Essential thrombocytosis pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Essential Thrombocytosis is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation | Essential Thrombocytosis is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation and proliferation in the bone marrow resulting in an 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. It may be used in targeted gene therapy in the near future. | ||
==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, | *As defined by WHO, ET is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation in the bone marrow, resulting in 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> | ||
*Recent studies have shown that other cell lineages can also be affected to some degree, resulting in their respective cell proliferation. | |||
No specific pathologic markers were identified | *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. | |||
*No specific pathologic markers were specifically identified 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 patients 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. | |||
==Microscopic findings of ET== | ==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. | *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. | |||
*Bonemarrow biopsy is a definitive test of diagnosis. 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> | |||
==References== | ==References== | ||
Revision as of 13:58, 4 November 2015
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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 and proliferation in the bone marrow resulting in an 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. It may be used in targeted gene therapy in the near future.
Pathophysiology
- As defined by WHO, ET is a clonal proliferation of pluripotent stem cells with predominantly megakaryocytic differentiation in the bone marrow, resulting in abnormally increased number of platelets released into the circulation .[1]
- Recent studies have shown that other cell lineages can also be affected to some degree, resulting in their respective cell proliferation.
- 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 specifically identified 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 patients 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.
- 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.
- Bonemarrow biopsy is a definitive test of diagnosis. 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.[1]
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.