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Molecular pathogenesis of congenital polycythemic disorders and polycythemia vera

Josef T Prchal, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Alan G Rosmarin, MD


Absolute polycythemia refers to settings in which there is an increase in red cell mass. This condition has also been called erythrocytosis, with three forms being recognized (table 1):

Primary polycythemia – Primary polycythemia is caused by acquired (somatic) or inherited (germline) mutations expressed within the erythroid progenitors that increase their proliferation; this can occur in polycythemia vera or the rare polycythemias such as those due to "gain-of-function" of the erythropoietin receptor (EPOR). The result of these mutations is an increased accumulation of erythrocytes (ie, polycythemia).

Secondary polycythemia – Secondary polycythemia refers to conditions in which there are circulating plasma factors stimulating erythropoiesis, usually erythropoietin (EPO) or an anabolic steroid (eg, testosterone). In rare instances, exposure to cobalt, dysregulated angiotensin/angiotensin receptor 1 erythroid signaling, such as that seen in postrenal transplant erythrocytosis, and elevated plasma levels of insulin-like growth factor-1 have also been shown to stimulate erythropoiesis. Secondary polycythemias can be acquired or congenital, most often from EPO stimulation by hypoxia; they can also result from an EPO-secreting tumor. Secondary congenital polycythemias may arise from inheritance of mutant hemoglobins associated with increased oxygen affinity or an inherited defect of 2,3 BPG (2,3 DPG) synthesis.

Congenital disorders of hypoxia sensing – Some of these disorders share features of both primary (ie, increased sensitivity of erythroid progenitors to EPO) and secondary polycythemia (ie, elevated EPO levels). This was demonstrated in Chuvash polycythemia, some other congenital von Hippel Lindau (VHL) gene mutations, and in some patients with gain-of-function hypoxia inducible factor (HIF-2 alpha) gene mutations.

Congenital polycythemias with established molecular lesions due to germline mutations that either modify hemoglobin oxygen affinity or modify the normal response to hypoxia will be discussed here. Current understanding of the molecular pathogenesis of polycythemia vera will also be discussed here. The clinical approaches to the patient with polycythemia or suspected polycythemia vera are discussed separately. (See "Diagnostic approach to the patient with polycythemia" and "Clinical manifestations and diagnosis of polycythemia vera".)


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