What is the appropriate workup for polycythemia?

Appropriate Workup for Polycythemia

The appropriate workup for polycythemia should begin with complete blood count (CBC), JAK2 mutation testing, and serum erythropoietin level to distinguish between polycythemia vera (PV) and secondary causes of polycythemia. 1

Initial Evaluation

• First-line testing:

  • Complete blood count (CBC) with peripheral blood smear
  • JAK2 V617F mutation testing
  • Serum erythropoietin level

• Clinical suspicion criteria:

  • Hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women
  • Hematocrit >99th percentile of reference range for age, sex, and altitude
  • Documented increase in hemoglobin/hematocrit above patient's baseline
  • PV-related features with borderline-high hematocrit

Diagnostic Algorithm

Step 1: Confirm Erythrocytosis

• Verify elevated hemoglobin/hematocrit levels
• Rule out relative/apparent polycythemia (dehydration, stress polycythemia)

Step 2: Measure Serum Erythropoietin Level

• Low serum erythropoietin: Suggests PV (proceed to JAK2 testing)
• Normal/elevated serum erythropoietin: Consider secondary causes but don't exclude PV 2

Step 3: JAK2 Mutation Testing

• JAK2 V617F positive (~95% of PV cases): Strongly supports PV diagnosis
• JAK2 V617F negative: Test for JAK2 exon 12 mutations

Step 4: Secondary Causes Evaluation (if JAK2 negative or EPO elevated)

• Hypoxia-driven causes:

  • Arterial blood gas analysis
  • Pulmonary function tests
  • Sleep study (for sleep apnea)
  • Smoking history (carbon monoxide exposure)
  • High-altitude exposure

• Non-hypoxic causes:

  • Renal ultrasound (renal tumors, cysts, stenosis)
  • Abdominal imaging (hepatocellular carcinoma, pheochromocytoma)
  • Hemoglobin electrophoresis (high-affinity hemoglobinopathy)
  • Review medications (androgens, EPO doping)

Step 5: Bone Marrow Biopsy

• Indicated when:
  • Diagnosis remains unclear after initial testing
  • JAK2 mutation negative but strong clinical suspicion of PV
  • Need to assess for other myeloproliferative features

Diagnostic Criteria (WHO)

PV diagnosis requires either:

1. Both major criteria plus one minor criterion:

   • Major: Elevated hemoglobin/hematocrit AND presence of JAK2 mutation
   • Minor: Low serum erythropoietin OR bone marrow findings OR endogenous erythroid colony formation

2. First major criterion plus two minor criteria:

   • For JAK2-negative cases with strong clinical suspicion

Common Pitfalls to Avoid

• Overlooking masked PV: Iron deficiency can normalize hemoglobin/hematocrit in PV patients 1
• Dismissing PV with elevated EPO: While uncommon, PV can present with normal or elevated erythropoietin levels 2
• Neglecting bone marrow examination: Essential for diagnosis in JAK2-negative cases
• Attributing findings solely to inflammation: Inflammatory conditions can mask or mimic myeloproliferative features
• Performing unnecessary repeated phlebotomies: Can lead to iron deficiency and mask true hemoglobin/hematocrit levels

By following this systematic approach, clinicians can effectively distinguish between polycythemia vera and secondary causes of polycythemia, leading to appropriate management strategies that reduce morbidity and mortality associated with thrombotic events and disease progression.