What is true about polycythemia vera except that EPO (erythropoietin) is raised?

Polycythemia Vera: Key Diagnostic Features

In polycythemia vera (PV), erythropoietin (EPO) is characteristically low or suppressed, not raised. 1, 2

Diagnostic Criteria for Polycythemia Vera

PV is a clonal myeloproliferative disorder characterized by the following key features:

• JAK2 mutation: Present in approximately 95% of cases (JAK2 V617F) or 5% (JAK2 exon 12 mutations) 2
• Low serum erythropoietin level: A hallmark finding that helps differentiate PV from secondary polycythemia 1, 2
• 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 2
• Bone marrow findings: Hypercellularity with trilineage growth (erythroid, myeloid, megakaryocytic) 1

Why EPO is Low in Polycythemia Vera

In PV, the JAK2 mutation leads to:

• Constitutive activation of the JAK-STAT signaling pathway 1, 3
• EPO-independent erythroid proliferation 3
• Negative feedback suppression of endogenous EPO production 1

This contrasts with secondary polycythemia, where:

• EPO levels are typically normal or elevated due to hypoxia-driven or tumor-related mechanisms 1
• The erythrocytosis is a physiological response to increased EPO 1

Diagnostic Algorithm

1. Initial evaluation: CBC with peripheral blood smear, JAK2 V617F mutation testing, and serum erythropoietin level 2

2. If JAK2 V617F is positive and EPO is low: Strong evidence for PV diagnosis 2, 4

3. If JAK2 V617F is negative but clinical suspicion remains high: Test for JAK2 exon 12 mutations 2

4. If JAK2 mutations are negative: Consider bone marrow biopsy to evaluate for other myeloproliferative neoplasms or secondary causes of erythrocytosis 2

Common Pitfalls in PV Diagnosis

• Overlooking masked PV: Iron deficiency can normalize hemoglobin levels despite underlying PV 2
• Misinterpreting normal EPO levels: About 32% of PV patients may have EPO levels within normal range, particularly those with obesity or smoking history 4
• Confusing relative polycythemia: Dehydration, diuretic use, or smoker's polycythemia can mimic true polycythemia 1, 2
• Missing secondary causes: When JAK2 mutation is absent, secondary causes must be thoroughly evaluated 2

Clinical Implications

The distinction between PV and secondary polycythemia is crucial because:

• PV requires specific management strategies including phlebotomy and potentially cytoreductive therapy 1, 5
• PV carries risks of thrombosis, disease progression to myelofibrosis, and potential transformation to acute leukemia 5
• Secondary polycythemia requires treatment of the underlying cause rather than hematologic interventions 1

Understanding that EPO is typically low (not raised) in PV is fundamental to making the correct diagnosis and implementing appropriate management strategies.