How should I evaluate and manage a patient with an elevated hemoglobin and hematocrit to differentiate primary polycythemia vera from secondary causes and determine appropriate treatment?

Approach to Polycythemia: Evaluation and Management

Initial Diagnostic Confirmation and Risk Assessment

Order JAK2 V617F mutation testing and serum erythropoietin (EPO) level immediately upon confirming sustained elevation of hemoglobin/hematocrit (>18.5 g/dL or >52% in men; >16.5 g/dL or >48% in women). 1, 2 This two-test combination provides the most efficient pathway to distinguish polycythemia vera (PV) from secondary causes, as JAK2 mutations are present in >95% of PV cases and low EPO has >90% specificity for PV. 1, 3

Critical Early Recognition Points

• Initiate workup even with borderline hemoglobin (16.0–18.4 g/dL in men, 15.0–16.4 g/dL in women) when accompanied by: thrombocytosis (>400×10⁹/L), leukocytosis (>15×10⁹/L), splenomegaly, aquagenic pruritus, unusual thrombosis (especially portal vein), or microcytosis (MCV <80 fL) with elevated RDW (>16–17%). 4 These features signal "masked PV" where iron deficiency obscures the true red cell mass.

• Do not exclude PV based on normal hemoglobin alone—iron deficiency from increased utilization or prior phlebotomy can suppress hemoglobin while the underlying clonal erythrocytosis persists. 4, 5

Algorithmic Diagnostic Pathway

Step 1: Exclude Relative (Apparent) Polycythemia

• Assess for plasma volume depletion: dehydration, diuretic use, vomiting, diarrhea, burns. 1
• If clinical signs of volume depletion are present, rehydrate and repeat hemoglobin/hematocrit after 48–72 hours. 1

Step 2: Interpret JAK2 and EPO Results

If JAK2 V617F positive + low/normal EPO:

• Proceed directly to bone marrow biopsy to confirm PV diagnosis per WHO 2016 criteria (requires hypercellularity with trilineage growth). 6, 3, 7
• PV diagnosis is established when both major criteria (elevated Hb/Hct AND JAK2 mutation) plus one minor criterion (bone marrow morphology OR subnormal EPO) are met. 6, 2

If JAK2 V617F negative:

• Test for JAK2 exon 12 mutations (present in 2–4% of PV cases). 1, 2
• If both JAK2 tests are negative, PV is effectively excluded—proceed to evaluate secondary causes. 1

If EPO is elevated:

• This strongly suggests secondary polycythemia; systematically evaluate hypoxia-driven and hypoxia-independent causes. 1

Step 3: Evaluate Secondary Causes (When JAK2 Negative or EPO Elevated)

Hypoxia-driven causes (most common):

• Smoking history and carboxyhemoglobin measurement—smoker's polycythemia is the most frequent secondary cause and resolves with cessation. 1, 7
• Sleep study for obstructive sleep apnea (nocturnal hypoxemia drives EPO production). 1, 2
• Arterial oxygen saturation and chest imaging to detect chronic lung disease (COPD, pulmonary fibrosis) or right-to-left cardiopulmonary shunts. 1, 2

Hypoxia-independent causes:

• Abdominal ultrasound or CT to screen for EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma, parathyroid carcinoma. 1, 2
• Medication review for exogenous testosterone, anabolic steroids, or erythropoietin therapy. 1, 2
• Post-renal transplant erythrocytosis in transplant recipients. 1

Step 4: Additional Laboratory Workup

• Complete blood count with differential and red cell indices to assess for thrombocytosis, leukocytosis, and microcytosis. 1, 2
• Serum ferritin, iron, and transferrin saturation—iron deficiency frequently coexists with PV and can mask the diagnosis by suppressing hemoglobin. 1, 4
• Peripheral blood smear to identify morphologic abnormalities. 2
• Renal and liver function tests to screen for secondary causes. 1

Management Based on Diagnosis

Confirmed Polycythemia Vera

Therapeutic phlebotomy to maintain hematocrit strictly <45% is the cornerstone of treatment, reducing thrombotic events from 9.8% to 2.7% (CYTO-PV trial). 2, 3, 7 A slightly lower target of ≈42% is reasonable for women and African Americans due to physiological differences. 2

• Low-dose aspirin (81–100 mg daily) is the second cornerstone for thrombosis prophylaxis, unless contraindicated. 2, 3, 7

• Risk stratification determines need for cytoreductive therapy:

  • High-risk (age >60 years OR prior thrombosis): Add hydroxyurea as first-line cytoreductive agent, or pegylated interferon-α as alternative. 3, 7
  • Low-risk (age ≤60 years AND no thrombosis history): Phlebotomy plus aspirin alone is sufficient. 3, 7

• Address cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) and mandate smoking cessation to reduce thrombotic risk. 7

Secondary Polycythemia Management

Treat the underlying condition—do NOT perform routine phlebotomy in secondary polycythemia, as this causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1, 2

• Smoking cessation for smoker's polycythemia (resolves within months). 1, 2
• CPAP therapy for obstructive sleep apnea. 1, 2
• Supplemental oxygen for chronic hypoxemia (arterial saturation <92%). 1
• Dose reduction or discontinuation of testosterone if causative. 2
• Tumor resection or treatment for EPO-producing malignancies. 1

Phlebotomy in secondary polycythemia is indicated ONLY when ALL of the following are met:

• Hemoglobin >20 g/dL AND hematocrit >65%
• Documented hyperviscosity symptoms (headache, blurred vision, confusion, bleeding)
• Adequate hydration confirmed
• Iron deficiency excluded (transferrin saturation ≥20%)
• Hematocrit remains elevated above baseline despite rehydration 1, 2

When phlebotomy is performed, replace removed blood volume with equal volume of isotonic saline or dextrose to prevent hemoconcentration. 1, 2

Critical Pitfalls to Avoid

• Do not assume normal EPO excludes PV—EPO sensitivity for PV is only 64–70%; normal EPO with elevated hemoglobin still requires JAK2 testing. 1

• Do not overlook iron deficiency in erythrocytosis—microcytosis (MCV <80 fL) with elevated RDW (>16%) signals iron-deficient PV and mandates JAK2 testing regardless of hemoglobin level. 4

• Do not perform aggressive phlebotomy in secondary polycythemia—this depletes iron, worsens oxygen delivery, and increases stroke risk. 1, 2

• Do not delay JAK2 testing in patients with unusual thrombosis (portal vein, hepatic vein, mesenteric vein)—these may be the first manifestation of masked PV with normal blood counts. 4, 5

• Do not rely on red cell mass measurement—modern JAK2 testing and EPO levels have largely replaced this cumbersome test except in truly equivocal cases. 1

Monitoring and Follow-Up

• For confirmed PV: Monitor CBC every 1–3 months initially, then every 3–6 months once stable. Maintain hematocrit <45% through phlebotomy. 2, 3

• For secondary polycythemia: Monitor CBC every 3–6 months and treat underlying condition. Avoid routine phlebotomy. 1

• For borderline cases with negative JAK2: Serial hemoglobin/hematocrit every 6–12 months to detect progression. 2