In polycythaemia vera (PV), there is a JAK2 V617F mutation causing erythrocytosis. Patients with PV characteristically have low serum erythropoietin (EPO) levels. What is the physiological mechanism explaining the EPO suppression?

• A JAK2 V617F directly phosphorylates and activates the EPO gene transcription factor HIF-1α, causing sustained EPO production that then negatively feeds back on its own synthesis
• B Elevated whole blood viscosity in PV reduces renal blood flow, activating tubular oxygen sensing that paradoxically suppresses EPO by the Haldane effect
• C The JAK2 V617F constitutively activates EPO receptor (EPOR) signalling in erythroid progenitors, expanding red cell mass independent of EPO; the resulting raised PaO2 delivered to the kidney (via elevated Hb) suppresses HIF-2α-driven EPO synthesis in interstitial fibroblasts ✓
• D Erythrocytosis causes polycythaemia-mediated bone marrow stromal cells to secrete inhibin, which directly suppresses renal EPO secretion via an endocrine loop

Explanation

Normal EPO synthesis in peritubular interstitial fibroblasts of the renal cortex is driven by HIF-2α (activated by hypoxia). In PV, the JAK2 V617F mutation renders erythroid progenitors constitutively active — they proliferate and differentiate without requiring EPO. The resulting polycythaemia increases blood oxygen-carrying capacity, raising tissue PO2 and thereby increasing renal parenchymal PO2; elevated PO2 promotes VHL-mediated proteasomal degradation of HIF-2α, suppressing EPO transcription. Low EPO in the context of erythrocytosis is a key diagnostic feature of PV (distinguishing it from secondary polycythaemia where EPO is high). The Haldane effect relates to CO2 binding by Hb and is not relevant here.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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