What is the initial approach to managing a patient with polycythemia?

Initial Approach to Polycythemia

Confirm true polycythemia by verifying hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, then immediately measure serum erythropoietin (EPO) to distinguish primary polycythemia vera from secondary causes. 1

Confirmation of True Polycythemia

• Pursue diagnostic evaluation when hemoglobin/hematocrit exceeds the 95th percentile adjusted for sex and race (hemoglobin >16.5 g/dL in men or >16.0 g/dL in women) 1
• Investigate any documented increase in hemoglobin/hematocrit above an individual patient's baseline, even if within the reference range 1
• Evaluate borderline-high hematocrit when accompanied by PV-related features including thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis, or erythromelalgia 1
• 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 1

Critical First Test: Serum Erythropoietin

Measure serum EPO as the critical first test after confirming true polycythemia—low EPO indicates probable polycythemia vera with specificity >90%. 1

If EPO is Low:

• Proceed directly to bone marrow examination, which is the cornerstone of diagnosis 1
• Evaluate bone marrow histology for hypercellularity, increased megakaryocytes with cluster formation, giant megakaryocytes and pleomorphism, mild reticulin fibrosis, and decreased bone marrow iron stores 1
• Test for JAK2 mutations, as >95% of PV patients have a JAK2 gene variant 2

If EPO is Elevated:

• Systematically evaluate for hypoxia-driven causes: chronic lung disease, right-to-left cardiopulmonary shunts, high-altitude habitation, hypoventilation syndromes, and high oxygen-affinity hemoglobinopathy 1
• Consider hypoxia-independent causes: malignant tumors, benign tumors, congenital causes, EPOR-mediated conditions, exogenous erythropoietic drugs, and post-renal transplant erythrocytosis 1
• Perform 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 1

Critical Pitfalls to Avoid

• Do not assume low EPO always means PV, as low EPO can occur in essential thrombocythemia and rare congenital polycythemia with EPOR mutations 1
• Do not exclude PV based on normal EPO, as sensitivity of low EPO for PV is only <70% 1
• Note that PV can present with elevated EPO levels in rare cases, requiring JAK2 mutation testing and bone marrow biopsy for definitive diagnosis 3
• 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 1

Immediate Management Once PV is Confirmed

Risk Stratification:

• High-risk: age ≥60 years and/or history of thrombosis 4
• Low-risk: age <60 years and no history of thrombosis 4

Universal Treatment for All Patients:

• Initiate phlebotomy immediately to maintain hematocrit strictly <45% (target approximately 42% for women and African Americans due to physiological differences) 4
• Start low-dose aspirin 81-100 mg/day for all patients without contraindications 4
• Aggressively manage all cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, with mandatory smoking cessation 4

Additional Treatment for High-Risk Patients:

• Add cytoreductive therapy with hydroxyurea as first-line (level II, A evidence) 4
• Consider interferon-α as first-line alternative for younger patients (<40 years), women of childbearing age, pregnant patients, or those with intractable pruritus 4
• Perform bone marrow aspirate and biopsy to rule out disease progression to myelofibrosis prior to initiating cytoreductive therapy 4