Approach to Polycythemia

Initial Assessment and Confirmation

The American College of Physicians recommends confirming true polycythemia through hemoglobin/hematocrit thresholds (>95th percentile adjusted for sex and race), then systematically distinguishing between primary polycythemia vera, secondary causes, and relative polycythemia using serum erythropoietin levels and bone marrow examination 1
Pursue diagnostic evaluation if hemoglobin/hematocrit exceeds the 95th percentile of normal distribution adjusted for sex and race (hemoglobin >16.5 g/dL in men or >16.0 g/dL in women) 1
Documented increase in hemoglobin/hematocrit above baseline for an individual patient, regardless of where the value lies within the reference range, warrants further evaluation 1
Borderline-high hematocrit accompanied by PV-related features such as thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis, or erythromelalgia should be investigated 1

Measure serum erythropoietin (EPO) as the critical first test after confirming true polycythemia, with low EPO indicating probable polycythemia vera (PV) with specificity >90% 1, 6
If EPO is low, proceed directly to bone marrow examination, which is the cornerstone of diagnosis 1, 6
Bone marrow histology should be evaluated for hypercellularity, increased megakaryocytes with cluster formation, giant megakaryocytes and pleomorphism in megakaryocyte morphology, mild reticulin fibrosis, and decreased bone marrow iron stores 1, 6, 7

When EPO is elevated, systematically evaluate for hypoxia-driven causes such as chronic lung disease, right-to-left cardiopulmonary shunts, high-altitude habitation, hypoventilation syndromes, and high oxygen-affinity hemoglobinopathy 4, 2, 5
Hypoxia-independent causes such as malignant tumors, benign tumors, congenital causes, EPOR-mediated, exogenous erythropoietic drugs, and post-renal transplant erythrocytosis should also be considered 4, 2, 5
Additional workup for secondary causes may include complete blood count with differential, renal function tests, liver function tests, arterial blood gas analysis or pulse oximetry for hypoxemia, and imaging of kidney, liver, and central nervous system if initial studies are unrevealing or EPO is persistently elevated 5, 8

Do not perform red cell mass (RCM) measurements in most cases, as normal-range RCM does not rule out PV and RCM measurement with hematocrit >60% without obvious hemoconcentration is costly redundancy 9, 1
Do not assume low EPO always means PV, as low EPO can occur in essential thrombocythemia and rare congenital polycythemia with EPOR mutations 1, 6
Do not exclude PV based on normal EPO, as sensitivity of low EPO for PV is only <70% 1, 6
Do not overlook smoking history, as smoker's polycythemia is real and resolves with cessation; risk reduction begins within 1 year and returns to baseline after 5 years 2, 5