What are the diagnostic criteria and treatment options for polycythemia vera?

Diagnosis of Polycythemia Vera

The diagnosis of polycythemia vera (PV) requires meeting specific WHO criteria, including elevated hemoglobin/hematocrit levels (≥16.5 g/dL in men, ≥16.0 g/dL in women, or hematocrit >49% in men, >48% in women), bone marrow biopsy showing hypercellularity with trilineage growth, and presence of JAK2 V617F or JAK2 exon 12 mutation. 1, 2

Diagnostic Criteria

2016 WHO Diagnostic Criteria for PV

Diagnosis requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion 1:

Major criteria:

• Hemoglobin >16.5 g/dL in men, >16.0 g/dL in women OR
• Hematocrit >49% in men, >48% in women OR
• Increased red cell mass (RCM)
• Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes
• Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor criterion:

• Subnormal serum erythropoietin level

Diagnostic Algorithm

1. Initial Testing:

   • Complete blood count with peripheral blood smear
   • JAK2 V617F mutation testing
   • Serum erythropoietin level 2

2. Additional Testing (if needed):

   • Bone marrow biopsy and aspiration
   • JAK2 exon 12 mutation testing (if JAK2 V617F is negative but PV still suspected)
   • Testing for secondary causes of erythrocytosis

3. Bone Marrow Findings:

   • Hypercellularity for age
   • Trilineage growth (panmyelosis)
   • Prominent erythroid, granulocytic, and megakaryocytic proliferation
   • Pleomorphic, mature megakaryocytes with differences in size 1
   • In JAK2 exon 12 mutations: erythroid hyperplasia with subtle megakaryocytic atypia 3

Important Diagnostic Considerations

Masked Polycythemia Vera

• Some patients may have "masked PV" with hemoglobin levels below the WHO thresholds but still showing characteristic bone marrow morphology and JAK2 mutations 4
• These patients may have worse overall survival compared to overt PV if not properly diagnosed and treated 4

Common Diagnostic Pitfalls

1. Overlooking iron deficiency: Iron deficiency can mask true hemoglobin/hematocrit levels in PV patients 2
2. Missing JAK2 exon 12 mutations: When JAK2 V617F is negative but clinical suspicion remains high 3
3. Attributing findings solely to inflammation or other causes 2
4. Neglecting bone marrow examination: Essential for confirming diagnosis and establishing baseline histomorphology 5
5. Overlooking relative polycythemia: Dehydration or other causes of plasma volume contraction 2

Treatment Approach

Risk Stratification

• Low risk: Age <60 years AND no history of thrombosis
• High risk: Age ≥60 years OR history of thrombosis 6, 7

Treatment Recommendations

1. All patients:

   • Therapeutic phlebotomy to maintain hematocrit <45% 2, 6, 7
   • Low-dose aspirin (81-100 mg daily) if no contraindications 2, 6

2. High-risk patients or symptomatic low-risk patients:

   • Cytoreductive therapy with:
     • Hydroxyurea (first-line option)
     • Interferon-α (alternative first-line, especially for younger patients)
     • Ruxolitinib (for those intolerant/resistant to hydroxyurea) 2, 6

3. Special considerations:

   • For extreme thrombocytosis (>1,500 × 10^9/L): Use caution with aspirin due to increased bleeding risk 2
   • For persistent pruritus: Consider ruxolitinib 6

Monitoring

• Regular CBC monitoring every 2-3 months during initial management
• Every 3-6 months once stable
• Evaluate for signs of disease progression, thrombotic and bleeding complications, and transformation to myelofibrosis or acute leukemia 2

By following these diagnostic criteria and treatment recommendations, clinicians can effectively diagnose PV and implement appropriate management strategies to reduce complications and improve patient outcomes.