JAK2 Unmutated Erythrocytosis: 2026 Update on Diagnosis and Management

DISEASE OVERVIEW: JAK2 unmutated erythrocytosis encompasses a heterogeneous spectrum of hereditary and acquired entities. DIAGNOSIS: The foremost step is excluding polycythemia vera (PV) with JAK2 mutation screening (exons 12-15). Apparent polycythemia such as physiological outliers or relative polycythemia secondary to volume contraction should be considered. A historical overview of hematocrit (Hct) and hemoglobin (Hgb) levels helps distinguish longstanding from acquired erythrocytosis. Serum erythropoietin (Epo) levels are variably informative. HEREDITARY ERYTHROCYTOSIS: Hereditary erythrocytosis should be considered in longstanding erythrocytosis with a positive family history; causes include EPOR mutations (subnormal Epo), high oxygen affinity hemoglobin variants, PIEZO1 mutations, 2,3-bisphosphoglycerate deficiency, methemoglobinemia, and germline oxygen sensing pathway mutations (HIF2A-PHD2-VHL). ACQUIRED ERYTHROCYTOSIS: Acquired erythrocytosis results from central (cardiopulmonary disease) or peripheral (renal artery stenosis) hypoxia, Epo-producing tumors (renal cell carcinoma) or drugs (testosterone, sodium glucose co-transporter-2 inhibitors (SGLT2-i), erythropoiesis stimulating agents). IDIOPATHIC ERYTHROCYTOSIS: Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. MANAGEMENT: Cytoreductive therapy should be avoided. Phlebotomy should be considered for symptom control. Cardiovascular risk optimization and low-dose aspirin are advised, while the role of HIF2A inhibitors remains unclear. RECENT ADVANCES: EPO mutations which produce hyperactive, hepatic-like Epo were identified. In cases with negative workup but high clinical suspicion, an expanded next generation sequencing panel for hereditary erythrocytosis is recommended. Among drugs, SGLT2-i-associated erythrocytosis is increasingly recognized. FUTURE DIRECTIONS: Advances in molecular hematology are expected to improve the characterization of "idiopathic erythrocytosis". Results from prospective studies are needed to elucidate the underlying pathology and guide management.