What is the initial workup for a patient with suspected polycythemia (excessive red blood cell count)?

Initial Workup for Suspected Polycythemia

The initial workup for suspected polycythemia should include a complete blood count, serum erythropoietin level, JAK2 mutation testing, and bone marrow examination with cytogenetic studies to distinguish between primary polycythemia vera and secondary causes of polycythemia. 1

Diagnostic Approach

Step 1: Determine if Polycythemia Should Be Suspected

Polycythemia should be considered when:

• Hemoglobin/hematocrit is higher than the 95th percentile of normal distribution (adjusted for sex and race)
• There is a documented increase in hemoglobin/hematocrit above the patient's baseline
• PV-related features accompany borderline-high hematocrit values 1

PV-related features include:

• Thrombocytosis
• Leukocytosis
• Microcytosis from iron deficiency
• Splenomegaly
• Aquagenic pruritus (intense itching after water contact)
• Unusual thrombosis (including Budd-Chiari syndrome)
• Erythromelalgia (burning pain in extremities) 1

Step 2: Initial Laboratory Tests

• Complete blood count with peripheral blood smear
• Serum erythropoietin (EPO) level
• Blood film
• Lactate dehydrogenase (LDH)
• Erythrocyte sedimentation rate (ESR) 1

Step 3: Interpretation of EPO Results

• Low EPO level: Highly suggestive of polycythemia vera (specificity >90%)
• Normal EPO level: Does not exclude PV (sensitivity of low EPO for PV is <70%)
• High EPO level: Suggests secondary polycythemia, but does not completely exclude PV 1, 2

Step 4: JAK2 Mutation Testing

• If PV is suspected, test for JAK2 V617F mutation (present in up to 97% of PV cases) 1, 3
• JAK2 mutation helps distinguish PV from secondary causes of erythrocytosis 3

Step 5: Bone Marrow Examination

• Bone marrow biopsy with cytogenetic studies is recommended when diagnosis remains unclear 1
• Characteristic findings in PV include:
  • Hypercellularity
  • Increased number of megakaryocytes with cluster formation
  • Giant megakaryocytes and pleomorphism
  • Mild reticulin fibrosis (in 12% of patients)
  • Decreased bone marrow iron stores 1

Step 6: Investigation of Secondary Causes

If JAK2 mutation is absent, investigate secondary causes of polycythemia:

• Clinical assessment
• Renal and liver function tests
• Measurement of oxygen saturation
• Chest X-ray
• Abdominal ultrasound 1

Secondary causes to consider:

• Hypoxia-driven: Lung disease, high altitude, smoking, sleep apnea
• Hypoxia-independent: Renal cancer, uterine leiomyoma, pheochromocytoma, meningioma
• Congenital causes: Chuvash polycythemia, EPOR mutations
• Exogenous: Erythropoietic drugs, androgen preparations 1

Clinical Pearls and Pitfalls

Important Distinctions

• True polycythemia: Actual increase in red cell mass (includes PV and secondary polycythemia)
• Apparent polycythemia: Spurious increase due to plasma volume depletion (relative polycythemia) 1

Common Pitfalls

1. Relying solely on EPO levels: While low EPO strongly suggests PV, normal or even high EPO levels do not exclude PV diagnosis. Always proceed with JAK2 mutation testing when clinical suspicion is high 2

2. Unnecessary red cell mass measurements: These are rarely needed with modern diagnostic approaches. They are redundant when hematocrit is >60% without obvious hemoconcentration 1

3. Missing secondary causes: Thorough investigation for secondary causes is essential, especially in JAK2-negative cases 1

4. Overlooking relative polycythemia: Common causes include dehydration, diuretics use, and smoker's polycythemia (due to carbon monoxide exposure) 1

5. Ignoring thrombotic risk: Arterial thrombosis occurs in 16% of patients and venous thrombosis in 7% at or before diagnosis 3

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 complications.