Although there may be an increase in hemoglobinuria with iron therapy, due to the increased production of PNH cells by the marrow, the net positive effect in red blood cell production may lessen the requirements for blood transfusion. Folate should be given concurrently with the iron to help augment hematopoiesis.

Nitric Oxide depletion / thrombosis;
During episodes of acute hemolysis free plasma hemoglobin that is released as a consequence of erythrocyte lysis may overpower haptoglobin, a hemoglobin-scavenging protein. Excess free hemoglobin depletes plasma nitric oxide, which can play an important role in the maintenance of normal platelet function. It has been postulated that nitric oxide down-regulates platelet aggregation, adhesion and regulating molecules in the coagulation cascade. Nitric oxide depletion may therefore lead to platelet activation and aggregation. With this in mind the chronic consumption of nitric oxide by intravascular hemoglobin can play a role in the thrombotic events that occur in patients with PNH. Depletion of nitric oxide at the tissue level contributes to numerous PNH manifestations including smooth muscle dystonia (eg esophageal spasm, abdominal pain, male erectile dysfunction), pulmonary hypertension, severe fatigue and renal insufficiency as well as thrombosis.

==Diagnosis==
A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called ''Ham's acid hemolysis'' test, is performed if the sugar test is positive for hemolysis.<ref>Ham TH. Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium. ''[[N Engl J Med]]'' 1937;217:915-918.</ref> In a positive sucrose lysis test ionic strength facilitates the complement binding whereas in a positive Ham acid hemolysis test acidic strength facilitates the complement binding. The differential diagnosis of a positive sugar lysis test includes some autoimmune hemolytic anemias; even leukemias can give a false positive result. The differential diagnosis for a positive Ham test includes congenital dyserythropoietic anemia; note that a negative Ham test doesn't rule out PNH. These assays do not reliably quantitate the percentage of PNH cells and can be falsely negative in patients who have received red blood cell transfusions. Occasionally the characteristic complement-sensitive erythrocytes cannot be demonstrated in patients with well-established PNH. This probably occurs when the production of PNH cells is relatively low and most of the PNH cells that have been made have already been destroyed either in the marrow or in the circulation. Therefore a single normal sucrose hemolysis test cannot be considered absolute evidence that a patient does not have PNH.

Modern methods include [[flow cytometry]] for [[CD55]], [[CD16]], [[CD59]] and other GPI anchored proteins on [[white blood cells|white]] and [[red blood cells]]. <ref>Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G, International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. ''[[Blood (journal)|Blood]] 2005;106:3699-709. PMID 16051736.</ref> Laboratories favor flow cytometry to evaluate PNH due to its high sensitivity and specificity. Flow cytometry of the peripheral blood, not the bone marrow aspirate, is required to evaluate the presence or absence of GPI linked proteins. The bone marrow biopsy in PNH shows erythroid hyperplasia. In addition, because of the short life of granulocytes, the peripheral blood samples need to reach the lab in an expedited manner. The most commonly used antibodies are CD59 (expressed on all hematocellular lineages), and CD55 but other GPI anchored antigens (CD14, CD16, CD24) can also be studied on leukocytes. Dependent on the predominance of these molecules on the red blood cell surface, they are classified as type I, II or III PNH cells.

PNH type II & III cell populations; definitions.
Some patients may have erythrocytes with low but detectable GPI anchored proteins; these cells are designated PNH type II. By contrast, cells that are completely devoid of GPI anchored proteins are referred to as PNH type III. Patients with large populations of PNH type II erythrocytes may have less hemolysis than those with comparable populations of PNH III cells but these patients are still at risk for both hemolysis and thrombosis.

===MRI===

*Renal cortical signal intensity loss (hemosiderin accumulates in the renal cortex when intravascular hemolysis results in the direct release of hemoglobin into the plasma).
*Venous thrombosis.
*Liver and spleen are usually of normal signal intensity in paroxysmal nocturnal hemoglobinuria, unless repeated transfusions have resulted in hepatic and splenic signal intensity loss owing to transfusional siderosis.

(Images shown below are courtesy of RadsWiki)

<gallery>
Image:Paroxysmal nocturnal hemoglobinuria 001.jpg
Image:Paroxysmal nocturnal hemoglobinuria 002.jpg
Image:Paroxysmal nocturnal hemoglobinuria 003.jpg
Image:Paroxysmal nocturnal hemoglobinuria 004.jpg
Image:Paroxysmal nocturnal hemoglobinuria 005.jpg
Image:Paroxysmal nocturnal hemoglobinuria 006.jpg
Image:Paroxysmal nocturnal hemoglobinuria 007.jpg
Image:Paroxysmal nocturnal hemoglobinuria 008.jpg
</gallery>

==Treatment==
There is no widely accepted evidence-based indication for the treatment of PNH. In classic PNH it is recommended to treat patients with disabling fatigue, thromboses, transfusion dependence, frequent painful paroxysms, renal insufficiency or other end-organ complications from this disease. Watchful waiting is appropriate for the asymptomatic patient or the patient with mild symptoms.

===Long-term===
PNH is a chronic condition. In patients who have only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventative treatment with [[warfarin]] decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).<ref name=parker2005/><ref>{{cite journal |author=Hall C, Richards S, Hillmen P |title=Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) |journal=Blood |volume=102 |issue=10 |pages=3587–91 |year=2003 |month=November |pmid=12893760 |doi=10.1182/blood-2003-01-0009 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3587}}</ref> Episodes of thrombosis are treated as they would in other patients, but given that PNH is a persisting underlying cause it is likely that treatment with [[warfarin]] or similar drugs needs to be continued long-term after an episode of thrombosis.<ref name=parker2005>{{cite journal |author=Parker C, Omine M, Richards S, ''et al'' |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |year=2005 |pmid=16051736 |doi=10.1182/blood-2005-04-1717|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/12/3699}} {{PMC|1895106}}</ref>

In patients with aplastic anemia / PNH treatment should be directed toward the underlying bone marrow failure with careful monitoring of the PNH clone using flow cytometry. Patients who meet the criteria of severe aplastic anemia should be managed with either an allogeneic bone marrow transplant or immunosuppressive treatment dependent on the age of the patient and the availability of a bone marrow donor. Treatment of bone marrow failure in PNH is similar to that for aplasia. Immunosuppressives can be administered such as antithymocyte globulin or cyclosporine. Supportive measures in terms of GCSF or erythropoeitin (EPO) can also be given. An allogeneic bone marrow transplant is the only curative treatment and is an option for younger patients. A bone marrow transplant is curative but is associated with significant morbidity and mortality. The 2 year survival with this modality is 56%; the majority of deaths occur within the first year of transplant (International Bone Marrow Registry).

===Acute attacks===
There is debate as to whether steroids (such as [[prednisolone]]) can be useful in decreasing the severity of hemolytic crises. Steroids can decrease complement activation which, subsequently, decreases hemolysis however high doses are usually necessary. Transfusion therapy may be needed; in addition to correcting significant [[anemia]] this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Some sources advocate the use of washed red cell transfusions. Leucocyte-depleted transfusions are also recommended for those requiring chronic transfusion therapy.

Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.<ref name=parker2005/> It may be necessary to give folate too in order to augment hematopoiesis. Erythropoeitin (EPO) can be given (10-20,000 u tiw) to help. As with steroid therapy tranfusions are given when the iron treatments do not suffice.

Eculizumab (AKA Soliris) is a monoclonal antibody against the complement protein C5, halting terminal complement-mediated intravascular hemolysis.<ref>{{cite journal |author=Hillmen P, Hall C, Marsh JC, ''et al'' |title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria |journal=N. Engl. J. Med. |volume=350 |issue=6 |pages=552–9 |year=2004 |pmid=14762182 |doi=10.1056/NEJMoa031688}}</ref> It binds to a subunit of the C5 convertase enzyme. It prevents C5 convertase from hydrolyzing C5 to C5a and C5b, the latter combining with C9 to form the terminal complement complex.

Selection of patients to be treated with Eculizumab should be guided by the degree of hemolysis and the risk of thrombosis. Although most of the patients with PNH have some degree of ongoing hemolysis not all are transfusion dependent nor even anemic.

Patients who take Eculizumab are at increase risk of life-threatening meningococcal infection. Patients must receive the meningococcal vaccine at least 2 weeks before Eculizumab is given. If the patient had already received the vaccine, they may need a booster. Patients have a 0.5% yearly risk of acquiring neisserial sepsis even after vaccination. Patients should be revaccinated against Neisseria meningitidis every 3-5 years after starting the treatment and they should seek medical care if they develop any signs or symptoms suggestive of neisserial infection. These include headache, nausea, vomiting, fever, stiff back or neck, rash, confusion, visual sensitization to light and myalgias with flu-like manifestations. Note that the most common toxicity of Eculizumab is headache which occurs in about 50% of patients given the first dose or two but, typically, this rarely recurs afterwards. Patients still need to be monitored for meningitis for at least 8 weeks after discontinuing Eculizumab.

Long term terminal complement inhibition by Eculizumab doesn't increase the incidence of myeloproliferative disease, myelodysplasia, acute leukemias or aplasia / pancytopenias in PNH patients. Eculizumab administration decreases hemolysis leading to stabilization of the hemoglobin concentration and reticulocyte count. This is manifest clinically with a decrease in the need for transfusions.

Breakthrough intravascular hemolysis and a return of PNH symptoms occurs in < 2% of PNH patients treated with Eculizumab. This typically occurs a day or two before the next scheduled dose and is accompanied by a spike in the LDH. The LDH usually returns to normal or near normal within days to weeks after Eculizumab. Since the (episodic) hemolysis of PNH is partly intravascular, the finding of urine hemosiderin is consistent with continued erythrocyte destruction. The reticulocyte count often remains elevated because most PNH patients on Eculizumab continue to have some extravascular hemolysis. If this occurs on a regular basis then the dosing interval can be shortened or the dose increased in order to compensate. It is also important to remember that increased complement activation accompanies infection (eg. flu or viral gastroenteritis) or trauma which can result in transient breakthrough hemolysis. It is not recommended to change the dosing with regard to a single episode of breakthrough hemolysis.

Anticoagulation is only partly effective in preventing thrombosis in PNH. Some sources state that thrombosis is an absolute indication for initiating treating with Eculizumab. Prophyllactic anticoagulation has never been proven to prevent thrombosis in all PNH patients and can be dangerous given the thrombocytopenia seen in this malady. Some sources state that patients who do not meet criteria for Eculizumab therapy should not receive anticoagulation. Possible exceptions to this rule might include patients with persistently elevated D-dimer levels, pregnant PNH patients and patients in the perioperative period.

Pregnant patients with PNH have an even greater need for folate and iron supplementation because of the hemolysis. Pregnancy, as with oral contraceptive use, increases the risk of thrombosis in PNH. Anticoagulation with a LMWH is recommended as long as there are no contraindications for full anticoagulation. Give 1 mg/kg subcutaneously every 12 hours when the pregnancy is confirmed in a PNH patient with a large PNH clone. Some sources state that it is often necessary to switch to unfractionated heparin around the time of delivery if a C-section is planned.

==References==
{{reflist|2}}

==Additional Resources==
* Ross L. Titton, and Fergus V. Coakley. [http://radiology.rsnajnls.org/cgi/content/short/225/1/67 Case 51: Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome and Renal Cortical Hemosiderin.] Radiology 2002 225: 67-70.
* Brodsky RA. "How I treat paroxysmal nocturnal hemoglobinuria" Blood. 2009;113:6522-6527.
* Devine DV, Gluck LW, Rosse WF and Weinberg JB. "Acute Myeloblastic Leukemia in Paroxysmal Nocturnal Hemoglobinuria". J Clin Invest. 1987; 79:314-317.

==External links==
*[http://www.aamds.org Aplastic Anemia & MDS International Foundation]
*[http://www.pnhdisease.org PNH Support Group]
*[http://www.pnhfoundation.org PNH Research and Support Foundation]
*[http://goldminer.arrs.org/search.php?query=Paroxysmal%20nocturnal%20hemoglobinuria Goldminer: Paroxysmal nocturnal hemoglobinuria]
*[http:// www.PNHSource.com]

{{Hematology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Rare diseases]]
[[category:Genetic disorders]]

[[de:Paroxysmale nächtliche Hämoglobinurie]]
[[es:Hemoglobinuria nocturna paroxística]]
[[fr:Hémoglobinurie paroxystique nocturne]]
[[it:Emoglobinuria parossistica notturna]]
[[nl:Paroxysmale nocturnale hemoglobinurie]]
[[pl:Napadowa nocna hemoglobinuria]]
[[pt:Hemoglobinúria paroxística noturna]]
[[sr:Пароксизмална ноћна хемоглобинурија]]
[[tr:Paroksismal noktürnal hemoglobinüri]]

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Paroxysmal nocturnal hemoglobinuria

2010-09-26T16:11:55Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 9688 |
ICD10 = {{ICD10|D|59|5|d|55}} |
ICD9 = {{ICD9|283.2}} |
ICDO = |
OMIM = 311770 |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2696 |
MeshID = D006457 |
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

'''Paroxysmal nocturnal hemoglobinuria''' ([[PNH]]) is a rare, acquired, potentially life-threatening disease of the blood characterised by [[hemolytic anemia]], [[thrombosis]] and red [[urine]] due to breakdown of [[red blood cell]]s. [[PNH]] is the only hemolytic anemia caused by an ''acquired'' intrinsic defect in the [[cell membrane]].

==History==
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852).<ref>Strübing P. Paroxysmale Hämoglobinurie. ''Dtsch Med Wochenschr'' 1882;8:1-3 and 17-21.</ref><ref>[http://www.whonamedit.com/synd.cfm/2918.html Whonamedit entry]</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>Marchiafava E, Nazari A. Nuovo contributo allo studio degli itteri cronici emolitici. ''Policlinico [Med]'' 1911;18:241-254.</ref> with further elaborations by Marchiafava in 1928<ref>Marchiafava E. Anemia emolitica con emosiderinuria perpetua. ''Policlinico [Med]'' 1928;35:105-117.</ref> and Dr Ferdinando Micheli in 1931.<ref>Micheli F. Uno caso di anemia emolitica con emosiderinuria perpetua. ''G Accad Med Torino'' 1931;13:148.</ref>

==Classification==
PNH is classified:
* ''Classic PNH''. Evidence of [[PNH]] in the absence of another bone marrow disorder.
* ''[[PNH]] in the setting of another specified bone marrow disorder''.
* ''Subclinical PNH''. [[PNH]] abnormalities on flow cytometry without signs of hemolysis.

==Pathophysiology==
All cells have proteins attached to their membranes and they are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. [[PNH]] occurs as a result of a defect in one of these mechanisms.

It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.<ref>Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. ''PIG-A mutations in normal hematopoiesis.'' Blood 2005;105:3848-54. PMID 15687243.</ref> The gene that codes for PIG-A is inherited in an [[Sex linkage|X-linked]] fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation'). Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected). Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease. The complement system is the part of the immune system that helps to destroy invading microorganisms. The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement. CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.

The increased destruction of red blood cells results in [[anemia]]. The increased rate of thrombosis is due to dysfunction of [[platelet]]s. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

==Signs and symptoms==
Quite paradoxically, the destruction of red blood cells ([[hemolysis]]) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). Patients with PNH manifest the clinical and laboratory signs of chronic hemolytic anemia. Weakness, dyspnea and pallor are common. Solenomegaly may be present.

A common finding in [[PNH]] is the presence of breakdown products of [[RBC]]s, hemoglobin (26% pf patients) and hemosiderin, in the urine. Hemosiderinuria is a more constant feature of this disease and typically doesn't occur in other forms of anemia unless there is considerable intravascular erythrocyte destruction. Hemolysis is increased in the evening however, the (classic) passage of dark, hemoglobin-containing urine upon rising in the morning is seen in only a minority of cases. Haptoglobin is decreased and LDH can be increased to as much as 2-10 times normal. Neutropenia as well as thrombocytopenia may be evident. The leukocyte alkaline phosphatase (LAP) score is decreased.

An inconsistent, but potentially life-threatening, complication of PNH is the development of venous thrombosis (~40% of patients). These thrombi are often found in the [[hepatic vein|hepatic]] (causing [[Budd-Chiari syndrome]]; the most comon cause of mortality), [[Portal vein|portal]] (causing [[portal vein thrombosis]]), and cerebral veins (causing [[cerebral venous thrombosis]]). The risk of thrombosis has been directly linked to the size of the PNH clone. The thrombotic risk increases with pregnancy.

PNH can present with or as other disease entities such as aplastic anemia or myelodysplasia (MDS). Patients who present with pancytopenia or thrombosis compounding anemia should be suspected of PNH. Many patients with bone marrow failure ([[aplastic anemia]]) develop [[PNH]] (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.<ref>Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."</ref> <ref>Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."</ref> A small percentage of PNH patients can have dysplasia that leads to Acute Myelocytic Leukemia. Interestingly, the blasts of the PNH-derived AML also lack leukocyte alkaline phosphatase (LAP) and decay accelerating factor (CD59;DAF).

Iron deficiency often occurs in PNH patients because of urinary loss and should be treated. The administration of oral iron is usually sufficient. Although there may be an increase in hemoglobinuria with iron therapy, due to the increased production of PNH cells by the marrow, the net positive effect in red blood cell production may lessen the requirements for blood transfusion. Folate should be given concurrently with the iron to help augment hematopoiesis.

Nitric Oxide depletion / thrombosis;
During episodes of acute hemolysis free plasma hemoglobin that is released as a consequence of erythrocyte lysis may overpower haptoglobin, a hemoglobin-scavenging protein. Excess free hemoglobin depletes plasma nitric oxide, which can play an important role in the maintenance of normal platelet function. It has been postulated that nitric oxide down-regulates platelet aggregation, adhesion and regulating molecules in the coagulation cascade. Nitric oxide depletion may lead to platelet activation and aggregation. With this in mind the chronic consumption of nitric oxide by intravascular hemoglobin can play a role in the thrombotic events that occur in patients with PNH. Depletion of nitric oxide at the tissue level contributes to numerous PNH manifestations including smooth muscle dystonia (eg esophageal spasm, abdominal pain, male erectile dysfunction), pulmonary hypertension, severe fatigue, renal insufficiency and thrombosis.

==Diagnosis==
A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called ''Ham's acid hemolysis'' test, is performed if the sugar test is positive for hemolysis.<ref>Ham TH. Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium. ''[[N Engl J Med]]'' 1937;217:915-918.</ref> In a positive sucrose lysis test ionic strength facilitates the complement binding whereas in a positive Ham acid hemolysis test acidic strength facilitates the complement binding. The differential diagnosis of a positive sugar lysis test includes some autoimmune hemolytic anemias, even leukemias can give a false positive result. The differential diagnosis for a positive Ham test includes congenital dyserythropoietic anemia; note that a negative Ham test doesn't rule out PNH. These assays do not reliably quantitate the percentage of PNH cells and can be falsely negative in patients who have received red blood cell transfusions. Occasionally the characteristic complement-sensitive erythrocytes cannot be demonstrated in patients with well-established PNH. This probably occurs when the production of PNH cells is relatively low and most of the PNH cells that have been made have already been destroyed either in the marrow or in the circulation. Therefore a single normal sucrose hemolysis test cannot be considered absolute evidence that a patient does not have PNH.

Modern methods include [[flow cytometry]] for [[CD55]], [[CD16]], [[CD59]] and other GPI anchored proteins on [[white blood cells|white]] and [[red blood cells]]. <ref>Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G, International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. ''[[Blood (journal)|Blood]] 2005;106:3699-709. PMID 16051736.</ref> Laboratories favor flow cytometry to evaluate PNH due to its high sensitivity and specificity. Flow cytometry of the peripheral blood, not the bone marrow aspirate, is required to evaluate the presence or absence of GPI linked proteins. The bone marrow biopsy in PNH shows erythroid hyperplasia. In addition, because of the short life of granulocytes, the peripheral blood samples need to reach the lab in an expedited manner. The most commonly used antibodies are CD59 (expressed on all hematocellular lineages), and CD55 but other GPI anchored antigens (CD14, CD16, CD24) can also be studied on leukocytes. Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells.

PNH type II & III cell populations; definitions.
Some patients may have erythrocytes with low but detectable GPI anchored proteins; these cells are designated PNH type II. By contrast, cells that are completely devoid of GPI anchored proteins are referred to as PNH type III. Patients with large populations of PNH type II erythrocytes may have less hemolysis than those with comparable populations of PNH III cells but these patients are still at risk for both hemolysis and thrombosis.

===MRI===

*Renal cortical signal intensity loss (hemosiderin accumulates in the renal cortex when intravascular hemolysis results in the direct release of hemoglobin into the plasma).
*Venous thrombosis.
*Liver and spleen are usually of normal signal intensity in paroxysmal nocturnal hemoglobinuria, unless repeated transfusions have resulted in hepatic and splenic signal intensity loss owing to transfusional siderosis.

(Images shown below are courtesy of RadsWiki)

<gallery>
Image:Paroxysmal nocturnal hemoglobinuria 001.jpg
Image:Paroxysmal nocturnal hemoglobinuria 002.jpg
Image:Paroxysmal nocturnal hemoglobinuria 003.jpg
Image:Paroxysmal nocturnal hemoglobinuria 004.jpg
Image:Paroxysmal nocturnal hemoglobinuria 005.jpg
Image:Paroxysmal nocturnal hemoglobinuria 006.jpg
Image:Paroxysmal nocturnal hemoglobinuria 007.jpg
Image:Paroxysmal nocturnal hemoglobinuria 008.jpg
</gallery>

==Treatment==
There is no widely accepted evidence-based indication for the treatment of PNH. In classic PNH it is recommended to treat patients with disabling fatigue, thromboses, transfusion dependence, frequent painful paroxysms, renal insufficiency or other end-organ complications from this disease. Watchful waiting is appropriate for the asymptomatic patient or the patient with mild symptoms.

===Long-term===
PNH is a chronic condition. In patients who have only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventative treatment with [[warfarin]] decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).<ref name=parker2005/><ref>{{cite journal |author=Hall C, Richards S, Hillmen P |title=Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) |journal=Blood |volume=102 |issue=10 |pages=3587–91 |year=2003 |month=November |pmid=12893760 |doi=10.1182/blood-2003-01-0009 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3587}}</ref> Episodes of thrombosis are treated as they would in other patients, but given that PNH is a persisting underlying cause it is likely that treatment with [[warfarin]] or similar drugs needs to be continued long-term after an episode of thrombosis.<ref name=parker2005>{{cite journal |author=Parker C, Omine M, Richards S, ''et al'' |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |year=2005 |pmid=16051736 |doi=10.1182/blood-2005-04-1717|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/12/3699}} {{PMC|1895106}}</ref>

In patients with aplastic anemia / PNH treatment should be directed toward the underlying bone marrow failure with careful monitoring of the PNH clone using flow cytometry. Patients who meet the criteria of severe aplastic anemia should be managed with either an allogeneic bone marrow transplant or immunosuppressive treatment dependent on the age of the patient and the availability of a bone marrow donor. Treatment of bone marrow failure in PNH is similar to that for aplasia. Immunosuppressives can be administered such as antithymocyte globulin or cyclosporine. Supportive measures in terms of GCSF or erythropoeitin (EPO) can also be given. An allogeneic bone marrow transplant is the only curative treatment and is an option for younger patients. A bone marrow transplant is curative but is associated with significant morbidity and mortality. The 2 year survival with this modality is 56%; the majority of deaths occur within the first year of transplant (International Bone Marrow Registry).

===Acute attacks===
There is debate as to whether steroids (such as [[prednisolone]]) can be useful in decreasing the severity of hemolytic crises. Steroids can decrease complement activation which, subsequently, decreases hemolysis however high doses are usually necessary. Transfusion therapy may be needed; in addition to correcting significant [[anemia]] this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Some sources advocate the use of washed red cell transfusions. Leucocyte-depleted transfusions are also recommended for those requiring chronic transfusion therapy.

Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.<ref name=parker2005/> It may be necessary to give folate too in order to augment hematopoiesis. Erythropoeitin (EPO) can be given (10-20,000 u tiw) to help. As with steroid therapy tranfusions are given when the iron treatments do not suffice.

Eculizumab (AKA Soliris) is a monoclonal antibody against the complement protein C5, halting terminal complement-mediated intravascular hemolysis.<ref>{{cite journal |author=Hillmen P, Hall C, Marsh JC, ''et al'' |title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria |journal=N. Engl. J. Med. |volume=350 |issue=6 |pages=552–9 |year=2004 |pmid=14762182 |doi=10.1056/NEJMoa031688}}</ref> It binds to a subunit of the C5 convertase enzyme. It prevents C5 convertase from hydrolyzing C5 to C5a and C5b, the latter combining with C9 to form the terminal complement complex.

Selection of patients to be treated with Eculizumab should be guided by the degree of hemolysis and the risk of thrombosis. Although most of the patients with PNH have some degree of ongoing hemolysis not all are transfusion dependent nor even anemic.

Patients who take Eculizumab are at increase risk of life-threatening meningococcal infection. Patients must receive the meningococcal vaccine at least 2 weeks before Eculizumab is given. If the patient had already received the vaccine, they may need a booster. Patients have a 0.5% yearly risk of acquiring neisserial sepsis even after vaccination. Patients should be revaccinated against Neisseria meningitidis every 3-5 years after starting the treatment and they should seek medical care if they develop any signs or symptoms suggestive of neisserial infection. These include headache, nausea, vomiting, fever, stiff back or neck, rash, confusion, visual sensitization to light and myalgias with flu-like manifestations. Note that the most common toxicity of Eculizumab is headache which occurs in about 50% of patients given the first dose or two but, typically, this rarely recurs afterwards. Patients still need to be monitored for meningitis for at least 8 weeks after discontinuing Eculizumab.

Long term terminal complement inhibition by Eculizumab doesn't increase the incidence of myeloproliferative disease, myelodysplasia, acute leukemias or aplasia / pancytopenias in PNH patients. Eculizumab administration decreases hemolysis leading to stabilization of the hemoglobin concentration and reticulocyte count. This is manifest clinically with a decrease in the need for transfusions.

Breakthrough intravascular hemolysis and a return of PNH symptoms occurs in < 2% of PNH patients treated with Eculizumab. This typically occurs a day or two before the next scheduled dose and is accompanied by a spike in the LDH. The LDH usually returns to normal or near normal within days to weeks after Eculizumab. Since the (episodic) hemolysis of PNH is partly intravascular, the finding of urine hemosiderin is consistent with continued erythrocyte destruction. The reticulocyte count often remains elevated because most PNH patients on Eculizumab continue to have some extravascular hemolysis. If this occurs on a regular basis then the dosing interval can be shortened or the dose increased in order to compensate. It is also important to remember that increased complement activation accompanies infection (eg. flu or viral gastroenteritis) or trauma which can result in transient breakthrough hemolysis. It is not recommended to change the dosing with regard to a single episode of breakthrough hemolysis.

Anticoagulation is only partly effective in preventing thrombosis in PNH. Some sources state that thrombosis is an absolute indication for initiating treating with Eculizumab. Prophyllactic anticoagulation has never been proven to prevent thrombosis in all PNH patients and can be dangerous given the thrombocytopenia seen in this malady. Some sources state that patients who do not meet criteria for Eculizumab therapy should not receive anticoagulation. Possible exceptions to this rule might include patients with persistently elevated D-dimer levels, pregnant PNH patients and patients in the perioperative period.

Pregnant patients with PNH have an even greater need for folate and iron supplementation because of the hemolysis. Pregnancy, as with oral contraceptive use, increases the risk of thrombosis in PNH. Anticoagulation with a LMWH is recommended as long as there are no contraindications for full anticoagulation. Give 1 mg/kg subcutaneously every 12 hours when the pregnancy is confirmed in a PNH patient with a large PNH clone. Some sources state that it is often necessary to switch to unfractionated heparin around the time of delivery if a C-section is planned.

==References==
{{reflist|2}}

==Additional Resources==
* Ross L. Titton, and Fergus V. Coakley. [http://radiology.rsnajnls.org/cgi/content/short/225/1/67 Case 51: Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome and Renal Cortical Hemosiderin.] Radiology 2002 225: 67-70.
* Brodsky RA. "How I treat paroxysmal nocturnal hemoglobinuria" Blood. 2009;113:6522-6527.
* Devine DV, Gluck LW, Rosse WF and Weinberg JB. "Acute Myeloblastic Leukemia in Paroxysmal Nocturnal Hemoglobinuria". J Clin Invest. 1987; 79:314-317.

==External links==
*[http://www.aamds.org Aplastic Anemia & MDS International Foundation]
*[http://www.pnhdisease.org PNH Support Group]
*[http://www.pnhfoundation.org PNH Research and Support Foundation]
*[http://goldminer.arrs.org/search.php?query=Paroxysmal%20nocturnal%20hemoglobinuria Goldminer: Paroxysmal nocturnal hemoglobinuria]
*[http:// www.PNHSource.com]

{{Hematology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Rare diseases]]
[[category:Genetic disorders]]

[[de:Paroxysmale nächtliche Hämoglobinurie]]
[[es:Hemoglobinuria nocturna paroxística]]
[[fr:Hémoglobinurie paroxystique nocturne]]
[[it:Emoglobinuria parossistica notturna]]
[[nl:Paroxysmale nocturnale hemoglobinurie]]
[[pl:Napadowa nocna hemoglobinuria]]
[[pt:Hemoglobinúria paroxística noturna]]
[[sr:Пароксизмална ноћна хемоглобинурија]]
[[tr:Paroksismal noktürnal hemoglobinüri]]

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Paroxysmal nocturnal hemoglobinuria

2010-09-25T22:41:39Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 9688 |
ICD10 = {{ICD10|D|59|5|d|55}} |
ICD9 = {{ICD9|283.2}} |
ICDO = |
OMIM = 311770 |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2696 |
MeshID = D006457 |
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

'''Paroxysmal nocturnal hemoglobinuria''' ([[PNH]]) is a rare, acquired, potentially life-threatening disease of the blood characterised by [[hemolytic anemia]], [[thrombosis]] and red [[urine]] due to breakdown of [[red blood cell]]s. [[PNH]] is the only hemolytic anemia caused by an ''acquired'' intrinsic defect in the [[cell membrane]].

==History==
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852).<ref>Strübing P. Paroxysmale Hämoglobinurie. ''Dtsch Med Wochenschr'' 1882;8:1-3 and 17-21.</ref><ref>[http://www.whonamedit.com/synd.cfm/2918.html Whonamedit entry]</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>Marchiafava E, Nazari A. Nuovo contributo allo studio degli itteri cronici emolitici. ''Policlinico [Med]'' 1911;18:241-254.</ref> with further elaborations by Marchiafava in 1928<ref>Marchiafava E. Anemia emolitica con emosiderinuria perpetua. ''Policlinico [Med]'' 1928;35:105-117.</ref> and Dr Ferdinando Micheli in 1931.<ref>Micheli F. Uno caso di anemia emolitica con emosiderinuria perpetua. ''G Accad Med Torino'' 1931;13:148.</ref>

==Classification==
PNH is classified:
* ''Classic PNH''. Evidence of [[PNH]] in the absence of another bone marrow disorder.
* ''[[PNH]] in the setting of another specified bone marrow disorder''.
* ''Subclinical PNH''. [[PNH]] abnormalities on flow cytometry without signs of hemolysis.

==Pathophysiology==
All cells have proteins attached to their membranes and they are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. [[PNH]] occurs as a result of a defect in one of these mechanisms.

It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.<ref>Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. ''PIG-A mutations in normal hematopoiesis.'' Blood 2005;105:3848-54. PMID 15687243.</ref> The gene that codes for PIG-A is inherited in an [[Sex linkage|X-linked]] fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation'). Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected). Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease. The complement system is the part of the immune system that helps to destroy invading microorganisms. The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement. CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.

The increased destruction of red blood cells results in [[anemia]]. The increased rate of thrombosis is due to dysfunction of [[platelet]]s. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

==Signs and symptoms==
Quite paradoxically, the destruction of red blood cells ([[hemolysis]]) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). Patients with PNH manifest the clinical and laboratory signs of chronic hemolytic anemia. Weakness, dyspnea and pallor are common. Solenomegaly may be present.

A common finding in [[PNH]] is the presence of breakdown products of [[RBC]]s, hemoglobin (26% pf patients) and hemosiderin, in the urine. Hemosiderinuria is a more constant feature of this disease and typically doesn't occur in other forms of anemia unless there is considerable intravascular erythrocyte destruction. Hemolysis is increased in the evening however, the (classic) passage of dark, hemoglobin-containing urine upon rising in the morning is seen in only a minority of cases. Haptoglobin is decreased and LDH can be increased to 2-10 times normal. Neutropenia as well as thrombocytopenia may be evident. The leukocyte alkaline phosphatase (LAP) score is decreased.

An inconsistent, but potentially life-threatening, complication of PNH is the development of venous thrombosis (~40% of patients). These thrombi are often found in the [[hepatic vein|hepatic]] (causing [[Budd-Chiari syndrome]]; the most comon cause of mortality), [[Portal vein|portal]] (causing [[portal vein thrombosis]]), and cerebral veins (causing [[cerebral venous thrombosis]]). The risk of thrombosis has been directly linked to the size of the PNH clone. The thrombotic risk increases with pregnancy.

PNH can present with or as other disease entities such as aplastic anemia or myelodysplasia (MDS). Patients who present with pancytopenia or thrombosis compounding anemia should be suspected of PNH. Many patients with bone marrow failure ([[aplastic anemia]]) develop [[PNH]] (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.<ref>Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."</ref> <ref>Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."</ref> A small percentage of PNH patients can have dysplasia that leads to Acute Myelocytic Leukemia. Interestingly, the blasts of the PNH-derived AML also lack leukocyte alkaline phosphatase (LAP) and decay accelerating factor (CD59;DAF).

Iron deficiency often occurs in PNH patients because of urinary loss and should be treated. The administration of oral iron is usually sufficient. Although there may be an increase in hemoglobinuria with iron therapy, due to the increased production of PNH cells by the marrow, the net positive effect in red blood cell production may lessen the requirements for blood transfusion. Folate should be given concurrently with the iron to help augment hematopoiesis.

Nitric Oxide depletion / thrombosis;
During episodes of acute hemolysis free plasma hemoglobin is released as a consequence of erythrocyte lysis may overpower haptoglobin, a hemoglobin-scavenging protein. Excess free hemoglobin depletes plasma nitric oxide, which may play an important role in the maintenance of normal platelet function. Because of this it has been postulated that nitric oxide down-regulates platelet aggregation, adhesion and regulating molecules in the coagulation cascade. Nitric oxide depletion may lead to platelet activation and aggregation. With this in mind the chronic consumption of nitric oxide by intravascular hemoglobin may play a role in the thrombotic events that occur in patients with PNH. Depletion of nitric oxide at the tissue level contributes to numerous PNH manifestations including smooth muscle dystonia (eg esophageal spasm, abdominal pain, male erectile dysfunction), pulmonary hypertension, severe fatigue, renal insufficiency and thrombosis.

==Diagnosis==
A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called ''Ham's acid hemolysis'' test, is performed if the sugar test is positive for hemolysis.<ref>Ham TH. Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium. ''[[N Engl J Med]]'' 1937;217:915-918.</ref> In a positive sucrose lysis test ionic strength facilitates the complement binding whereas in a positive Ham acid hemolysis test acidic strength facilitates the complement binding. The differential diagnosis of a positive sugar lysis test includes some autoimmune hemolytic anemias, even leukemias can give a false positive result. The differential diagnosis for a positive Ham test includes congenital dyserythropoietic anemia; note that a negative Ham test doesn't rule out PNH. These assays do not reliably quantitate the percentage of PNH cells and can be falsely negative in patients who have received red blood cell transfusions. Occasionally the characteristic complement-sensitive erythrocytes cannot be demonstrated in patients with well-established PNH. This probably occurs when the production of PNH cells is relatively low and most of the PNH cells that have been made have already been destroyed either in the marrow or in the circulation. Therefore a single normal sucrose hemolysis test cannot be considered absolute evidence that a patient does not have PNH.

Modern methods include [[flow cytometry]] for [[CD55]], [[CD16]], [[CD59]] and other GPI anchored proteins on [[white blood cells|white]] and [[red blood cells]]. <ref>Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G, International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. ''[[Blood (journal)|Blood]] 2005;106:3699-709. PMID 16051736.</ref> Laboratories favor flow cytometry to evaluate PNH due to its high sensitivity and specificity. Flow cytometry of the peripheral blood, not the bone marrow aspirate, is required to evaluate the presence or absence of GPI linked proteins. The bone marrow biopsy in PNH shows erythroid hyperplasia. In addition, because of the short life of granulocytes, the peripheral blood samples need to reach the lab in an expedited manner. The most commonly used antibodies are CD59 (expressed on all hematocellular lineages), and CD55 but other GPI anchored antigens (CD14, CD16, CD24) can also be studied on leukocytes. Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells.

PNH type II & III cell populations; definitions.
Some patients may have erythrocytes with low but detectable GPI anchored proteins; these cells are designated PNH type II. By contrast, cells that are completely devoid of GPI anchored proteins are referred to as PNH type III. Patients with large populations of PNH type II erythrocytes may have less hemolysis than those with comparable populations of PNH III cells but these patients are still at risk for both hemolysis and thrombosis.

===MRI===

*Renal cortical signal intensity loss (hemosiderin accumulates in the renal cortex when intravascular hemolysis results in the direct release of hemoglobin into the plasma).
*Venous thrombosis.
*Liver and spleen are usually of normal signal intensity in paroxysmal nocturnal hemoglobinuria, unless repeated transfusions have resulted in hepatic and splenic signal intensity loss owing to transfusional siderosis.

(Images shown below are courtesy of RadsWiki)

<gallery>
Image:Paroxysmal nocturnal hemoglobinuria 001.jpg
Image:Paroxysmal nocturnal hemoglobinuria 002.jpg
Image:Paroxysmal nocturnal hemoglobinuria 003.jpg
Image:Paroxysmal nocturnal hemoglobinuria 004.jpg
Image:Paroxysmal nocturnal hemoglobinuria 005.jpg
Image:Paroxysmal nocturnal hemoglobinuria 006.jpg
Image:Paroxysmal nocturnal hemoglobinuria 007.jpg
Image:Paroxysmal nocturnal hemoglobinuria 008.jpg
</gallery>

==Treatment==
===Long-term===
PNH is a chronic condition. In patients who have only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventative treatment with [[warfarin]] decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).<ref name=parker2005/><ref>{{cite journal |author=Hall C, Richards S, Hillmen P |title=Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) |journal=Blood |volume=102 |issue=10 |pages=3587–91 |year=2003 |month=November |pmid=12893760 |doi=10.1182/blood-2003-01-0009 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3587}}</ref>

Episodes of thrombosis are treated as they would in other patients, but given that PNH is a persisting underlying cause it is likely that treatment with [[warfarin]] or similar drugs needs to be continued long-term after an episode of thrombosis.<ref name=parker2005>{{cite journal |author=Parker C, Omine M, Richards S, ''et al'' |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |year=2005 |pmid=16051736 |doi=10.1182/blood-2005-04-1717|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/12/3699}} {{PMC|1895106}}</ref>

===Acute attacks===
There is disagreement as to whether steroids (such as [[prednisolone]]) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant [[anemia]] this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.<ref name=parker2005/>

Eculizumab (AKA Soliris) is a monoclonal antibody against the complement protein C5, halting terminal complement-mediated intravascular hemolysis.<ref>{{cite journal |author=Hillmen P, Hall C, Marsh JC, ''et al'' |title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria |journal=N. Engl. J. Med. |volume=350 |issue=6 |pages=552–9 |year=2004 |pmid=14762182 |doi=10.1056/NEJMoa031688}}</ref> It binds to a subunit of the C5 convertase enzyme. It prevents C5 convertase from hydrolyzing C5 to C5a and C5b, the latter combining with C9 to form the terminal complement complex.

Selection of patients to be treated with Eculizumab should be guided by the degree of hemolysis and the risk of thrombosis. Although most of the patients with PNH have some degree of ongoing hemolysis not all are transfusion dependent nor even anemic.

Patients who take Eculizumab are at increase risk of life-threatening meningococcal infection. Patients must receive the meningococcal vaccine at least 2 weeks before Eculizumab is given. If the patient had already received the vaccine, they may need a booster. Patients have a 0.5% yearly risk of acquiring neisserial sepsis even after vaccination. Patients should be revaccinated against Neisseria meningitidis every 3-5 years after starting the treatment and they should seek medical care if they develop any signs or symptoms suggestive of neisserial infection. These include headache, nausea, vomiting, fever, stiff back or neck, rash, confusion, visual sensitization to light and myalgias with flu-like manifestations. Note that the most common toxicity of Eculizumab is headache which occurs in about 50% of patients given the first dose or two but, typically, this rarely recurs afterwards. Patients still need to be monitored for meningitis for at least 8 weeks after discontinuing Eculizumab.

Long term terminal complement inhibition by Eculizumab doesn't increase the incidence of myeloproliferative disease, myelodysplasia, acute leukemias or aplasia / pancytopenias in PNH patients. Eculizumab administration decreases hemolysis leading to stabilization of the hemoglobin concentration and reticulocyte count. This is manifest clinically with a decrease in the need for transfusions.

Breakthrough intravascular hemolysis and a return of PNH symptoms occurs in < 2% of PNH patients treated with Eculizumab. This typically occurs a day or two before the next scheduled dose and is accompanied by a spike in the LDH. The LDH usually returns to normal or near normal within days to weeks after Eculizumab. Since the (episodic) hemolysis of PNH is partly intravascular, the finding of urine hemosiderin is consistent with continued erythrocyte destruction. The reticulocyte count often remains elevated because most PNH patients on Eculizumab continue to have some extravascular hemolysis. If this occurs on a regular basis then the dosing interval can be shortened or the dose increased in order to compensate. It is also important to remember that increased complement activation accompanies infection (eg. flu or viral gastroenteritis) or trauma which can result in transient breakthrough hemolysis. It is not recommended to change the dosing with regard to a single episode of breakthrough hemolysis.

Anticoagulation is only partly effective in preventing thrombosis in PNH. Some sources state that thrombosis is an absolute indication for initiating treating with Eculizumab. Prophyllactic anticoagulation has never been proven to prevent thrombosis in all PNH patients and can be dangerous given the thrombocytopenia seen in this malady. Some sources state that patients who do not meet criteria for Eculizumab therapy should not receive anticoagulation. Possible exceptions to this rule might include patients with persistently elevated D-dimer levels, pregnant PNH patients and patients in the perioperative period.

==References==
{{reflist|2}}

==Additional Resources==
* Ross L. Titton, and Fergus V. Coakley. [http://radiology.rsnajnls.org/cgi/content/short/225/1/67 Case 51: Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome and Renal Cortical Hemosiderin.] Radiology 2002 225: 67-70.
* Brodsky RA. "How I treat paroxysmal nocturnal hemoglobinuria" Blood. 2009;113:6522-6527.
* Devine DV, Gluck LW, Rosse WF and Weinberg JB. "Acute Myeloblastic Leukemia in Paroxysmal Nocturnal Hemoglobinuria". J Clin Invest. 1987; 79:314-317.

==External links==
*[http://www.aamds.org Aplastic Anemia & MDS International Foundation]
*[http://www.pnhdisease.org PNH Support Group]
*[http://www.pnhfoundation.org PNH Research and Support Foundation]
*[http://goldminer.arrs.org/search.php?query=Paroxysmal%20nocturnal%20hemoglobinuria Goldminer: Paroxysmal nocturnal hemoglobinuria]

{{Hematology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Rare diseases]]
[[category:Genetic disorders]]

[[de:Paroxysmale nächtliche Hämoglobinurie]]
[[es:Hemoglobinuria nocturna paroxística]]
[[fr:Hémoglobinurie paroxystique nocturne]]
[[it:Emoglobinuria parossistica notturna]]
[[nl:Paroxysmale nocturnale hemoglobinurie]]
[[pl:Napadowa nocna hemoglobinuria]]
[[pt:Hemoglobinúria paroxística noturna]]
[[sr:Пароксизмална ноћна хемоглобинурија]]
[[tr:Paroksismal noktürnal hemoglobinüri]]

{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

Paroxysmal nocturnal hemoglobinuria

2010-09-25T01:55:10Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 9688 |
ICD10 = {{ICD10|D|59|5|d|55}} |
ICD9 = {{ICD9|283.2}} |
ICDO = |
OMIM = 311770 |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2696 |
MeshID = D006457 |
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

'''Paroxysmal nocturnal hemoglobinuria''' ([[PNH]]) is a rare, acquired, potentially life-threatening disease of the blood characterised by [[hemolytic anemia]], [[thrombosis]] and red [[urine]] due to breakdown of [[red blood cell]]s. [[PNH]] is the only hemolytic anemia caused by an ''acquired'' intrinsic defect in the [[cell membrane]].

==History==
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852).<ref>Strübing P. Paroxysmale Hämoglobinurie. ''Dtsch Med Wochenschr'' 1882;8:1-3 and 17-21.</ref><ref>[http://www.whonamedit.com/synd.cfm/2918.html Whonamedit entry]</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>Marchiafava E, Nazari A. Nuovo contributo allo studio degli itteri cronici emolitici. ''Policlinico [Med]'' 1911;18:241-254.</ref> with further elaborations by Marchiafava in 1928<ref>Marchiafava E. Anemia emolitica con emosiderinuria perpetua. ''Policlinico [Med]'' 1928;35:105-117.</ref> and Dr Ferdinando Micheli in 1931.<ref>Micheli F. Uno caso di anemia emolitica con emosiderinuria perpetua. ''G Accad Med Torino'' 1931;13:148.</ref>

==Classification==
PNH is classified:
* ''Classic PNH''. Evidence of [[PNH]] in the absence of another bone marrow disorder.
* ''[[PNH]] in the setting of another specified bone marrow disorder''.
* ''Subclinical PNH''. [[PNH]] abnormalities on flow cytometry without signs of hemolysis.

==Pathophysiology==
All cells have proteins attached to their membranes and they are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. [[PNH]] occurs as a result of a defect in one of these mechanisms.

It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.<ref>Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. ''PIG-A mutations in normal hematopoiesis.'' Blood 2005;105:3848-54. PMID 15687243.</ref> The gene that codes for PIG-A is inherited in an [[Sex linkage|X-linked]] fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation'). Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected). Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease. The complement system is the part of the immune system that helps to destroy invading microorganisms. The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement. CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.

The increased destruction of red blood cells results in [[anemia]]. The increased rate of thrombosis is due to dysfunction of [[platelet]]s. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

==Signs and symptoms==
Quite paradoxically, the destruction of red blood cells ([[hemolysis]]) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). Patients with PNH manifest the clinical and laboratory signs of chronic hemolytic anemia. Weakness, dyspnea and pallor are common. Solenomegaly may be present.

A common finding in [[PNH]] is the presence of breakdown products of [[RBC]]s, hemoglobin (26% pf patients) and hemosiderin, in the urine. Hemosiderinuria is a more constant feature of this disease and typically doesn't occur in other forms of anemia unless there is considerable intravascular erythrocyte destruction. Hemolysis is increased in the evening however, the (classic) passage of dark, hemoglobin-containing urine upon rising in the morning is seen in only a minority of cases. Haptoglobin is decreased and LDH can be increased to 2-10 times normal. Neutropenia as well as thrombocytopenia may be evident. The leukocyte alkaline phosphatase (LAP) score is decreased.

An inconsistent, but potentially life-threatening, complication of PNH is the development of venous thrombosis (~40% of patients). These thrombi are often found in the [[hepatic vein|hepatic]] (causing [[Budd-Chiari syndrome]]; the most comon cause of mortality), [[Portal vein|portal]] (causing [[portal vein thrombosis]]), and cerebral veins (causing [[cerebral venous thrombosis]]). The risk of thrombosis has been directly linked to the size of the PNH clone. The thrombotic risk increases with pregnancy.

PNH can present with or as other disease entities such as aplastic anemia or myelodysplasia (MDS). Patients who present with pancytopenia or thrombosis compounding anemia should be suspected of PNH. Many patients with bone marrow failure ([[aplastic anemia]]) develop [[PNH]] (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.<ref>Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."</ref> <ref>Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."</ref>

Iron deficiency often occurs in PNH patients because of urinary loss and should be treated. The administration of oral iron is usually sufficient. Although there may be an increase in hemoglobinuria with iron therapy, due to the increased production of PNH cells by the marrow, the net positive effect in red blood cell production may lessen the requirements for blood transfusion. Folate should be given concurrently with the iron to help augment hematopoiesis.

Nitric Oxide depletion / thrombosis;
During episodes of acute hemolysis free plasma hemoglobin is released as a consequence of erythrocyte lysis may overpower haptoglobin, a hemoglobin-scavenging protein. Excess free hemoglobin depletes plasma nitric oxide, which may play an important role in the maintenance of normal platelet function. Because of this it has been postulated that nitric oxide down-regulates platelet aggregation, adhesion and regulating molecules in the coagulation cascade. Nitric oxide depletion may lead to platelet activation and aggregation. With this in mind the chronic consumption of nitric oxide by intravascular hemoglobin may play a role in the thrombotic events that occur in patients with PNH. Depletion of nitric oxide at the tissue level contributes to numerous PNH manifestations including smooth muscle dystonia (eg esophageal spasm, abdominal pain, male erectile dysfunction), pulmonary hypertension, severe fatigue, renal insufficiency and thrombosis.

==Diagnosis==
A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called ''Ham's acid hemolysis'' test, is performed if the sugar test is positive for hemolysis.<ref>Ham TH. Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium. ''[[N Engl J Med]]'' 1937;217:915-918.</ref> In a positive sucrose lysis test ionic strength facilitates the complement binding whereas in a positive Ham acid hemolysis test acidic strength facilitates the complement binding. The differential diagnosis of a positive sugar lysis test includes some autoimmune hemolytic anemias, even leukemias can give a false positive result. The differential diagnosis for a positive Ham test includes congenital dyserythropoietic anemia; note that a negative Ham test doesn't rule out PNH. These assays do not reliably quantitate the percentage of PNH cells and can be falsely negative in patients who have received red blood cell transfusions. Occasionally the characteristic complement-sensitive erythrocytes cannot be demonstrated in patients with well-established PNH. This probably occurs when the production of PNH cells is relatively low and most of the PNH cells that have been made have already been destroyed either in the marrow or in the circulation. Therefore a single normal sucrose hemolysis test cannot be considered absolute evidence that a patient does not have PNH.

Modern methods include [[flow cytometry]] for [[CD55]], [[CD16]], [[CD59]] and other GPI anchored proteins on [[white blood cells|white]] and [[red blood cells]]. <ref>Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G, International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. ''[[Blood (journal)|Blood]] 2005;106:3699-709. PMID 16051736.</ref> Laboratories favor flow cytometry to evaluate PNH due to its high sensitivity and specificity. Flow cytometry of the peripheral blood, not the bone marrow aspirate, is required to evaluate the presence or absence of GPI linked proteins. The bone marrow biopsy in PNH shows erythroid hyperplasia. In addition, because of the short life of granulocytes, the peripheral blood samples need to reach the lab in an expedited manner. The most commonly used antibodies are CD59 (expressed on all hematocellular lineages), and CD55 but other GPI anchored antigens (CD14, CD16, CD24) can also be studied on leukocytes. Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells.

PNH type II & III cell populations; definitions.
Some patients may have erythrocytes with low but detectable GPI anchored proteins; these cells are designated PNH type II. By contrast, cells that are completely devoid of GPI anchored proteins are referred to as PNH type III. Patients with large populations of PNH type II erythrocytes may have less hemolysis than those with comparable populations of PNH III cells but these patients are still at risk for both hemolysis and thrombosis.

===MRI===

*Renal cortical signal intensity loss (hemosiderin accumulates in the renal cortex when intravascular hemolysis results in the direct release of hemoglobin into the plasma).
*Venous thrombosis.
*Liver and spleen are usually of normal signal intensity in paroxysmal nocturnal hemoglobinuria, unless repeated transfusions have resulted in hepatic and splenic signal intensity loss owing to transfusional siderosis.

(Images shown below are courtesy of RadsWiki)

<gallery>
Image:Paroxysmal nocturnal hemoglobinuria 001.jpg
Image:Paroxysmal nocturnal hemoglobinuria 002.jpg
Image:Paroxysmal nocturnal hemoglobinuria 003.jpg
Image:Paroxysmal nocturnal hemoglobinuria 004.jpg
Image:Paroxysmal nocturnal hemoglobinuria 005.jpg
Image:Paroxysmal nocturnal hemoglobinuria 006.jpg
Image:Paroxysmal nocturnal hemoglobinuria 007.jpg
Image:Paroxysmal nocturnal hemoglobinuria 008.jpg
</gallery>

==Treatment==
===Long-term===
PNH is a chronic condition. In patients who have only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventative treatment with [[warfarin]] decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).<ref name=parker2005/><ref>{{cite journal |author=Hall C, Richards S, Hillmen P |title=Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) |journal=Blood |volume=102 |issue=10 |pages=3587–91 |year=2003 |month=November |pmid=12893760 |doi=10.1182/blood-2003-01-0009 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3587}}</ref>

Episodes of thrombosis are treated as they would in other patients, but given that PNH is a persisting underlying cause it is likely that treatment with [[warfarin]] or similar drugs needs to be continued long-term after an episode of thrombosis.<ref name=parker2005>{{cite journal |author=Parker C, Omine M, Richards S, ''et al'' |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |year=2005 |pmid=16051736 |doi=10.1182/blood-2005-04-1717|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/12/3699}} {{PMC|1895106}}</ref>

===Acute attacks===
There is disagreement as to whether steroids (such as [[prednisolone]]) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant [[anemia]] this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.<ref name=parker2005/>

Eculizumab (AKA Soliris) is a monoclonal antibody against the complement protein C5, halting terminal complement-mediated intravascular hemolysis.<ref>{{cite journal |author=Hillmen P, Hall C, Marsh JC, ''et al'' |title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria |journal=N. Engl. J. Med. |volume=350 |issue=6 |pages=552–9 |year=2004 |pmid=14762182 |doi=10.1056/NEJMoa031688}}</ref> It binds to a subunit of the C5 convertase enzyme. It prevents C5 convertase from hydrolyzing C5 to C5a and C5b, the latter combining with C9 to form the terminal complement complex.

Selection of patients to be treated with Eculizumab should be guided by the degree of hemolysis and the risk of thrombosis. Although most of the patients with PNH have some degree of ongoing hemolysis not all are transfusion dependent nor even anemic.

Patients who take Eculizumab are at increase risk of life-threatening meningococcal infection. Patients must receive the meningococcal vaccine at least 2 weeks before Eculizumab is given. If the patient had already received the vaccine, they may need a booster. Patients have a 0.5% yearly risk of acquiring neisserial sepsis even after vaccination. Patients should be revaccinated against Neisseria meningitidis every 3-5 years after starting the treatment and they should seek medical care if they develop any signs or symptoms suggestive of neisserial infection. These include headache, nausea, vomiting, fever, stiff back or neck, rash, confusion, visual sensitization to light and myalgias with flu-like manifestations. Note that the most common toxicity of Eculizumab is headache which occurs in about 50% of patients given the first dose or two but, typically, this rarely recurs afterwards. Patients still need to be monitored for meningitis for at least 8 weeks after discontinuing Eculizumab.

Long term terminal complement inhibition by Eculizumab doesn't increase the incidence of myeloproliferative disease, myelodysplasia, acute leukemias or aplasia / pancytopenias in PNH patients. Eculizumab administration decreases hemolysis leading to stabilization of the hemoglobin concentration and reticulocyte count. This is manifest clinically with a decrease in the need for transfusions.

Breakthrough intravascular hemolysis and a return of PNH symptoms occurs in < 2% of PNH patients treated with Eculizumab. This typically occurs a day or two before the next scheduled dose and is accompanied by a spike in the LDH. The LDH usually returns to normal or near normal within days to weeks after Eculizumab. Since the (episodic) hemolysis of PNH is partly intravascular, the finding of urine hemosiderin is consistent with continued erythrocyte destruction. The reticulocyte count often remains elevated because most PNH patients on Eculizumab continue to have some extravascular hemolysis. If this occurs on a regular basis then the dosing interval can be shortened or the dose increased in order to compensate. It is also important to remember that increased complement activation accompanies infection (eg. flu or viral gastroenteritis) or trauma which can result in transient breakthrough hemolysis. It is not recommended to change the dosing with regard to a single episode of breakthrough hemolysis.

Anticoagulation is only partly effective in preventing thrombosis in PNH. Some sources state that thrombosis is an absolute indication for initiating treating with Eculizumab. Prophyllactic anticoagulation has never been proven to prevent thrombosis in all PNH patients and can be dangerous given the thrombocytopenia seen in this malady. Some sources state that patients who do not meet criteria for Eculizumab therapy should not receive anticoagulation. Possible exceptions to this rule might include patients with persistently elevated D-dimer levels, pregnant PNH patients and patients in the perioperative period.

==References==
{{reflist|2}}

==Additional Resources==
* Ross L. Titton, and Fergus V. Coakley. [http://radiology.rsnajnls.org/cgi/content/short/225/1/67 Case 51: Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome and Renal Cortical Hemosiderin.] Radiology 2002 225: 67-70.
* Brodsky RA. "How I treat paroxysmal nocturnal hemoglobinuria" Blood. 2009;113:6522-6527.

==External links==
*[http://www.aamds.org Aplastic Anemia & MDS International Foundation]
*[http://www.pnhdisease.org PNH Support Group]
*[http://www.pnhfoundation.org PNH Research and Support Foundation]
*[http://goldminer.arrs.org/search.php?query=Paroxysmal%20nocturnal%20hemoglobinuria Goldminer: Paroxysmal nocturnal hemoglobinuria]

{{Hematology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Rare diseases]]
[[category:Genetic disorders]]

[[de:Paroxysmale nächtliche Hämoglobinurie]]
[[es:Hemoglobinuria nocturna paroxística]]
[[fr:Hémoglobinurie paroxystique nocturne]]
[[it:Emoglobinuria parossistica notturna]]
[[nl:Paroxysmale nocturnale hemoglobinurie]]
[[pl:Napadowa nocna hemoglobinuria]]
[[pt:Hemoglobinúria paroxística noturna]]
[[sr:Пароксизмална ноћна хемоглобинурија]]
[[tr:Paroksismal noktürnal hemoglobinüri]]

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Paroxysmal nocturnal hemoglobinuria

2010-09-25T01:35:47Z

Robert Killeen:

{{Infobox_Disease |
Name = {{PAGENAME}} |
Image = |
Caption = |
DiseasesDB = 9688 |
ICD10 = {{ICD10|D|59|5|d|55}} |
ICD9 = {{ICD9|283.2}} |
ICDO = |
OMIM = 311770 |
MedlinePlus = |
eMedicineSubj = med |
eMedicineTopic = 2696 |
MeshID = D006457 |
}}
{{Search infobox}}
{{CMG}}

{{Editor Help}}

'''Paroxysmal nocturnal hemoglobinuria''' ([[PNH]]) is a rare, acquired, potentially life-threatening disease of the blood characterised by [[hemolytic anemia]], [[thrombosis]] and red [[urine]] due to breakdown of [[red blood cell]]s. [[PNH]] is the only hemolytic anemia caused by an ''acquired'' intrinsic defect in the [[cell membrane]].

==History==
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (1852).<ref>Strübing P. Paroxysmale Hämoglobinurie. ''Dtsch Med Wochenschr'' 1882;8:1-3 and 17-21.</ref><ref>[http://www.whonamedit.com/synd.cfm/2918.html Whonamedit entry]</ref> A more detailed description was made by Dr Ettore Marchiafava and Dr Alessio Nazari in 1911,<ref>Marchiafava E, Nazari A. Nuovo contributo allo studio degli itteri cronici emolitici. ''Policlinico [Med]'' 1911;18:241-254.</ref> with further elaborations by Marchiafava in 1928<ref>Marchiafava E. Anemia emolitica con emosiderinuria perpetua. ''Policlinico [Med]'' 1928;35:105-117.</ref> and Dr Ferdinando Micheli in 1931.<ref>Micheli F. Uno caso di anemia emolitica con emosiderinuria perpetua. ''G Accad Med Torino'' 1931;13:148.</ref>

==Classification==
PNH is classified:
* ''Classic PNH''. Evidence of [[PNH]] in the absence of another bone marrow disorder.
* ''[[PNH]] in the setting of another specified bone marrow disorder''.
* ''Subclinical PNH''. [[PNH]] abnormalities on flow cytometry without signs of hemolysis.

==Pathophysiology==
All cells have proteins attached to their membranes and they are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. [[PNH]] occurs as a result of a defect in one of these mechanisms.

It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.<ref>Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. ''PIG-A mutations in normal hematopoiesis.'' Blood 2005;105:3848-54. PMID 15687243.</ref> The gene that codes for PIG-A is inherited in an [[Sex linkage|X-linked]] fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation'). Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected). Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease. The complement system is the part of the immune system that helps to destroy invading microorganisms. The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement. CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.

The increased destruction of red blood cells results in [[anemia]]. The increased rate of thrombosis is due to dysfunction of [[platelet]]s. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.

==Signs and symptoms==
Quite paradoxically, the destruction of red blood cells ([[hemolysis]]) is neither paroxysmal nor nocturnal the majority of the time (this constellation of symptoms is seen in only 25% of patients). Patients with PNH manifest the clinical and laboratory signs of chronic hemolytic anemia. Weakness, dyspnea and pallor are common. Solenomegaly may be present.

A common finding in [[PNH]] is the presence of breakdown products of [[RBC]]s, hemoglobin (26% pf patients) and hemosiderin, in the urine. Hemosiderinuria is a more constant feature of this disease and typically doesn't occur in other forms of anemia unless there is considerable intravascular erythrocyte destruction. Hemolysis is increased in the evening however, the (classic) passage of dark, hemoglobin-containing urine upon rising in the morning is seen in only a minority of cases. Haptoglobin is decreased and LDH can be increased to 2-10 times normal. Neutropenia as well as thrombocytopenia may be evident. The leukocyte alkaline phosphatase (LAP) score is decreased.

An inconsistent, but potentially life-threatening, complication of PNH is the development of venous thrombosis (~40% of patients). These thrombi are often found in the [[hepatic vein|hepatic]] (causing [[Budd-Chiari syndrome]]; the most comon cause of mortality), [[Portal vein|portal]] (causing [[portal vein thrombosis]]), and cerebral veins (causing [[cerebral venous thrombosis]]). The risk of thrombosis has been directly linked to the size of the PNH clone. The thrombotic risk increases with pregnancy.

PNH can present with or as other disease entities such as aplastic anemia or myelodysplasia (MDS). Patients who present with pancytopenia or thrombosis compounding anemia should be suspected of PNH. Many patients with bone marrow failure ([[aplastic anemia]]) develop [[PNH]] (10-33%). Aplastic anemia can be caused by an attack by the immune system against the bone marrow. For this reason, drugs that suppress the immune system are being researched as a therapy for PNH.<ref>Sacher, Ronald A. and Richard A. McPherson. "Wildman's Clinical Interpretation of Laboratory Tests, 11th edition."</ref> <ref>Kumar, Vinay, Abu Abbas, and Nelson Fausto. "Robbins and Cotran Pathologic Basis of Disease, 7th edition."</ref>

Iron deficiency often occurs in PNH patients because of urinary loss and should be treated. The administration of oral iron is usually sufficient. Although there may be an increase in hemoglobinuria with iron therapy, due to the increased production of PNH cells by the marrow, the net positive effect in red blood cell production may lessen the requirements for blood transfusion. Folate should be given concurrently with the iron to help augment hematopoiesis.

Nitric Oxide depletion / thrombosis;
During episodes of acute hemolysis free plasma hemoglobin is released as a consequence of erythrocyte lysis may overpower haptoglobin, a hemoglobin-scavenging protein. Excess free hemoglobin depletes plasma nitric oxide, which may play an important role in the maintenance of normal platelet function. Because of this it has been postulated that nitric oxide down-regulates platelet aggregation, adhesion and regulating molecules in the coagulation cascade. Nitric oxide depletion may lead to platelet activation and aggregation. With this in mind the chronic consumption of nitric oxide by intravascular hemoglobin may play a role in the thrombotic events that occur in patients with PNH. Depletion of nitric oxide at the tissue level contributes to numerous PNH manifestations including smooth muscle dystonia (eg esophageal spasm, abdominal pain, male erectile dysfunction), pulmonary hypertension, severe fatigue, renal insufficiency and thrombosis.

==Diagnosis==
A sugar or sucrose lysis test, in which a patient's red blood cells are placed in low ionic strength solution and observed for hemolysis, is used for screening. A more specific test for PNH, called ''Ham's acid hemolysis'' test, is performed if the sugar test is positive for hemolysis.<ref>Ham TH. Chronic haemolytic anaemia with paroxysmal nocturnal haemoglobinuria: study of the mechanism of haemolysis in relation to acid-base equilibrium. ''[[N Engl J Med]]'' 1937;217:915-918.</ref> In a positive sucrose lysis test ionic strength facilitates the complement binding whereas in a positive Ham acid hemolysis test acidic strength facilitates the complement binding. The differential diagnosis of a positive sugar lysis test includes some autoimmune hemolytic anemias, even leukemias can give a false positive result. The differential diagnosis for a positive Ham test includes congenital dyserythropoietic anemia; note that a negative Ham test doesn't rule out PNH. These assays do not reliably quantitate the percentage of PNH cells and can be falsely negative in patients who have received red blood cell transfusions. <ref>Brodsky RA. ' ' How I treat paroxysmal nocturnal hemoglobinuria.' 'Blood 2009;113:6522-6527. <ref> Occasionally the characteristic complement-sensitive erythrocytes cannot be demonstrated in patients with well-established PNH. This probably occurs when the production of PNH cells is relatively low and most of the PNH cells that have been made have already been destroyed either in the marrow or in the circulation. Therefore a single normal sucrose hemolysis test cannot be considered absolute evidence that a patient does not have PNH.

The bone marrow biopsy in PNH shows erythroid hyperplasia.

Modern methods include [[flow cytometry]] for [[CD55]], [[CD16]], [[CD59]] and other GPI anchored proteins on [[white blood cells|white]] and [[red blood cells]]. <ref>Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, Hillmen P, Luzzatto L, Young N, Kinoshita T, Rosse W, Socie G, International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. ''[[Blood (journal)|Blood]] 2005;106:3699-709. PMID 16051736.</ref> Laboratories favor flow cytometry to evaluate PNH due to its high sensitivity and specificity. Flow cytometry of the peripheral blood, not the bone marrow aspirate, is required to evaluate the presence or absence of GPI linked proteins. In addition, because of the short life of granulocytes, the peripheral blood samples need to reach the lab in an expedited manner. The most commonly used antibodies are CD59 (expressed on all hematocellular lineages), and CD55 but other GPI anchored antigens (CD14, CD16, CD24) can also be studied on leukocytes. Dependent on the presence of these molecules on the cell surface, they are classified as type I, II or III PNH cells.

PNH type II & III cell populations; definitions.
Some patients may have erythrocytes with low but detectable GPI anchored proteins; these cells are designated PNH type II. By contrast, cells that are completely devoid of GPI anchored proteins are referred to as PNH type III. Patients with large populations of PNH type II erythrocytes may have less hemolysis than those with comparable populations of PNH III cells but these patients are still at risk for both hemolysis and thrombosis.

===MRI===

*Renal cortical signal intensity loss (hemosiderin accumulates in the renal cortex when intravascular hemolysis results in the direct release of hemoglobin into the plasma).
*Venous thrombosis.
*Liver and spleen are usually of normal signal intensity in paroxysmal nocturnal hemoglobinuria, unless repeated transfusions have resulted in hepatic and splenic signal intensity loss owing to transfusional siderosis.

(Images shown below are courtesy of RadsWiki)

<gallery>
Image:Paroxysmal nocturnal hemoglobinuria 001.jpg
Image:Paroxysmal nocturnal hemoglobinuria 002.jpg
Image:Paroxysmal nocturnal hemoglobinuria 003.jpg
Image:Paroxysmal nocturnal hemoglobinuria 004.jpg
Image:Paroxysmal nocturnal hemoglobinuria 005.jpg
Image:Paroxysmal nocturnal hemoglobinuria 006.jpg
Image:Paroxysmal nocturnal hemoglobinuria 007.jpg
Image:Paroxysmal nocturnal hemoglobinuria 008.jpg
</gallery>

==Treatment==
===Long-term===
PNH is a chronic condition. In patients who have only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventative treatment with [[warfarin]] decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).<ref name=parker2005/><ref>{{cite journal |author=Hall C, Richards S, Hillmen P |title=Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) |journal=Blood |volume=102 |issue=10 |pages=3587–91 |year=2003 |month=November |pmid=12893760 |doi=10.1182/blood-2003-01-0009 |url=http://bloodjournal.hematologylibrary.org/cgi/content/full/102/10/3587}}</ref>

Episodes of thrombosis are treated as they would in other patients, but given that PNH is a persisting underlying cause it is likely that treatment with [[warfarin]] or similar drugs needs to be continued long-term after an episode of thrombosis.<ref name=parker2005>{{cite journal |author=Parker C, Omine M, Richards S, ''et al'' |title=Diagnosis and management of paroxysmal nocturnal hemoglobinuria |journal=Blood |volume=106 |issue=12 |pages=3699–709 |year=2005 |pmid=16051736 |doi=10.1182/blood-2005-04-1717|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/12/3699}} {{PMC|1895106}}</ref>

===Acute attacks===
There is disagreement as to whether steroids (such as [[prednisolone]]) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant [[anemia]] this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.<ref name=parker2005/>

Eculizumab (AKA Soliris) is a monoclonal antibody against the complement protein C5, halting terminal complement-mediated intravascular hemolysis.<ref>{{cite journal |author=Hillmen P, Hall C, Marsh JC, ''et al'' |title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria |journal=N. Engl. J. Med. |volume=350 |issue=6 |pages=552–9 |year=2004 |pmid=14762182 |doi=10.1056/NEJMoa031688}}</ref> It binds to a subunit of the C5 convertase enzyme. It prevents C5 convertase from hydrolyzing C5 to C5a and C5b, the latter combining with C9 to form the terminal complement complex.

Selection of patients to be treated with Eculizumab should be guided by the degree of hemolysis and the risk of thrombosis. Although most of the patients with PNH have some degree of ongoing hemolysis not all are transfusion dependent nor even anemic.

Patients who take Eculizumab are at increase risk of life-threatening meningococcal infection. Patients must receive the meningococcal vaccine at least 2 weeks before Eculizumab is given. If the patient had already received the vaccine, they may need a booster. Patients have a 0.5% yearly risk of acquiring neisserial sepsis even after vaccination. Patients should be revaccinated against Neisseria meningitidis every 3-5 years after starting the treatment and they should seek medical care if they develop any signs or symptoms suggestive of neisserial infection. These include headache, nausea, vomiting, fever, stiff back or neck, rash, confusion, visual sensitization to light and myalgias with flu-like manifestations. Note that the most common toxicity of Eculizumab is headache which occurs in about 50% of patients given the first dose or two but, typically, this rarely recurs afterwards. Patients still need to be monitored for meningitis for at least 8 weeks after discontinuing Eculizumab.

Long term terminal complement inhibition by Eculizumab doesn't increase the incidence of myeloproliferative disease, myelodysplasia, acute leukemias or aplasia / pancytopenias in PNH patients. Eculizumab administration decreases hemolysis leading to stabilization of the hemoglobin concentration and reticulocyte count. This is manifest clinically with a decrease in the need for transfusions.

Breakthrough intravascular hemolysis and a return of PNH symptoms occurs in < 2% of PNH patients treated with Eculizumab. This typically occurs a day or two before the next scheduled dose and is accompanied by a spike in the LDH. The LDH usually returns to normal or near normal within days to weeks after Eculizumab. Since the (episodic) hemolysis of PNH is partly intravascular, the finding of urine hemosiderin is consistent with continued erythrocyte destruction. The reticulocyte count often remains elevated because most PNH patients on Eculizumab continue to have some extravascular hemolysis. If this occurs on a regular basis then the dosing interval can be shortened or the dose increased in order to compensate. It is also important to remember that increased complement activation accompanies infection (eg. flu or viral gastroenteritis) or trauma which can result in transient breakthrough hemolysis. It is not recommended to change the dosing with regard to a single episode of breakthrough hemolysis.

Anticoagulation is only partly effective in preventing thrombosis in PNH. Some sources state that thrombosis is an absolute indication for initiating treating with Eculizumab. Prophyllactic anticoagulation has never been proven to prevent thrombosis in all PNH patients and can be dangerous given the thrombocytopenia seen in this malady. Some sources state that patients who do not meet criteria for Eculizumab therapy should not receive anticoagulation. Possible exceptions to this rule might include patients with persistently elevated D-dimer levels, pregnant PNH patients and patients in the perioperative period.

==References==
{{reflist|2}}

==Additional Resources==
* Ross L. Titton, and Fergus V. Coakley. [http://radiology.rsnajnls.org/cgi/content/short/225/1/67 Case 51: Paroxysmal Nocturnal Hemoglobinuria with Thrombotic Budd-Chiari Syndrome and Renal Cortical Hemosiderin.] Radiology 2002 225: 67-70.

==External links==
*[http://www.aamds.org Aplastic Anemia & MDS International Foundation]
*[http://www.pnhdisease.org PNH Support Group]
*[http://www.pnhfoundation.org PNH Research and Support Foundation]
*[http://goldminer.arrs.org/search.php?query=Paroxysmal%20nocturnal%20hemoglobinuria Goldminer: Paroxysmal nocturnal hemoglobinuria]

{{Hematology}}
{{SIB}}
[[Category:Hematology]]
[[Category:Rare diseases]]
[[category:Genetic disorders]]

[[de:Paroxysmale nächtliche Hämoglobinurie]]
[[es:Hemoglobinuria nocturna paroxística]]
[[fr:Hémoglobinurie paroxystique nocturne]]
[[it:Emoglobinuria parossistica notturna]]
[[nl:Paroxysmale nocturnale hemoglobinurie]]
[[pl:Napadowa nocna hemoglobinuria]]
[[pt:Hemoglobinúria paroxística noturna]]
[[sr:Пароксизмална ноћна хемоглобинурија]]
[[tr:Paroksismal noktürnal hemoglobinüri]]

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Paroxysmal nocturnal hemoglobinuria

2010-09-21T01:17:19Z

Robert Killeen:

Paroxysmal nocturnal hemoglobinuria

2010-09-18T23:43:27Z

Robert Killeen: