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__NOTOC__
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{{Polycythemia vera}}
{{Polycythemia vera}}
{{CMG}}{{AE}}{{MJK}} {{shyam}}
{{CMG}} {{AE}}{{MJK}}; {{shyam}}
==Overview==
==Overview==
Primary [[polycythemia]] occurs when excess red blood cells are produced as a result of an abnormality of the [[bone marrow]]. Often, excess [[white blood cell]]s and [[platelet]]s are also produced. Polycythemia vera is classified as a [[myeloproliferative neoplasm]]. Polycythemia vera arises from hematopoietic stem cells, which give rise to erythrocytes cells that are normally involved in delivering oxygen to the body tissue. The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US. Common risk factors in the development of polycythemia vera are history of [[thrombosis]] and old age ( 65 year old and older). If left untreated, patients with polycythemia vera may progress to develop [[headache]], [[fatigue]], and [[dyspnea]]. Common complications of polycythemia vera include [[bleeding]], [[thrombosis]], [[tinnitus]] , and [[splenomegaly]]. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years. People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include [[headache]], [[fatigue]], and [[pruritis]]. Laboratory findings associated with the diagnosis of polycythemia vera include [[erythrocytosis]], [[leukocytosis]], and[[thrombocytosis]]. The mainstay of therapy for polycythemia vera is [[phlebotomy]], [[hydroxyurea]] (alone or with phlebotomy), [[interferon-alpha]] and pegylated interferon-alpha, [[chlorambucil]], and low-dose [[aspirin]].
Primary [[polycythemia]] occurs when excess red blood cells are produced as a result of an abnormality of the [[bone marrow]]. Often, excess [[white blood cell]]s and [[platelet]]s are also produced. Polycythemia vera is classified as a [[myeloproliferative neoplasm]]. Polycythemia vera arises from hematopoietic stem cells, which give rise to erythrocytes cells that are normally involved in delivering oxygen to the body tissue. The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US. Common risk factors in the development of polycythemia vera are history of [[thrombosis]] and old age ( 65 year old and older). If left untreated, patients with polycythemia vera may progress to develop [[headache]], [[fatigue]], and [[dyspnea]]. Common complications of polycythemia vera include [[bleeding]], [[thrombosis]], [[tinnitus]] , and [[splenomegaly]]. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years. People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include [[headache]], [[fatigue]], and [[pruritis]]. Laboratory findings associated with the diagnosis of polycythemia vera include [[erythrocytosis]], [[leukocytosis]], and[[thrombocytosis]]. The mainstay of therapy for polycythemia vera is [[phlebotomy]], [[hydroxyurea]] (alone or with phlebotomy), [[interferon-alpha]] and pegylated interferon-alpha, [[chlorambucil]], and low-dose [[aspirin]].


==Historical Perspective==
==Historical Perspective==
The first description of polycythemia vera dates back to the late 19th century. At that time, Louis Henry Vaquez and Sir William Osler were the first to describe this condition. Over the subsequent decades, the disease became better characterized. In the late 20th century, therapeutics were conceptualized, and it was found that [[hydroxyurea]] and [[interferon-alpha]] were effective in treating polycythemia vera. In 2005, a mutation in the ''[[JAK2]]'' kinase (V617F) was found in multiple patients with [[myeloproliferative neoplasms]] (including polycythemia vera) by different researchers. The WHO developed diagnostic criteria for this condition in 2008. The WHO recently revised their criteria for the diagnosis of polycythemia vera in 2016.
The first description of polycythemia vera dates back to the late 19th century. At that time, Louis Henry Vaquez and Sir William Osler were the first to describe this condition. Over the subsequent decades, the disease became better characterized. In the late 20th century, therapeutics were conceptualized, and it was found that [[hydroxyurea]] and [[interferon-alpha]] were effective in treating polycythemia vera. In 2005, a mutation in the ''[[JAK2]]'' kinase (V617F) was found in multiple patients with [[myeloproliferative neoplasm]]<nowiki/>s (including polycythemia vera) by different researchers. The WHO developed diagnostic criteria for this condition in 2008. The WHO recently revised their criteria for the diagnosis of polycythemia vera in 2016.


==Classification==
==Classification==
Polycythemia vera is a subtype of [[myeloproliferative neoplasm]]. [[Myeloproliferative neoplasm]] may be classified according to the World Health Organization into eight subtypes: [[chronic myelogenous leukemia]], [[chronic neutrophilic leukemia]], [[polycythemia vera]], [[primary myelofibrosis]], [[essential thrombocythemia]], [[chronic eosinophilic leukemia]], [[mastocytosis]], and myeloproliferative neoplasms, unclassifiable. The classification of polycythemia is subdivided into primary polycythemia (which is a clonal process caused by the JAK2 mutation) and secondary polycythemia (which is a reactive process due to a state of chronic hypoxia). There are numerous causes of secondary polycythemia, and most of these causes are cardiopulmonary in origin.
Polycythemia vera is a subtype of [[myeloproliferative neoplasm]]. [[Myeloproliferative neoplasm]] may be classified according to the World Health Organization into eight subtypes: [[chronic myelogenous leukemia]], [[chronic neutrophilic leukemia]], [[polycythemia vera]], [[primary myelofibrosis]], [[essential thrombocythemia]], [[chronic eosinophilic leukemia]], [[mastocytosis]], and myeloproliferative neoplasms, unclassifiable. The classification of polycythemia is subdivided into primary polycythemia (which is a clonal process caused by the JAK2 mutation) and secondary polycythemia (which is a reactive process due to a state of chronic [[hypoxia]]). There are numerous causes of secondary polycythemia, and most of these causes are cardiopulmonary in origin.


==Pathophysiology==
==Pathophysiology==
Normal physiology of [[red blood cell]] production involves the stimulation of the [[erythropoietin]] receptor on [[erythroid]] cells by the hormone [[erythropoietin]]. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of [[red blood cells]] in an erythropoietin-independent manner due to an activating JAK2 mutation. The mutation is usually a point mutation (V617F). The JAK2 mutation causes hyperactivity of the [[red blood cell]] production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of [[hemoglobin]] and [[red blood cell]] mass predisposes patients to thrombosis.
Normal physiology of [[red blood cell]] production involves the stimulation of the [[erythropoietin]] receptor on [[erythroid]] cells by the hormone [[erythropoietin]]. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of [[red blood cells]] in an erythropoietin-independent manner due to an activating [[JAK2]] mutation. The [[Mutations|mutation]] is usually a point [[mutation]] (V617F). The [[JAK2]] [[mutation]] causes hyperactivity of the [[red blood cell]] production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of [[hemoglobin]] and [[red blood cell]] mass predisposes patients to thrombosis.


==Causes==
==Causes==
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==Differentiating Polycythemia Vera from other Diseases==
==Differentiating Polycythemia Vera from other Diseases==
Polycythemia vera must be differentiated from other myeloproliferative neoplasms, such as [[chronic myelogenous leukemia]], [[essential thrombocythemia]], and [[primary myelofibrosis]]. Polycythemia vera must also be differentiated from secondary polycythemia, which is usually due to chronic hypoxia. Each of these conditions have different etiologies, symptoms, laboratory abnormalities, physical exam findings, and treatments.
Polycythemia vera must be differentiated from other [[myeloproliferative neoplasm]]<nowiki/>s, such as [[chronic myelogenous leukemia]], [[essential thrombocythemia]], and [[primary myelofibrosis]]. Polycythemia vera must also be differentiated from secondary polycythemia, which is usually due to chronic [[hypoxia]]. Each of these conditions have different etiologies, symptoms, laboratory abnormalities, physical exam findings, and treatments.


==Epidemiology and Demographics==
==Epidemiology and Demographics==
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==Risk factors==
==Risk factors==
Common risk factors in the development of polycythemia vera are old age (65 year old and older), family history, and Ashkenazi Jewish descent. After a patient is diagnosed with polycythemia vera, risk stratification involves assessment of age and thrombotic history. The risk assessment for development of post-PV myelofibrosis or post-PV acute myeloid leukemia include a variety of factors.
Common risk factors in the development of polycythemia vera are old age (65 year old and older), family history, and Ashkenazi Jewish descent. After a patient is diagnosed with polycythemia vera, risk stratification involves assessment of age and [[thrombotic]] history. The risk assessment for development of post-PV [[myelofibrosis]] or post-PV acute myeloid leukemia include a variety of factors.


==Screening==
==Screening==
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==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
The natural history of polycythemia vera begins with symptoms such as headache, fatigue, and dyspnea. Common complications of polycythemia vera include thrombosis (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke), bleeding, and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years in the absence of complications. However, there is a variable risk for progression to myelofibrosis and acute myeloid leukemia, and these are the most devastating complications of the disease. Myelofibrosis and acute myeloid leukemia are part of the natural history of the disease.
The natural history of polycythemia vera begins with symptoms such as headache, fatigue, and dyspnea. Common complications of polycythemia vera include thrombosis (such as [[deep vein thrombosis]], [[pulmonary embolism]], [[myocardial infarction]], and stroke), bleeding, and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years in the absence of complications. However, there is a variable risk for progression to myelofibrosis and [[acute myeloid leukemia]], and these are the most devastating complications of the disease. [[Myelofibrosis]] and [[acute myeloid leukemia]] are part of the natural history of the disease.


==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===
===Diagnostic Criteria===
The diagnosis of polycythemia vera is based on the world health organization criteria, which include high levels of hemoglobin, presence of ''[[JAK2|JAK2617VF]]'', hypercellularity on bone marrow biopsy, low serum erythropoietin levels, and endogenous erythroid colony formation in vitro.<ref name="pmid17488875">{{cite journal| author=Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA et al.| title=Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. | journal=Blood | year= 2007 | volume= 110 | issue= 4 | pages= 1092-7 | pmid=17488875 | doi=10.1182/blood-2007-04-083501 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17488875  }} </ref>
The diagnosis of polycythemia vera is based on the World Health Organization criteria, which was initially proposed in 2008 then revised in 2016. In general, the diagnosis of polycythemia vera requires a combination of elevated [[hemoglobin]], which include high levels of [[hemoglobin]], presence of [[JAK2]] V617F mutation, hypercellularity on [[bone marrow biopsy]], low serum [[erythropoietin]] level, and [[endogenous]] [[erythroid]] colony formation [[in vitro]].[1] The 2016 WHO criteria more accurately reflect the disease biology of polycythemia vera.  
===History and Symptoms===
===History and Symptoms===
People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include [[headache]], [[fatigue]], and [[pruritis]].<ref name="cancer.ca">Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia/leukemia/polycythemia-vera/?region=ab</ref>
People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include [[headache]], [[fatigue]], and [[pruritis]]. The symptomatology is highly variable between patients. Some patients can present with a minimal symptom burden that does not result in any change in quality of life, and other patients can have severe symptom burden.
 
===Physical Examination===
===Physical Examination===
Patients with polycythemia vera are usually well-appearing. Physical examination of patients with polycythemia vera is usually remarkable for skin [[bruising]], [[fever]], and [[splenomegaly]].<ref name="cancer.ca">Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia/leukemia/polycythemia-vera/?region=ab</ref><ref name="pmid22211080">{{cite journal| author=Dust N, Daboval T, Guerra L| title=Evaluation and management of priapism in a newborn: A case report and review of the literature. | journal=Paediatr Child Health | year= 2011 | volume= 16 | issue= 1 | pages= e6-8 | pmid=22211080 | doi= | pmc=PMC3043029 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22211080  }} </ref>
Patients with polycythemia vera are usually well-appearing. Physical examination of patients with polycythemia vera is usually remarkable for skin [[bruising]], [[fever]], and [[splenomegaly]].
 
===Laboratory Findings===
===Laboratory Findings===
Laboratory findings associated with the diagnosis of polycythemia vera include [[erythrocytosis]], [[leukocytosis]], and[[thrombocytosis]].<ref name="cancer.ca">Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia/leukemia/polycythemia-vera/?region=ab</ref>
Laboratory findings associated with the diagnosis of polycythemia vera include [[erythrocytosis]], [[leukocytosis]], and [[thrombocytosis]]. The most sensitive test for polycythemia vera is JAK2 V617F mutation testing in the peripheral blood. A specific finding in patients with polycythemia vera is low [[erythropoietin]] level.
 
===CT===
===CT===
Abdominal and chest [[CT scan]] may be helpful in the diagnosis of polycythemia vera. Findings on CT scan suggestive of polycythemia vera include enlarged lymph nodes, [[splenomegaly]], and splanchnic venous thrombosis.<ref name="cancer.ca">Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia-chronic-myelogenous-cml/diagnosis/?region=ab</ref><ref name="pmid23716157">{{cite journal| author=Lim BK| title=Clinics in diagnostic imaging (146). Polycythaemia vera (PV). | journal=Singapore Med J | year= 2013 | volume= 54 | issue= 5 | pages= 289-91; quiz 292 | pmid=23716157 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23716157  }} </ref>
Abdominal and chest CT scan may be helpful in the diagnosis of polycythemia vera. Findings on CT scan suggestive of polycythemia vera include enlarged lymph nodes, [[splenomegaly]], and [[splanchnic]] [[venous thrombosis]].
===Brain MRI===
 
Brain MRI may be helpful in the detection of ischemic stroke in patients with polycythemia vera.<ref name="cancer.ca">Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia-chronic-myelogenous-cml/diagnosis/?region=ab</ref><ref name="pmid11328338">{{cite journal| author=Koennecke HC, Bernarding J| title=Diffusion-weighted magnetic resonance imaging in two patients with polycythemia rubra vera and early ischemic stroke. | journal=Eur J Neurol | year= 2001 | volume= 8 | issue= 3 | pages= 273-7 | pmid=11328338 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11328338  }} </ref>
===MRI===
===Abdominal Ultrasound===
Brain MRI may be helpful in the detection of [[ischemic stroke]] in patients with polycythemia vera. Abdominal MRI can help with diagnosis of mesenteric thrombosis.
Abdominal ultrasound may be helpful in the diagnosis of myeloproliferative neoplasm. Findings on abdominal ultrasound suggestive of myeloproliferative neoplasm include [[splenomegaly]], abdominal fluid, and hepatic lesions.<ref name="pmid25143825">{{cite journal| author=Khan J, Sykes DB| title=Case report: a 37-year-old male with telangiectasias, polycythemia vera, perinephric fluid collections, and intrapulmonary shunting. | journal=BMC Hematol | year= 2014 | volume= 14 | issue= 1 | pages= 11 | pmid=25143825 | doi=10.1186/2052-1839-14-11 | pmc=PMC4138393 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25143825  }} </ref>
 
===Ultrasound===
Abdominal ultrasound may be helpful in the diagnosis of myeloproliferative neoplasm. Findings on abdominal ultrasound suggestive of [[myeloproliferative neoplasm]] include [[splenomegaly]], abdominal fluid, and hepatic lesions. Ultrasound of the extremities can assist with diagnosis of deep vein thrombosis, which is commonly associated with high-risk polycythemia vera.
 
===Other Imaging Studies===
===Other Imaging Studies===
Other imaging studies for polycythemia vera include [[PET]] scan, which helps to detect metastasis in bone marrow and to follow up medical treatment.<ref name="pmid20625724">{{cite journal| author=Agool A, Glaudemans AW, Boersma HH, Dierckx RA, Vellenga E, Slart RH| title=Radionuclide imaging of bone marrow disorders. | journal=Eur J Nucl Med Mol Imaging | year= 2011 | volume= 38 | issue= 1 | pages= 166-78 | pmid=20625724 | doi=10.1007/s00259-010-1531-0 | pmc=PMC3005118 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20625724  }} </ref>
Other imaging studies for polycythemia vera include [[PET]] scan, which helps to detect metastasis in bone marrow and to follow up medical treatment.
 
===Other Diagnostic Studies===
===Other Diagnostic Studies===
Other diagnostic studies for polycythemia vera include [[bone marrow aspiration]] and [[biopsy|trephine biopsy]].<ref name="cancer.ca">Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia/leukemia/polycythemia-vera/?region=ab</ref>
Other diagnostic studies for polycythemia vera include [[bone marrow aspiration]] and [[biopsy|trephine biopsy]]. [[Erythropoietin]] levels can also be measured.
 
==Treatment==
==Treatment==
===Medical Therapy===
===Medical Therapy===
The mainstay of therapy for polycythemia vera is [[phlebotomy]], [[hydroxyurea]] (alone or with phlebotomy), [[interferon-alpha]] and pegylated interferon-alpha, [[chlorambucil]], and low-dose [[aspirin]].<ref name="cancergov">National Cancer Institute. Physician Data Query Database 2015.http://www.cancer.gov/types/myeloproliferative/hp/chronic-treatment-pdq#section/_5</ref><ref name="pmid3704665">{{cite journal| author=Berk PD, Goldberg JD, Donovan PB, Fruchtman SM, Berlin NI, Wasserman LR| title=Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. | journal=Semin Hematol | year= 1986 | volume= 23 | issue= 2 | pages= 132-43 | pmid=3704665 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3704665  }} </ref><ref name="pmid9209196">{{cite journal| author=Lamy T, Devillers A, Bernard M, Moisan A, Grulois I, Drenou B et al.| title=Inapparent polycythemia vera: an unrecognized diagnosis. | journal=Am J Med | year= 1997 | volume= 102 | issue= 1 | pages= 14-20 | pmid=9209196 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9209196  }} </ref><ref name="pmid3749925">{{cite journal| author=Kaplan ME, Mack K, Goldberg JD, Donovan PB, Berk PD, Wasserman LR| title=Long-term management of polycythemia vera with hydroxyurea: a progress report. | journal=Semin Hematol | year= 1986 | volume= 23 | issue= 3 | pages= 167-71 | pmid=3749925 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3749925  }} </ref><ref name="pmid10803930">{{cite journal| author=Lengfelder E, Berger U, Hehlmann R| title=Interferon alpha in the treatment of polycythemia vera. | journal=Ann Hematol | year= 2000 | volume= 79 | issue= 3 | pages= 103-9 | pmid=10803930 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10803930  }} </ref><ref name="pmid16804923">{{cite journal| author=Silver RT| title=Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. | journal=Cancer | year= 2006 | volume= 107 | issue= 3 | pages= 451-8 | pmid=16804923 | doi=10.1002/cncr.22026 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16804923  }} </ref><ref name="pmid25069759">{{cite journal| author=Huang BT, Zeng QC, Zhao WH, Li BS, Chen RL| title=Interferon α-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation. | journal=Leuk Res | year= 2014 | volume= 38 | issue= 10 | pages= 1177-83 | pmid=25069759 | doi=10.1016/j.leukres.2014.06.019 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25069759  }} </ref><ref name="pmid19826111">{{cite journal| author=Quintás-Cardama A, Kantarjian H, Manshouri T, Luthra R, Estrov Z, Pierce S et al.| title=Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. | journal=J Clin Oncol | year= 2009 | volume= 27 | issue= 32 | pages= 5418-24 | pmid=19826111 | doi=10.1200/JCO.2009.23.6075 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19826111  }} </ref>
The mainstay of therapy for polycythemia vera is phlebotomy, aspirin, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil. Some of these medications are targeted agents that work specifically in polycythemia vera, while others are non-specific therapies that can have numerous off-target adverse effects. Some of these treatments can modify the course of the disease, while others simply alleviate symptom burden.
 
===Surgery===
===Surgery===
Surgical intervention is recommended for the management of polycythemia vera in case of [[splenomegaly]].
Surgical intervention is a consideration in the management of polycythemia vera in case of [[splenomegaly]], though surgery is not typically done.
<ref name="pmid25327078">{{cite journal| author=Inamdar S, Sangle S, Bote NN, Nagargoje N| title=Splenic infarction in polycythaemia vera: can the spleen be saved? | journal=J Assoc Physicians India | year= 2014 | volume= 62 | issue= 3 | pages= 276-8 | pmid=25327078 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25327078  }} </ref>
 
===Primary Prevention===
===Primary Prevention===
There is no established method for primary prevention of polycythemia vera.<ref name="cancergov">National Cancer Institute. Physician Data Query Database 2015.http://www.cancer.gov/types/myeloproliferative</ref><ref name="NHLBI">National Heart, lung and Blood institute. How Can Polycythemia Vera Be Prevented?.http://www.nhlbi.nih.gov/health/health-topics/topics/poly/prevention</ref>
There is no established method for primary prevention of polycythemia vera.
 
===Secondary Prevention===
===Secondary Prevention===
Secondary prevention strategy following polycythemia vera include low dose [[aspirin]].<ref name="pmid16462024">{{cite journal| author=Maeda T, Wakasawa T, Shima Y, Tsuboi I, Aizawa S, Tamai I| title=Role of polyamines derived from arginine in differentiation and proliferation of human blood cells. | journal=Biol Pharm Bull | year= 2006 | volume= 29 | issue= 2 | pages= 234-9 | pmid=16462024 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16462024  }} </ref>
Secondary prevention strategy following polycythemia vera include low dose [[aspirin]].


==References==
==References==

Latest revision as of 22:49, 21 January 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]; Shyam Patel [3]

Overview

Primary polycythemia occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow. Often, excess white blood cells and platelets are also produced. Polycythemia vera is classified as a myeloproliferative neoplasm. Polycythemia vera arises from hematopoietic stem cells, which give rise to erythrocytes cells that are normally involved in delivering oxygen to the body tissue. The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US. Common risk factors in the development of polycythemia vera are history of thrombosis and old age ( 65 year old and older). If left untreated, patients with polycythemia vera may progress to develop headache, fatigue, and dyspnea. Common complications of polycythemia vera include bleeding, thrombosis, tinnitus , and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years. People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include headache, fatigue, and pruritis. Laboratory findings associated with the diagnosis of polycythemia vera include erythrocytosis, leukocytosis, andthrombocytosis. The mainstay of therapy for polycythemia vera is phlebotomy, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil, and low-dose aspirin.

Historical Perspective

The first description of polycythemia vera dates back to the late 19th century. At that time, Louis Henry Vaquez and Sir William Osler were the first to describe this condition. Over the subsequent decades, the disease became better characterized. In the late 20th century, therapeutics were conceptualized, and it was found that hydroxyurea and interferon-alpha were effective in treating polycythemia vera. In 2005, a mutation in the JAK2 kinase (V617F) was found in multiple patients with myeloproliferative neoplasms (including polycythemia vera) by different researchers. The WHO developed diagnostic criteria for this condition in 2008. The WHO recently revised their criteria for the diagnosis of polycythemia vera in 2016.

Classification

Polycythemia vera is a subtype of myeloproliferative neoplasm. Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes: chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic eosinophilic leukemia, mastocytosis, and myeloproliferative neoplasms, unclassifiable. The classification of polycythemia is subdivided into primary polycythemia (which is a clonal process caused by the JAK2 mutation) and secondary polycythemia (which is a reactive process due to a state of chronic hypoxia). There are numerous causes of secondary polycythemia, and most of these causes are cardiopulmonary in origin.

Pathophysiology

Normal physiology of red blood cell production involves the stimulation of the erythropoietin receptor on erythroid cells by the hormone erythropoietin. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of red blood cells in an erythropoietin-independent manner due to an activating JAK2 mutation. The mutation is usually a point mutation (V617F). The JAK2 mutation causes hyperactivity of the red blood cell production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of hemoglobin and red blood cell mass predisposes patients to thrombosis.

Causes

Polycythemia vera is caused by a mutation in the JAK2 gene (V617F mutation). This mutation occurs in more than 98% of cases of polycythemia vera. The JAK2 exon 12 mutation occurs in a small proportion of patients. There are no other causes of this disease.

Differentiating Polycythemia Vera from other Diseases

Polycythemia vera must be differentiated from other myeloproliferative neoplasms, such as chronic myelogenous leukemia, essential thrombocythemia, and primary myelofibrosis. Polycythemia vera must also be differentiated from secondary polycythemia, which is usually due to chronic hypoxia. Each of these conditions have different etiologies, symptoms, laboratory abnormalities, physical exam findings, and treatments.

Epidemiology and Demographics

The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US.[1] The prevalence of polycythemia vera is 48 to 57 cases per 100,000 individuals in the United States. Males are more commonly affected than females. The life expectancy is variable but is typically more than 10 years for patients who have uncomplicated polycythemia vera and is significantly shorter in the case of post-PV myelofibrosis or post-PV acute myeloid leukemia.

Risk factors

Common risk factors in the development of polycythemia vera are old age (65 year old and older), family history, and Ashkenazi Jewish descent. After a patient is diagnosed with polycythemia vera, risk stratification involves assessment of age and thrombotic history. The risk assessment for development of post-PV myelofibrosis or post-PV acute myeloid leukemia include a variety of factors.

Screening

Screening for polycythemia vera is not a routine clinical practice. However, assessment of a complete blood count (CBC), which is done routinely, usually gives the first indication for the presence of polycythemia vera in a patient.

Natural History, Complications and Prognosis

The natural history of polycythemia vera begins with symptoms such as headache, fatigue, and dyspnea. Common complications of polycythemia vera include thrombosis (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke), bleeding, and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years in the absence of complications. However, there is a variable risk for progression to myelofibrosis and acute myeloid leukemia, and these are the most devastating complications of the disease. Myelofibrosis and acute myeloid leukemia are part of the natural history of the disease.

Diagnosis

Diagnostic Criteria

The diagnosis of polycythemia vera is based on the World Health Organization criteria, which was initially proposed in 2008 then revised in 2016. In general, the diagnosis of polycythemia vera requires a combination of elevated hemoglobin, which include high levels of hemoglobin, presence of JAK2 V617F mutation, hypercellularity on bone marrow biopsy, low serum erythropoietin level, and endogenous erythroid colony formation in vitro.[1] The 2016 WHO criteria more accurately reflect the disease biology of polycythemia vera.

History and Symptoms

People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include headache, fatigue, and pruritis. The symptomatology is highly variable between patients. Some patients can present with a minimal symptom burden that does not result in any change in quality of life, and other patients can have severe symptom burden.

Physical Examination

Patients with polycythemia vera are usually well-appearing. Physical examination of patients with polycythemia vera is usually remarkable for skin bruising, fever, and splenomegaly.

Laboratory Findings

Laboratory findings associated with the diagnosis of polycythemia vera include erythrocytosis, leukocytosis, and thrombocytosis. The most sensitive test for polycythemia vera is JAK2 V617F mutation testing in the peripheral blood. A specific finding in patients with polycythemia vera is low erythropoietin level.

CT

Abdominal and chest CT scan may be helpful in the diagnosis of polycythemia vera. Findings on CT scan suggestive of polycythemia vera include enlarged lymph nodes, splenomegaly, and splanchnic venous thrombosis.

MRI

Brain MRI may be helpful in the detection of ischemic stroke in patients with polycythemia vera. Abdominal MRI can help with diagnosis of mesenteric thrombosis.

Ultrasound

Abdominal ultrasound may be helpful in the diagnosis of myeloproliferative neoplasm. Findings on abdominal ultrasound suggestive of myeloproliferative neoplasm include splenomegaly, abdominal fluid, and hepatic lesions. Ultrasound of the extremities can assist with diagnosis of deep vein thrombosis, which is commonly associated with high-risk polycythemia vera.

Other Imaging Studies

Other imaging studies for polycythemia vera include PET scan, which helps to detect metastasis in bone marrow and to follow up medical treatment.

Other Diagnostic Studies

Other diagnostic studies for polycythemia vera include bone marrow aspiration and trephine biopsy. Erythropoietin levels can also be measured.

Treatment

Medical Therapy

The mainstay of therapy for polycythemia vera is phlebotomy, aspirin, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil. Some of these medications are targeted agents that work specifically in polycythemia vera, while others are non-specific therapies that can have numerous off-target adverse effects. Some of these treatments can modify the course of the disease, while others simply alleviate symptom burden.

Surgery

Surgical intervention is a consideration in the management of polycythemia vera in case of splenomegaly, though surgery is not typically done.

Primary Prevention

There is no established method for primary prevention of polycythemia vera.

Secondary Prevention

Secondary prevention strategy following polycythemia vera include low dose aspirin.

References

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