What are the diagnostic tests and treatment options for Polycythemia Vera (PV)?

Diagnostic Testing for Polycythemia Vera

The diagnosis of polycythemia vera (PV) should begin with serum erythropoietin (EPO) level measurement followed by bone marrow examination with cytogenetic studies when clinically suspected. 1

When to Suspect PV

PV should be considered in the following scenarios:

• Hemoglobin/hematocrit above the 95th percentile of normal distribution adjusted for sex and race 1
• Documented increase in hemoglobin/hematocrit above patient's baseline, regardless of where the value falls within reference range 1
• Borderline-high hematocrit with PV-related features such as:
  • Thrombocytosis
  • Leukocytosis
  • Microcytosis from iron deficiency
  • Splenomegaly
  • Aquagenic pruritus
  • Unusual thrombosis (e.g., Budd-Chiari syndrome)
  • Erythromelalgia 1

Diagnostic Algorithm

Step 1: Serum Erythropoietin Level

• Low serum EPO: Highly suggestive of PV (specificity >90%) 1
• Normal serum EPO: PV remains possible (sensitivity of low EPO for PV <70%) 1
• High serum EPO: Evaluate for secondary polycythemia 1

Step 2: Bone Marrow Examination

• Characteristic findings supporting PV diagnosis:
  • Hypercellularity
  • Increased megakaryocytes with cluster formation
  • Giant megakaryocytes with pleomorphic morphology
  • Mild reticulin fibrosis (in 12% of patients)
  • Decreased bone marrow iron stores 1
• Cytogenetic studies: Abnormalities in 13-18% of patients (limited diagnostic value) 1

Step 3: Specialized Testing (for equivocal cases, ~10% of patients)

• JAK2 mutation testing: Present in >95% of PV patients (JAK2V617F or exon 12 mutations) 2, 3
• Decreased megakaryocyte expression of TPO receptor (c-mpl) 1
• Peripheral blood neutrophil assay for PRV-1 expression 1
• Spontaneous (endogenous) erythroid colony assays (limited availability) 1

Pitfalls to Avoid

• Do not rely solely on red cell mass (RCM) measurement: 1

  • Normal RCM does not rule out PV (may miss patients at left tail of distribution)
  • RCM measurement is redundant when hematocrit >60% without obvious hemoconcentration
  • Isolated hematocrit <60% without other PV features is rarely due to PV 1

• Do not overvalue traditional markers: 1

  • Splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack both sensitivity and specificity 1

• Do not miss iron deficiency: 4

  • Low MCHC may indicate iron deficiency, which can mask erythrocytosis
  • Check iron studies if hypochromia is present 4

Distinguishing PV from Secondary Polycythemia

• Secondary causes to consider: 1

  • Hypoxia-driven (chronic lung disease, high altitude, smoking)
  • Pathologic EPO production (renal cell cancer, hepatocellular carcinoma)
  • Congenital causes (high oxygen-affinity hemoglobinopathy)
  • Drug-associated (EPO doping, androgen preparations) 1

• Key differentiating factors:

  • JAK2 mutation (>95% in PV, absent in secondary causes) 2, 5
  • Serum EPO (low/normal in PV, high in most secondary causes) 1
  • Bone marrow morphology (characteristic changes in PV) 1

Treatment Considerations After Diagnosis

Once diagnosed, treatment should focus on preventing thrombotic complications:

• All patients require phlebotomy to maintain hematocrit <45% 2, 5
• Low-dose aspirin (81 mg daily or twice daily) unless contraindicated 6, 5
• Cytoreductive therapy (hydroxyurea, interferon-α) for high-risk patients (age >60 years or history of thrombosis) 6, 5