Essential thrombocytosis pathophysiology: Difference between revisions
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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> | *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> | ||
*Janus kinase 2, a non-receptor tyrosine kinase protein belonging to the [[Janus kinase]] family | *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]], [[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> | ||
*''[[MPL]]'' and ''[[THPO]]'' | *''[[MPL]]'' and ''[[THPO]]'' mutations also result in the activation of JAK-STAT pathway, resulting in abnormal platelet proliferation. | ||
*[[Thrombopoietin]] (TPO) is a hormone produced | *[[Thrombopoietin]] (TPO) destruction is also critical to the development of essential thrombocytosis. TPO is a hormone that is predominantly produced by the liver, the bone marrow, and the kidney. It normally regulates the stimulation, production, and proliferation of megakaryocytes. Once thrombopoietin binds to the TPO receptors on the megakaryocytes, it is destroyed, 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> | ||
** | **Despite the high platelet count, essential thrombocytosis paradoxically manifests with an increase in free circulating concentration of thrombopoietin as the abnormal platelets have defective TPO receptors that 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 | ||
Revision as of 20:52, 22 December 2015
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Essential thrombocytosis Microchapters |
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Differentiating Essential thrombocytosis from other Diseases |
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Diagnosis |
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Treatment |
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Essential thrombocytosis pathophysiology On the Web |
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American Roentgen Ray Society Images of Essential thrombocytosis pathophysiology |
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Risk calculators and risk factors for Essential thrombocytosis pathophysiology |
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
- 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.[2]
- 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, interleukin-3,5).[3] 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.[4]
- MPL and THPO mutations also result in the activation of JAK-STAT pathway, resulting in abnormal platelet proliferation.
- Thrombopoietin (TPO) destruction is also critical to the development of essential thrombocytosis. TPO is a hormone that is predominantly produced by the liver, the bone marrow, and the kidney. It normally regulates the stimulation, production, and proliferation of megakaryocytes. Once thrombopoietin binds to the TPO receptors on the megakaryocytes, it is destroyed, making the megakaryocyte unavailable for further hormonal interaction.[5]
- Despite the high platelet count, essential thrombocytosis paradoxically manifests with an increase in free circulating concentration of thrombopoietin as the abnormal platelets have defective TPO receptors that impair proper binding of thrombopoietin.[6]
- 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[7]. 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.
- 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) -> megakaryoblast -> promegakaryocyte -> megakaryocyte.[8]](/images/e/e6/Blood_cell_lineage2.jpg)
CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) -> megakaryoblast -> promegakaryocyte -> megakaryocyte.[8]
![CFU-Me (pluripotential hemopoietic stem cell or hemocytoblast) -> megakaryoblast -> promegakaryocyte -> megakaryocyte.[8]](/index.php/File:Blood_cell_lineage2.jpg)
Genetics
- 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.
- In recent studies, another mutation 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.
- Other genes that may be involved in the pathogenesis of essential thrombocytosis are MPL and THPO genes.[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]
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![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]](/images/0/0c/Essential_Thrombocythemia%2C_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.[11]
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![Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia. Hematoxylin & eosin stain.[12]](/images/3/31/Bone_marrow_biopsy_ET.jpg)
Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia. Hematoxylin & eosin stain.[12]
![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]](/index.php/File:Essential_Thrombocythemia,_Peripheral_Blood.jpg)
![Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia. Hematoxylin & eosin stain.[12]](/index.php/File:Bone_marrow_biopsy_ET.jpg)
References
- ↑ Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.
- ↑ 2.0 2.1 Sanchez S, Ewton A (2006). "Essential thrombocythemia: a review of diagnostic and pathologic features". 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). - ↑ 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.
- ↑ Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.
- ↑ Thrombopoietin. Wikipedia. https://en.wikipedia.org/wiki/Thrombopoietin#Function_and_regulation. Accessed on Novenber 3rd,2015.
- ↑ 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) - ↑ Platelet. Wikipedia.https://en.wikipedia.org/wiki/Platelet#Granule_secretion. Accessed on Novenber 3rd,2015.
- ↑ Megakaryocyte. Wikipedia. https://en.wikipedia.org/wiki/Megakaryocyte#/media/File:Illu_blood_cell_lineage.jpg Accessed on November 16,2015.
- ↑ 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.
- ↑ Essential thrombocythemia. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/essential-thrombocythemia Accessed on November 16, 2015.
- ↑ 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.
- ↑ 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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