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]; Shyam Patel [3]
Overview
Normal physiology of red blood cell production involves the stimulation of the erythropoietin receptor on erythroid cells by the hormone erythropoietin. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of red blood cells in an erythropoietin-independent manner due to an activating JAK2 mutation. The mutation is usually a point mutation (V617F). The JAK2 mutation causes hyperactivity of the red blood cell production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of hemoglobin and red blood cell mass predisposes patients to thrombosis.
Pathophysiology
Physiology
The normal physiology of polycythemia vera can be understood as follows:
- Under normal circumstances, erythrocytes are produced at a basal rate in response to erythropoietin. Erythropoietin is a hormone produced by the peritubular capillaries of the kidneys and serves as a signal for expansion of the erythrocyte pool. This process is normally tightly controlled. Janus kinase JAK2 is the receptor for erythropoietin, and this receptor (in the wild-type form) becomes activated when erythropoietin is present. JAK2 is a protein of the Janus kinase family, located on chromosome 9.[1] JAK2 signals through STAT molecules, which are signal transducers and activators of transcription. Under conditions of low oxygen content, such as high altitude or smoking, erythropoietin production increases, and red blood cell production increases. This is the normal physiologic response to hypoxia, and this response serves to ensure adequate oxygen delivery to tissues.
Pathogenesis
- The presence of a JAK2 mutation within a hematopoietic stem cell and therefore within an erythroid precursor.[1]
- The mutation that occurs is a point mutation that induces conversion of valine to phenylalanine at the 617th position within the JAK2 gene (JAK2 V617F).
- The JAK2 V617F point mutation is an activating mutation that results in autonomous activity of the JAK2 pathway, resulting in excess red blood cell production in an erythropoietin-independent manner.
- The JAK2 V617F mutation has been established to be positive in about 96% of people with polycythemia vera.[2]
- There could also be a mutation in exon 12 of JAK2 which results in a smililar phenotype as JAK2 V617F. It is seen in about 2-3% of people with polycythemia vera.
- A very few patients with erythrocytosis and low erythropoetin (EPO) levels may have mutations in LNK (SH2B3), which is an inhibitor of the JAK-STAT signaling pathway.
- In addition to the JAK2 point mutation, epigenetic factors also contribute to the pathogenesis of polycythemia vera. This conclusion was made after it was determined that the same JAK2 activating mutation could contribute to the pathogenesis of essential thrombocythemia and primary myelofibrosis. In essential thrombocythemia, for example, the JAK2 mutation is found in ~50% of patients. These diseases have overlapping clinical features.[2][3]
- On average, patients with polycythemia vera harbor 6-7 mutations. Besides the JAK2 mutation, other mutations occur in genes such as TET2 (found in 8.3% of patients), SF3B1 (involved in RNA splicing), DNMT3A (involved in epigenetic regulation), and ASXL1 (associated with a poor prognosis).[2]
Pathophysiology leading to thrombosis
- 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.[4][5]
- 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
Genes involved in the pathogenesis of polycythemia vera include:[2]
- JAK2 kinase (V617F)
- TET2
- SF3B1
- DNMT3A
- ASXL1
Associated Conditions
Conditions associated with polycythemia vera include:[2]
- Myelofibrosis
- Secondary acute myeloid leukemia
Microscopic Pathology
- On microscopic histopathological analysis, characteristic findings of polycythemia vera include:[6][7]
- Erythroid hyperplasia
- Granulocytic hyperplasia
- Increased number of atypical megakaryocytes of different sizes
- Monolobate to hyperlobate megakaryocyte nuclei with complex nuclear folding
- Megakaryocyte nuclear chromatin pattern: dispersed with prominent eosinophilic nucleoli to distinctly hyperchromatic
- Megakaryocytic clusters (greater than or equal to 3 megakaryocytes lying adjacent to each other with the absence of intervening cells)
- Normal or slightly increased bone marrow reticulin fibers
- Lymphoid nodules may be found in some patients
References
- ↑ 1.0 1.1 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.
- ↑ 2.0 2.1 2.2 2.3 2.4 Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK, Abboud CN, Adler K, Heaney ML, Jabbour EJ, Komrokji RS, Moliterno AR, Ritchie EK, Rice L, Mascarenhas J, Hoffman R (November 2015). "Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F". J. Clin. Oncol. 33 (33): 3953–60. doi:10.1200/JCO.2015.61.6474. PMC 4979103. PMID 26324368.
- ↑ Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR; et al. (2014). "Two clinical phenotypes in polycythemia vera". N Engl J Med. 371 (9): 808–17. doi:10.1056/NEJMoa1403141. PMC 4211877. PMID 25162887.
- ↑ 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
- ↑ Lakey MA, Pardanani A, Hoyer JD, Nguyen PL, Lasho TL, Tefferi A; et al. (2010). "Bone marrow morphologic features in polycythemia vera with JAK2 exon 12 mutations". Am J Clin Pathol. 133 (6): 942–8. doi:10.1309/AJCP3Z2AKUWRGTNM. PMID 20472853.
- ↑ Thiele J, Kvasnicka HM, Zankovich R, Diehl V (2001). "The value of bone marrow histology in differentiating between early stage Polycythemia vera and secondary (reactive) Polycythemias". Haematologica. 86 (4): 368–74. PMID 11325641.