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==Pathophysiology==
==Pathophysiology==
*As defined by [[WHO]], essential thrombocytosis is a clonal proliferation of [[pluripotent]] stem cells with predominantly megakaryocytic differentiation in the bone marrow, resulting in an abnormally increased number of platelets released into the circulation.<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 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?
*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 phenylalanine at amino acid 617 of the ''JAK2'' protein, that activates the tyrosine kinase in ''JAK2'', resulting in the activation of the JAK-STAT pathway. This 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>
dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16879015  }} </ref>  
*''[[MPL]]'' and ''[[THPO]]'' genetic mutations also result in the activation of JAK-STAT pathway resulting in abnormal platelet proliferation.    
*Essential thrombocytosis is caused by point mutations in ''janus kinase'' 2 (''JAK''2) gene in 50% of the patients   
*[[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>  
*[[Thrombopoietin]] destruction is also critical to the development of essential thrombocytosis.
**With high platelet counts, essential thrombocytosis should hypothetically present with lower [[thrombopoietin]] levels. However, there is a paradoxical increase in free circulating levels of thrombopoietin as the abnormal platelets in essential thrombocytosis have defective TPO receptors that do not allow proper binding of thrombopoietin.<ref>{{Cite journal
**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]]
| author = [[J. Li]], [[Y. Xia]] & [[D. J. Kuter]]
  | title = The platelet thrombopoietin receptor number and function are markedly decreased in patients with essential thrombocythaemia
  | title = The platelet thrombopoietin receptor number and function are markedly decreased in patients with essential thrombocythaemia
Line 22: Line 23:
  | pmid = 11122159
  | pmid = 11122159
}}</ref>  
}}</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) that impairs the process of aggregation.  
*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>.  
*On the other hand, patients with secondary or reactive thrombocytosis have normal platelet activity with no defects in [[aggregation]].
**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]].


<gallery>
<gallery>
image:Blood cell lineage2.jpg|CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) -> megakaryoblast -> promegakaryocyte -> megakaryocyte.<ref>Megakaryocyte. Wikipedia. https://en.wikipedia.org/wiki/Megakaryocyte#/media/File:Illu_blood_cell_lineage.jpg Accessed on November 16,2015.</ref>
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>


</gallery>
</gallery>


==Genetics==
==Genetics==
*Essential thrombocytosis is associated with mutations in janus kinase 2 (''[[JAK2]]'') gene in 50% of the patients.  
*Essential thrombocytosis is associated with mutations in ''janus kinase 2'' (''[[JAK2]]'') gene in 50% of the patients.  
*For unknown reasons, a point mutation in the amino acid 617 of ''JAK2'' protein, results in the substitution of [[valine]] for [[phenylalanine]] from a G to T replacement. This activates the janus kinase protein, signaling the process of hematopoiesis that results in the differentiation and proliferation of platelets.
*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>
*In recent studies, another mutation 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.
**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.
*Other genes that may be involved in the pathogenesis of essential thrombocytosis are ''MPL'' and ''THPO'' genes.<ref>Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.</ref>
**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==
==Microscopic Pathology==

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.
  • CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) to the formation of megakaryocyte.[6]

    CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) to the formation of megakaryocyte.[6]

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]
  • 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.[11]

    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.[11]

  • Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia. Hematoxylin & eosin stain.[12]

    Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia. Hematoxylin & eosin stain.[12]

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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