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

Diagnosis of Polycythemia Vera

The diagnosis of polycythemia vera requires either both major criteria (elevated hemoglobin/hematocrit and presence of JAK2 mutation) plus at least one minor criterion, or the first major criterion plus at least two minor criteria according to the WHO diagnostic criteria. 1

Diagnostic Criteria

Major Criteria

1. Elevated red blood cell parameters:

   • Hemoglobin >18.5 g/dL in men, >16.5 g/dL in women, OR
   • Hematocrit >49% in men, >48% in women, OR
   • Increased red cell mass >25% above mean normal predicted value, OR
   • Sustained increase in hemoglobin level >2 g/dL from baseline without reaching threshold values 2

2. Presence of JAK2 mutation:

   • JAK2 V617F (present in ~97% of cases) OR
   • JAK2 exon 12 mutation (in JAK2 V617F-negative cases) 1

Minor Criteria

1. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis)
2. Subnormal serum erythropoietin level
3. Endogenous erythroid colony formation in vitro 2

Diagnostic Algorithm

1. Initial suspicion should be raised when:

   • Hemoglobin/hematocrit above the 95th percentile adjusted for sex and race
   • Documented increase in hemoglobin/hematocrit above patient's baseline
   • PV-related features with borderline-high hematocrit (thrombocytosis, leukocytosis, microcytosis, splenomegaly, aquagenic pruritus, unusual thrombosis, erythromelalgia) 2

2. First-line testing:

   • Complete blood count with peripheral blood smear
   • JAK2 V617F mutation testing
   • Serum erythropoietin level 1

3. Interpretation of results:

   • JAK2 positive + low EPO: PV highly likely
   • JAK2 positive + normal/high EPO: Consider PV with concurrent condition causing EPO elevation
   • JAK2 negative + low EPO: Consider JAK2 exon 12 testing
   • JAK2 negative + normal/high EPO: Investigate secondary causes 1

4. Additional testing when indicated:

   • Bone marrow biopsy (especially in equivocal cases)
   • JAK2 exon 12 mutation testing (if JAK2 V617F negative but PV still suspected)
   • Red cell mass measurement (rarely needed with modern diagnostic approaches) 2, 1

Differential Diagnosis

Secondary Polycythemia

• Hypoxia-driven causes:

  • Chronic lung disease
  • Right-to-left cardiopulmonary shunts
  • High-altitude habitat
  • Carbon monoxide poisoning/smoking
  • Sleep apnea 2

• Non-hypoxia driven causes:

  • Pathologic EPO production (renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)
  • Benign conditions (uterine leiomyomas, renal cysts, pheochromocytoma, meningioma)
  • Drug-associated (EPO doping, androgen preparations) 2, 1

Apparent Polycythemia

• Relative polycythemia (hemoconcentration due to reduced plasma volume)
• Dehydration
• Diuretic use
• Stress polycythemia (Gaisböck syndrome) 2

Common Diagnostic Pitfalls

1. Missing PV due to iron deficiency: Iron deficiency can mask the degree of erythrocytosis by lowering hemoglobin/hematocrit levels 2

2. Overlooking relative polycythemia: Dehydration, diuretics use, or smoker's polycythemia can cause apparent erythrocytosis 1

3. Unnecessary red cell mass measurements: These are redundant when hematocrit is >60% without obvious hemoconcentration 2, 1

4. Failure to recognize early/masked PV: Cases with borderline elevated counts but with PV-related features should still be evaluated for JAK2 mutations 2

5. Overlooking secondary causes: When JAK2 mutation is absent, thorough investigation of secondary causes is essential 1

Clinical Features Supporting Diagnosis

• Thrombotic events: Present in 16% (arterial) and 7% (venous) of patients at or before diagnosis 3
• Unusual site thrombosis: Splanchnic vein thrombosis should raise suspicion for PV 3
• Symptoms: Pruritus (33%), erythromelalgia (5.3%), visual disturbances (14%), splenomegaly (36%) 3
• Laboratory findings: Thrombocytosis (53%), leukocytosis (49%) 3

Treatment Considerations After Diagnosis

Once diagnosed, treatment should focus on:

• Phlebotomy: Goal hematocrit <45% for all patients 3, 4
• Low-dose aspirin: For all patients without contraindications 3
• Cytoreductive therapy: For high-risk patients (age ≥60 years or prior thrombosis) 3, 5
• Symptom management: Ruxolitinib for patients with persistent symptoms or intolerance to hydroxyurea 3

By following this diagnostic approach, clinicians can accurately identify PV and distinguish it from secondary causes of polycythemia, allowing for appropriate treatment to reduce complications and improve outcomes.