Polycythemia vera pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]
Overview
Polycythemia vera arises from hematopoietic stem cells, which give rise to erythrocytes cells that are normally involved in delivering oxygen to the body tissue.[1]
Pathophysiology
The JAK2 mutation
The pathophysiology of polycythemia vera is founded upon the presence of a JAK2 mutation within a hematopoietic stem cell (and therefore within an erythroid precursor). JAK2 is a protein of the Janus kinase family, located on chromosome 9.[2] JAK2 signals through STAT molecules, which are signal transducers and activators of transcription. A point mutation that converts valine to phenylalanine at the 617th position within the JAK2 gene is found in more than 95% of polycythemia vera. The JAK2 V617F point mutation is an activating mutation that resulting in autonomous activity of the JAK2 pathway, resulting in excess red blood cell production in an erythropoietin-independent manner.[2] The JAK2 exon 12 mutation results in a similar phenotype.
Consequences of the JAK2 mutation
In polycythemia vera, the erythrocyte count can be as high as 8 to 9 million erythrocytes per cubic millimeter of blood (normal is 3 million per cubic millimeter). The hematocrit may be as high as 70 to 80% (normal is 45% for men and 43% for women). In addition, the total blood volume sometimes increases to as much as twice the normal values. These lab abnormalities arise from autonomous red blood cell production triggered by the JAK2 mutation in erythroid precursors. The entire vascular system can become markedly engorged with blood, and the blood circulation time throughout the body can increase up to twice the normal value. The increased numbers of erythrocytes causes a five time increase in blood viscosity. Capillaries can become plugged by the very viscous blood which results in an extremely sluggish flow of blood.[3][4] This represents the pathophysiology of thrombosis in polycythemia vera. Plugging of capillaries within the cerebral vasculature can result in stroke. Plugging of capillaries within the coronary vasculature can result in myocardial infarction. Plugging of capillaries within the pulmonary circulation can result in pulmonary embolism.
Genetics
Gene involved in the pathogenesis of polycythemia vera include JAK2 kinase (V617F).[5][6]
References
- ↑ Jamieson CH, Gotlib J, Durocher JA, Chao MP, Mariappan MR, Lay M; et al. (2006). "The JAK2 V617F mutation occurs in hematopoietic stem cells in polycythemia vera and predisposes toward erythroid differentiation". Proc Natl Acad Sci U S A. 103 (16): 6224–9. doi:10.1073/pnas.0601462103. PMC 1434515. PMID 16603627.
- ↑ 2.0 2.1 Means RT (2010). "JAK2 V617F and the evolving paradigm of polycythemia vera". Korean J Hematol. 45 (2): 90–4. doi:10.5045/kjh.2010.45.2.90. PMC 2983020. PMID 21120186.
- ↑ Thurmes PJ, Steensma DP (July 2006). "Elevated serum erythropoietin levels in patients with Budd-Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis". Eur. J. Haematol. 77 (1): 57–60. doi:10.1111/j.1600-0609.2006.00667.x. PMID 16827884.
- ↑ National Cancer Institute. Polycythemia vera.https://en.wikipedia.org/wiki/Polycythemia_vera
- ↑ Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR (2005). "Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders". Lancet. 365 (9464): 1054–61. PMID 15781101.
- ↑ Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Frohling S, Dohner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG (2005). "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis". Cancer Cell. 7 (4): 387–97. PMID 15837627.