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{{Essential thrombocytosis}}
{{Essential thrombocytosis}}
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==Overview==
==Overview==
Essential Thrombocytosis is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation.The megakaryocyte proliferation in the bone marrow results in the abnormally increased number of platelets into the circulation. Once thrombopoietin binds to the TPO receptors on the megakaryocytes, it is destroyed thus making the megakaryocyte unavailable for further hormonal interaction. Given the higher platelet count, ET should be presenting with lower thrombopoietin levels. But there is a paradoxical increase in the free circulating levels of thrombopoietin as the abnormal platelets in ET have defective TPO receptors that do not allow proper binding of thrombopoietin. Platelets contain different types of granules alpha(contain P-selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII), Delta(δ) or Dense granules(contain  ADP or ATP, calcium, and serotonin), Gamma(γ) and Lambda(λ) granules. With defective granules in ET, there is a deficiency in clotting factors like fibrinogen and von Willebrand(vWF) that impair the process of aggregation. On the other hand patients with secondary or reactive thrombocytosis have a normal platelet activity with no defects in aggregation.  A point mutation G to T, results in the substitution of valine for phenyl alanine at amino acid 617 of the JAK2 protein that activates the tyrosine kinase in JAK2.  A mutation in the [[JAK2]] kinase (V617F) was found to be associated with essential thrombocytosis in around 50% of cases
Essential thrombocytosis arises from hematopoietic stem cells which give rise to [[megakaryocytes]] which give rise to [[platelets]] ([[thrombocytes]]), that are normally involved in blood clotting. Development of essential thrombocytosis is the result of a genetic mutation in the [[janus kinase]] 2 (''[[JAK2]]'') gene in 50% of the patients. Other genes that may be involved in the pathogenesis of essential thrombocytosis are ''CALR'', ''MPL'', and ''THPO'' genes.<ref>Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.</ref> On microscopic histopathological analysis, thrombocytosis, bone marrow hyperplasia with hyperlobated megakaryotic nuclei evident of thrombopoiesis are characteristic findings of essential thrombocytosis.


==Pathophysiology==
==Pathophysiology==
As defined by WHO, ET is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation.<ref name="pmidPMID: 16879015">{{cite journal| author=Sanchez S, Ewton A| title=Essential thrombocythemia: a review of diagnostic and pathologic features. | journal=Arch Pathol Lab Med | year= 2006 | volume= 130 | issue= 8 | pages= 1144-50 | pmid=PMID: 16879015 | doi=10.1043/1543-2165(2006)130[1144:ET]2.0.CO;2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16879015  }} </ref> Recent studies have shown that other cell lineages can also be affected to some degree,  resulting in their respective cell proliferation. The megakaryocyte proliferation in the bone marrow results in the abnormally increased number of platelets into the circulation. Thrombopoietin(TPO) is a hormone produced predominantly by the liver, bone marrow and kidney, that regulates the stimulation,production and proliferation of megakaryocytes. Once thrombopoietin binds to the TPO receptors on the megakaryocytes, it is destroyed thus making the megakaryocyte unavailable for further hormonal interaction.<ref>Thrombopoietin. Wikipedia. https://en.wikipedia.org/wiki/Thrombopoietin#Function_and_regulation. Accessed on Novenber 3rd,2015.</ref> Given the higher platelet count, ET should be presenting with lower thrombopoietin levels. But there is a paradoxical increase in the free circulating levels of thrombopoietin as the abnormal platelets in ET have defective TPO receptors that do not allow proper binding of thrombopoietin. Platelets contain different types of granules alpha(contain P-selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII), Delta(δ) or Dense granules(contain  ADP or ATP, calcium, and serotonin), Gamma(γ) and Lambda(λ) granules<ref>Platelet. Wikipedia.https://en.wikipedia.org/wiki/Platelet#Granule_secretion. Accessed on Novenber 3rd,2015.</ref>. With defective granules in ET, there is a deficiency in clotting factors like fibrinogen and von Willebrand(vWF) that impair the process of aggregation. On the other hand patients with secondary or reactive thrombocytosis have a normal platelet activity with no defects in aggregation.
*Essential thrombocytosis arises from [[pluripotent]] hematopoietic stem cells of megakaryocytic lineage that give rise to platelets.<ref name="pmidPMID: 16879015">{{cite journal| author=Sanchez S, Ewton A| title=Essential thrombocythemia: a review of diagnostic and pathologic features. | journal=Arch Pathol Lab Med | year= 2006 | volume= 130 | issue= 8 | pages= 1144-50 | pmid=PMID: 16879015 | doi=10.1043/1543-2165(2006)130[1144:ET]2.0.CO;2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?
dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16879015  }} </ref>  
*Essential thrombocytosis is caused by point mutations in ''janus kinase'' 2 (''JAK''2) gene in 50% of the patients   
*[[Thrombopoietin]] destruction is also critical to the development of essential thrombocytosis.
**Thrombopoietin normally regulates the stimulation, production, and proliferation of megakaryocytes.<ref>Thrombopoietin. Wikipedia. https://en.wikipedia.org/wiki/Thrombopoietin#Function_and_regulation. Accessed on Novenber 3rd,2015.</ref>
**Despite the high platelet count, essential thrombocytosis paradoxically manifests with an increase in free circulating concentration of [[thrombopoietin]] as the abnormal platelets have defective thrombopoietin receptors which impair proper binding of thrombopoietin.<ref>{{Cite journal
| author = [[J. Li]], [[Y. Xia]] & [[D. J. Kuter]]
| title = The platelet thrombopoietin receptor number and function are markedly decreased in patients with essential thrombocythaemia
| journal = [[British journal of haematology]]
| volume = 111
| issue = 3
| pages = 943–953
| year = 2000
| month = December
| pmid = 11122159
}}</ref>
*Platelets contain different types of granules: alpha (contain [[P-selectin]], platelet factor 4, transforming growth factor-β1, [[platelet-derived growth factor]], [[fibronectin]], B-thromboglobulin, [[vWF]], [[fibrinogen]], and coagulation factors V and XIII), delta (δ) or dense granules (contain  [[ADP]] or [[ATP]], calcium, and [[serotonin]]), gamma (γ), and lambda (λ) granules<ref>Platelet. Wikipedia.https://en.wikipedia.org/wiki/Platelet#Granule_secretion. Accessed on Novenber 3rd,2015.</ref>.  
**With defective granules in essential thrombocytosis, there is a deficiency in clotting factors like fibrinogen and von Willebrand (vWF), which impairs the process of aggregation.  
**On the other hand, patients with secondary or reactive thrombocytosis have normal platelet activity with no defects in [[aggregation]].


No specific pathologic markers were identified specifically for ET for a long time until some studies showed mutations in the janus kinase 2(JAK2) gene. Though not a standardized test, about 50% of the patient have this mutation. Janus kinase 2 a non-receptor tyrosine kinase protein belonging to the Janus kinase family that helps in signaling pathways involved in hematopoiesis(including thrombopoietin,erythropoietin,granulocyte-colony stimulating factor, Bcl-2, interleukin-3,5).<ref name="pmid15920007">{{cite journal| author=Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L et al.| title=Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. | journal=Blood | year= 2005 | volume= 106 | issue= 6 | pages= 2162-8 | pmid=15920007 | doi=10.1182/blood-2005-03-1320 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15920007  }} </ref> A point mutation G to T, results in the substitution of valine for phenyl alanine at amino acid 617 of the JAK2 protein that activates the tyrosine kinase in JAK2. JAK2 mutations are also found in other malignancies and they should be ruled out before making a diagnosis of ET. The mutation may be used in the diagnosis and probably in targeted gene therapy in future.
<gallery>
image:Blood cell lineage2.jpg|CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) to the formation of megakaryocyte.<ref>Megakaryocyte. Wikipedia. https://en.wikipedia.org/wiki/Megakaryocyte#/media/File:Illu_blood_cell_lineage.jpg Accessed on November 16,2015.</ref>


==Microscopic findings of ET==
</gallery>
A complete blood count shows marked elevation of platelet count greater than or equal to 600,000/μL of blood and sometimes even higher. Though the shape and sizes remain unchanged, variations may occur. The red cell morphology depends on the presence and degree of bleeding. The white cell count remains slightly elevated. Bonemarrow biopsy is a definitive test in diagnosis. The bone marrow is usually hypercellular though it can be normocellular. The megakaryocytes are bigger in size and havehyperlobated nuclei which is characteristic of increased thrombopoiesis. Cells are usually stainable with iron provided the patient had no significant hemorrhagic events. Collagen fibrosis is typically absent.<ref name="pmidPMID: 16879015">{{cite journal| author=Sanchez S, Ewton A| title=Essential thrombocythemia: a review of diagnostic and pathologic features. | journal=Arch Pathol Lab Med | year= 2006 | volume= 130 | issue= 8 | pages= 1144-50 | pmid=PMID: 16879015 | doi=10.1043/1543-2165(2006)130[1144:ET]2.0.CO;2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16879015  }} </ref>


In 2005, a mutation in the [[JAK2]] kinase (V617F) was found by multiple research groups <ref name=Kralovics>{{cite journal | author=Kralovics R, Passamonti F, Buser AS, Teo SS, et al |title=A gain-of-function mutation of JAK2 in myeloproliferative disorders| journal=N Engl J Med |date=2005 Apr 28 |volume=352|issue=17 |pages=1779-90}}</ref><ref name=Baxter>Baxter EJ et al. ''Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.'' Lancet. 2005;365:1054-61. PMID 15781101</ref> <ref name=Levine>Levine RL et al. ''Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.'' Cancer Cell. 2005;7:387-97. PMID 15837627</ref> to be associated with essential thrombocytosis in around 30% of cases. ''JAK2'' is a member of the [[Janus kinase]] family.
==Genetics==
*Essential thrombocytosis is associated with mutations in ''janus kinase 2'' (''[[JAK2]]'') gene in 50% of the patients.
*Janus kinase 2, a non-receptor tyrosine kinase protein belonging to the [[janus kinase]] family, helps in signaling pathways involved in [[hematopoiesis]] (including thrombopoietin, [[erythropoietin]], granulocyte-colony stimulating factor, [[Bcl-2]], and [[interleukin]]-3,5).<ref name="pmid15920007">{{cite journal| author=Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L et al.| title=Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. | journal=Blood | year= 2005 | volume= 106 | issue= 6 | pages= 2162-8 | pmid=15920007 | doi=10.1182/blood-2005-03-1320 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15920007  }} </ref>  
**A point mutation from G to T that results in the substitution of [[valine]] for phenylalanine at amino acid 617 of the JAK2 protein first activates the tyrosine kinase in JAK2 and subsequently results in the activation of the JAK-STAT pathway.
**Activation of the JAK-STAT pathway results in abnormal differentiation and proliferation of the precursor cells, releasing the increased pool of platelets into the circulation.<ref>Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.</ref>
*Mutations in the ''[[calreticulin]]'' (''CALR'') gene has been identified in patients with essential thrombocytosis who lacked ''JAK2'' mutations.<ref name="RotunnoMannarelli2013">{{cite journal|last1=Rotunno|first1=G.|last2=Mannarelli|first2=C.|last3=Guglielmelli|first3=P.|last4=Pacilli|first4=A.|last5=Pancrazzi|first5=A.|last6=Pieri|first6=L.|last7=Fanelli|first7=T.|last8=Bosi|first8=A.|last9=Vannucchi|first9=A. M.|title=Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia|journal=Blood|volume=123|issue=10|year=2013|pages=1552–1555|issn=0006-4971|doi=10.1182/blood-2013-11-538983}}</ref>
**The mechanism by which the mutation triggers the disease remains unknown.
*''[[MPL]]'' (myeloproliferative leukemia protein) and ''[[THPO]]'' (thrombopoietin) gene mutations may also result in the activation of JAK-STAT pathway, causing abnormal platelet proliferation.<ref>Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.</ref>
 
==Microscopic Pathology==
*A complete blood count shows marked elevation of platelet count greater than or equal to 600,000/μL of blood and sometimes even higher.
*The platelet shape and size usually remain unchanged, but variations may occur.
*The red cell morphology depends on the presence and severity of bleeding.
*The white cell count remains slightly elevated.
*Bone marrow biopsy is the definitive diagnostic test for essential thrombocytosis. The bone marrow is usually [[hypercellular]], though it can be normocellular. The megakaryocytes are bigger in size and have hyperlobated nuclei which is the characteristic feature of increased thrombopoiesis. Cells are usually stainable with iron, provided the patient had no significant hemorrhagic events. [[Collagen]] fibrosis is typically absent.<ref name="pmidPMID: 16879015">{{cite journal| author=Sanchez S, Ewton A| title=Essential thrombocythemia: a review of diagnostic and pathologic features. | journal=Arch Pathol Lab Med | year= 2006 | volume= 130 | issue= 8 | pages= 1144-50 | pmid=PMID: 16879015 | doi=10.1043/1543-2165(2006)130[1144:ET]2.0.CO;2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16879015  }} </ref>
 
<gallery>
image:Essential_Thrombocythemia,_Peripheral_Blood.jpg|This represents a platelet count between 1.5 and 2 million per microliter (normal range is between 0.150 and 0.450 million). The patient had had an elevated count for at least 15 years but is asymptomatic.<ref>File:Essential Thrombocythemia, Peripheral Blood (10189570483).jpg. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Essential_Thrombocythemia,_Peripheral_Blood_(10189570483).jpg Accessed on November 12, 2015. </ref>
 
image:Bone_marrow_biopsy_ET.jpg|Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia. Hematoxylin & eosin stain.<ref>File:Essential thrombocythemia (1).jpg. Wikimedia commons. https://commons.wikimedia.org/wiki/File:Essential_thrombocythemia_(1).jpg Accessed on November 12, 2015.</ref>
 
</gallery>


==References==
==References==

Latest revision as of 15:49, 6 January 2016

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Soujanya Thummathati, MBBS [2]

Overview

Essential thrombocytosis arises from hematopoietic stem cells which give rise to megakaryocytes which give rise to platelets (thrombocytes), that are normally involved in blood clotting. Development of essential thrombocytosis is the result of a genetic mutation in the janus kinase 2 (JAK2) gene in 50% of the patients. Other genes that may be involved in the pathogenesis of essential thrombocytosis are CALR, MPL, and THPO genes.[1] On microscopic histopathological analysis, thrombocytosis, bone marrow hyperplasia with hyperlobated megakaryotic nuclei evident of thrombopoiesis are characteristic findings of essential thrombocytosis.

Pathophysiology

  • Essential thrombocytosis arises from pluripotent hematopoietic stem cells of megakaryocytic lineage that give rise to platelets.[2]
  • Essential thrombocytosis is caused by point mutations in janus kinase 2 (JAK2) gene in 50% of the patients
  • Thrombopoietin destruction is also critical to the development of essential thrombocytosis.
    • Thrombopoietin normally regulates the stimulation, production, and proliferation of megakaryocytes.[3]
    • Despite the high platelet count, essential thrombocytosis paradoxically manifests with an increase in free circulating concentration of thrombopoietin as the abnormal platelets have defective thrombopoietin receptors which impair proper binding of thrombopoietin.[4]
  • Platelets contain different types of granules: alpha (contain P-selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII), delta (δ) or dense granules (contain ADP or ATP, calcium, and serotonin), gamma (γ), and lambda (λ) granules[5].
    • With defective granules in essential thrombocytosis, there is a deficiency in clotting factors like fibrinogen and von Willebrand (vWF), which impairs the process of aggregation.
    • On the other hand, patients with secondary or reactive thrombocytosis have normal platelet activity with no defects in aggregation.

Genetics

  • Essential thrombocytosis is associated with mutations in janus kinase 2 (JAK2) gene in 50% of the patients.
  • Janus kinase 2, a non-receptor tyrosine kinase protein belonging to the janus kinase family, helps in signaling pathways involved in hematopoiesis (including thrombopoietin, erythropoietin, granulocyte-colony stimulating factor, Bcl-2, and interleukin-3,5).[7]
    • A point mutation from G to T that results in the substitution of valine for phenylalanine at amino acid 617 of the JAK2 protein first activates the tyrosine kinase in JAK2 and subsequently results in the activation of the JAK-STAT pathway.
    • Activation of the JAK-STAT pathway results in abnormal differentiation and proliferation of the precursor cells, releasing the increased pool of platelets into the circulation.[8]
  • Mutations in the calreticulin (CALR) gene has been identified in patients with essential thrombocytosis who lacked JAK2 mutations.[9]
    • The mechanism by which the mutation triggers the disease remains unknown.
  • MPL (myeloproliferative leukemia protein) and THPO (thrombopoietin) gene mutations may also result in the activation of JAK-STAT pathway, causing abnormal platelet proliferation.[10]

Microscopic Pathology

  • A complete blood count shows marked elevation of platelet count greater than or equal to 600,000/μL of blood and sometimes even higher.
  • The platelet shape and size usually remain unchanged, but variations may occur.
  • The red cell morphology depends on the presence and severity of bleeding.
  • The white cell count remains slightly elevated.
  • Bone marrow biopsy is the definitive diagnostic test for essential thrombocytosis. The bone marrow is usually hypercellular, though it can be normocellular. The megakaryocytes are bigger in size and have hyperlobated nuclei which is the characteristic feature of increased thrombopoiesis. Cells are usually stainable with iron, provided the patient had no significant hemorrhagic events. Collagen fibrosis is typically absent.[2]

References

  1. Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.
  2. 2.0 2.1 Sanchez S, Ewton A (2006). [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi? dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16879015 "Essential thrombocythemia: a review of diagnostic and pathologic features"] Check |url= value (help). Arch Pathol Lab Med. 130 (8): 1144–50. doi:10.1043/1543-2165(2006)130[1144:ET]2.0.CO;2. PMID 16879015 PMID: 16879015 Check |pmid= value (help). line feed character in |url= at position 54 (help)
  3. Thrombopoietin. Wikipedia. https://en.wikipedia.org/wiki/Thrombopoietin#Function_and_regulation. Accessed on Novenber 3rd,2015.
  4. J. Li, Y. Xia & D. J. Kuter (2000). "The platelet thrombopoietin receptor number and function are markedly decreased in patients with essential thrombocythaemia". British journal of haematology. 111 (3): 943–953. PMID 11122159. Unknown parameter |month= ignored (help)
  5. Platelet. Wikipedia.https://en.wikipedia.org/wiki/Platelet#Granule_secretion. Accessed on Novenber 3rd,2015.
  6. Megakaryocyte. Wikipedia. https://en.wikipedia.org/wiki/Megakaryocyte#/media/File:Illu_blood_cell_lineage.jpg Accessed on November 16,2015.
  7. Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L; et al. (2005). "Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders". Blood. 106 (6): 2162–8. doi:10.1182/blood-2005-03-1320. PMID 15920007.
  8. Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.
  9. Rotunno, G.; Mannarelli, C.; Guglielmelli, P.; Pacilli, A.; Pancrazzi, A.; Pieri, L.; Fanelli, T.; Bosi, A.; Vannucchi, A. M. (2013). "Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia". Blood. 123 (10): 1552–1555. doi:10.1182/blood-2013-11-538983. ISSN 0006-4971.
  10. Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.
  11. File:Essential Thrombocythemia, Peripheral Blood (10189570483).jpg. Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Essential_Thrombocythemia,_Peripheral_Blood_(10189570483).jpg Accessed on November 12, 2015.
  12. File:Essential thrombocythemia (1).jpg. Wikimedia commons. https://commons.wikimedia.org/wiki/File:Essential_thrombocythemia_(1).jpg Accessed on November 12, 2015.


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