What is Polycythemia vera?

Polycythemia Vera: Definition, Pathophysiology, and Management

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by autonomous overproduction of red blood cells, resulting in increased red cell mass, with over 95% of cases harboring a JAK2 gene mutation. 1, 2

Pathophysiology

PV is driven by an intrinsic anomaly of hematopoietic progenitors that leads to autonomous erythrocyte production, resulting in:

• Increased red blood cell mass (primary feature)
• Low erythropoietin (EPO) levels, even when hemoglobin is normalized after phlebotomy 1
• JAK2 V617F mutation in >95% of cases, which helps distinguish PV from secondary causes of erythrocytosis 1, 2

Unlike secondary polycythemia (which is driven by external stimuli and has normal or elevated EPO levels), PV demonstrates:

• Autonomous cell proliferation
• Potential for additional hematologic abnormalities:
  • Thrombocytosis (53% of patients)
  • Leukocytosis (49% of patients) 2

Clinical Manifestations

Common symptoms and findings include:

• Erythrocytosis (hemoglobin >16.5 g/dL in men or >16.0 g/dL in women) 2
• Splenomegaly (36% of patients) 2
• Pruritus (33% of patients), often worse after warm showers 2
• Erythromelalgia (5.3% of patients) - burning pain and redness in extremities 2
• Transient visual disturbances (14% of patients) 2
• Abdominal discomfort from splenomegaly 2
• Hyperviscosity symptoms (headache, dizziness, visual disturbances)

Complications

PV is associated with significant morbidity and mortality:

1. Thrombotic events (major cause of morbidity and mortality)

   • Arterial thrombosis in 16% of patients at or before diagnosis
   • Venous thrombosis in 7% of patients, including unusual sites like splanchnic veins 2

2. Hemorrhagic complications

   • Especially in patients with extreme thrombocytosis (≥1,000 × 10⁹/L) due to acquired von Willebrand syndrome 2, 3

3. Disease progression

   • Myelofibrosis (12.7% of patients)
   • Acute myeloid leukemia (6.8% of patients) 2

Diagnosis

Diagnostic criteria include:

• Elevated hemoglobin/hematocrit (>16.5 g/dL/49% in men; >16.0 g/dL/48% in women) 1, 2
• Presence of JAK2 mutation (>95% of cases) 1, 2
• Low serum erythropoietin level 1
• Splenomegaly (common but not required for diagnosis) 1

Risk Stratification

Patients are stratified based on thrombotic risk:

• High-risk: Age >60 years or history of thrombosis
• Low-risk: Absence of both risk factors 2, 3

Additional risk factors that contribute to thrombotic risk include:

• Leukocytosis
• Cardiovascular risk factors (hypertension, smoking) 4

Management

Treatment focuses on preventing thrombotic complications:

1. All patients should receive:

   • Therapeutic phlebotomy to maintain hematocrit <45% 1, 2
   • Low-dose aspirin (81-100 mg/day) unless contraindicated 1, 2

2. Cytoreductive therapy is indicated for:

   • High-risk patients (age >60 or prior thrombosis)
   • Symptomatic low-risk patients
   • Options include:
     • Hydroxyurea (first-line) 1, 5
     • Pegylated interferon (alternative first-line, especially in younger patients) 1, 5
     • Ruxolitinib (for hydroxyurea resistance/intolerance or significant symptoms) 1, 2
     • Busulfan (typically reserved for older patients) 5

Monitoring

Regular monitoring should include:

• Complete blood count every 2-3 months initially, then every 3-6 months if stable 1
• Assessment of spleen size and hyperviscosity symptoms 1
• Monitoring for disease progression to myelofibrosis or leukemia 1

Prognosis

Without treatment, life expectancy was historically less than 2 years. With modern management:

• Median survival ranges from 14.1 to 27.6 years 2
• Young patients may have survival exceeding 35 years 5
• 20-year rates of complications: thrombosis (26%), fibrotic progression (16%), leukemic transformation (4%) 5

Common Pitfalls

1. Misdiagnosis: Failing to distinguish PV from secondary causes of erythrocytosis
2. Inadequate hematocrit control: Target should be <45% to reduce thrombotic risk
3. Overlooking cardiovascular risk factors: Aggressive management of these factors is essential
4. Missing "masked PV": Cases with lower hemoglobin/hematocrit levels that still represent PV and have worse outcomes if not properly diagnosed and treated 4

Current treatments focus on preventing thrombotic complications rather than modifying disease progression, highlighting the need for continued research into disease-modifying therapies.