What is the pathophysiology of polycythemia vera (PV)?

Updated: Sep 20, 2021
  • Author: Srikanth Nagalla, MD, MS, FACP; Chief Editor: Sara J Grethlein, MD, FACP  more...
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The bone marrow of patients with polycythemia vera (PV),contains normal stem cells but also contains abnormal clonal stem cells that interfere with or suppress normal stem cell growth and maturation. Evidence indicates that the etiology of panmyelosis is unregulated neoplastic proliferation. The origin of the stem cell transformation remains unknown. See the image below.

Bone marrow film at 100X magnification demonstrati Bone marrow film at 100X magnification demonstrating hypercellularity and increased number of megakaryocytes. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Progenitors of the blood cells in these patients display abnormal responses to growth factors, suggesting the presence of a defect in a signaling pathway common to different growth factors. The observation that in vitro erythroid colonies grow when no endogenous erythropoietin (Epo) is added to the culture and the presence of a truncated Epo receptor in familial erythrocytosis indicate that the defect is in the transmission of the signal. The sensitivity of polycythemia vera progenitors to multiple cytokines suggests that the defect may lie in a common pathway downstream from multiple receptors. Increased expression of BCLX suggests an additional decrease in cellular apoptosis.

A mutation of the Janus kinase–2 gene (JAK2) is the most likely source of PV pathogenesis, as JAK2 is directly involved in the intracellular signaling following exposure to cytokines to which polycythemia vera progenitor cells display hypersensitivity. [6] A recurrent unique acquired clonal mutation in JAK2 has been found in most patients with polycythemia vera and other myeloproliferative diseases (MPDs), including essential thrombocythemia and idiopathic myelofibrosis.

A unique valine-to-phenylalanine substitution at position 617 (V617F) in the pseudokinase JAK2 domain has been identified. The substitution, called JAK2V617F, leads to a permanently turned-on signaling at the affected cytokine receptors. [7, 8, 9, 10]  The JAK2V617F mutation is present in more than 95% of PV cases, but is also found in 50%-60% of essential thrombocytosis and primary myelofibrosis cases. [11] How these mutations interact with the wild-type kinase genes and how they manifest into different forms of MPDs need to be elucidated.

Thrombosis and bleeding are frequent in persons with PV, as a result of the disruption of hemostatic mechanisms because of (1) an increased level of red blood cells and (2) an elevation of the platelet count. There are findings that indicate the additional roles of tissue factor and polymorphonuclear leukocytes (PMLs) in clotting, the platelet surface as a contributor to phospholipid-dependent coagulation reactions, and the entity of platelet microparticles. Tissue factor is also synthesized by blood leukocytes, the level of which is increased in persons with MPD, which can contribute to thrombosis.

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