What is the next management step for an asymptomatic gentleman with elevated hemoglobin (Hb) and packed cell volume (PCV), presenting with polycythemia, as indicated by Hb 18g/dl and PCV 57%?

Management of Asymptomatic Erythrocytosis

The immediate next step is to confirm true erythrocytosis with repeat hemoglobin and hematocrit measurements, followed by JAK2 mutation testing and a complete diagnostic workup to distinguish polycythemia vera from secondary causes. 1, 2

Initial Diagnostic Confirmation

• Repeat hemoglobin and hematocrit measurements are essential, as a single measurement is insufficient for establishing a diagnosis, particularly with borderline values like Hb 18 g/dL and PCV 57%. 2

• Order a complete blood count with red cell indices, reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation, and C-reactive protein immediately. 2

• Review the peripheral blood smear to assess red cell morphology and identify any abnormalities. 2

JAK2 Mutation Testing

• Test for JAK2 mutations (both exon 14 V617F and exon 12) immediately, as this is present in up to 97% of polycythemia vera cases. 1, 2

• If JAK2 is positive, this strongly suggests polycythemia vera and warrants immediate hematology referral. 2

• The World Health Organization diagnostic criteria for polycythemia vera require either both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria. 2

Evaluation for Secondary Causes

• If JAK2 is negative, systematically evaluate for secondary causes including:

  • Smoking history and carbon monoxide exposure (causes "smoker's polycythemia" through chronic tissue hypoxia). 2
  • Obstructive sleep apnea (order sleep study if nocturnal hypoxemia suspected). 2
  • Chronic lung disease (COPD or other pulmonary conditions). 2
  • Testosterone use (prescribed or unprescribed, particularly relevant in younger adults). 2
  • Renal disease or erythropoietin-producing tumors (renal cell carcinoma, hepatocellular carcinoma). 2

• Measure serum erythropoietin levels to differentiate primary from secondary causes, though this has limited sensitivity (<70%) but high specificity (>90%). 2

Critical Management Decision Point

Do NOT perform therapeutic phlebotomy at this stage. 1, 2

• Therapeutic phlebotomy is indicated ONLY when hemoglobin exceeds 20 g/dL AND hematocrit exceeds 65% with associated symptoms of hyperviscosity, after excluding dehydration. 1, 2

• This patient's values (Hb 18 g/dL, PCV 57%) do not meet these thresholds. 1, 2

• Repeated routine phlebotomies without a confirmed diagnosis are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1, 2

If Polycythemia Vera is Confirmed

Initiate immediate treatment with two cornerstones of therapy: 1, 3

1. Phlebotomy to maintain hematocrit strictly below 45% (the CYTO-PV study definitively showed increased thrombotic events at hematocrit 45-50%, with event rates of 2.7% vs 9.8%, P=0.007). 1, 3

2. Low-dose aspirin 81-100 mg daily (the ECLAP study demonstrated significant reduction in cardiovascular death, myocardial infarction, stroke, and venous thromboembolism). 1, 3

• Perform risk stratification: high-risk patients (age ≥60 years OR history of thrombosis) require additional cytoreductive therapy with hydroxyurea or interferon-α. 1, 3

• Low-risk patients (age <60 years AND no thrombosis history) are managed with phlebotomy and aspirin alone. 1, 3

Common Pitfalls to Avoid

• Never accept hematocrit targets of 45-50% in confirmed polycythemia vera, as this significantly increases thrombotic risk. 1, 3

• Do not overlook coexisting iron deficiency, which can occur even with erythrocytosis and causes microcytic hypochromic red cells with reduced oxygen-carrying capacity and increased stroke risk. 4, 2

• Avoid aggressive phlebotomy without adequate volume replacement, as this increases hemoconcentration and stroke risk. 2

• Do not assume this is "relative polycythemia" without measuring red cell mass, as hemoglobin levels above 185 g/L confirm absolute erythrocytosis in only 50% of males. 5

Immediate Referral Indications

• Refer immediately to hematology if JAK2 mutation is positive, hemoglobin exceeds 20 g/dL with hyperviscosity symptoms, or diagnosis remains unclear after initial workup. 2