Essential thrombocytosis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Soujanya Thummathati, MBBS [2]
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 30% of cases
Pathophysiology
As defined by WHO, ET is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation.[1] 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.[2] 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[3]. 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.
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).[4] 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.
Microscopic findings of ET
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.[1]
In 2005, a mutation in the JAK2 kinase (V617F) was found by multiple research groups [5][6] [7] to be associated with essential thrombocytosis in around 30% of cases. JAK2 is a member of the Janus kinase family.
References
- ↑ 1.0 1.1 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). - ↑ Thrombopoietin. Wikipedia. https://en.wikipedia.org/wiki/Thrombopoietin#Function_and_regulation. Accessed on Novenber 3rd,2015.
- ↑ Platelet. Wikipedia.https://en.wikipedia.org/wiki/Platelet#Granule_secretion. Accessed on Novenber 3rd,2015.
- ↑ 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.
- ↑ Kralovics R, Passamonti F, Buser AS, Teo SS; et al. (2005 Apr 28). "A gain-of-function mutation of JAK2 in myeloproliferative disorders". N Engl J Med. 352 (17): 1779–90. Check date values in:
|date=(help) - ↑ Baxter EJ et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-61. PMID 15781101
- ↑ 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