USMLE Guide: Hematology of Polycythemia Vera

Introduction

Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by the abnormal proliferation of red blood cells (RBCs), white blood cells (WBCs), and platelets in the bone marrow. This USMLE guide aims to provide a comprehensive overview of the hematology of Polycythemia Vera, including its pathogenesis, clinical presentation, diagnosis, and management.

Pathogenesis

PV results from a somatic mutation in the Janus Kinase 2 (JAK2) gene, specifically the V617F mutation. This mutation leads to constitutive activation of the JAK-STAT pathway, promoting abnormal cell proliferation and survival.

Clinical Presentation

• Erythrocytosis: PV patients typically exhibit increased RBC mass, leading to elevated hemoglobin (Hb) and hematocrit (Hct) levels.
• Plethora: Patients may present with a ruddy or flushed complexion due to increased RBC count.
• Splenomegaly: Enlargement of the spleen is common in PV due to extramedullary hematopoiesis.
• Thrombosis: PV patients have an increased risk of arterial and venous thrombotic events, including stroke, myocardial infarction, and deep vein thrombosis.
• Bleeding: Despite increased platelet count, qualitative platelet dysfunction may result in abnormal bleeding.

Diagnosis

The World Health Organization (WHO) criteria are used to diagnose PV. It requires the presence of both major criteria or the first major criterion plus two minor criteria: Major criteria:

1. Hemoglobin >16.5 g/dL in men or >16 g/dL in women, or elevated hematocrit (>49% in men, >48% in women).
2. Presence of JAK2 V617F mutation or other functionally similar mutations (e.g., JAK2 exon 12 mutations).

Minor criteria:

1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis), accompanied by an increase in granulopoiesis.
2. Serum erythropoietin level below the reference range for normal.

Management

Management of PV aims to reduce the risk of thrombotic complications and control symptoms. Key aspects include:

• Phlebotomy: Regular venesection is the primary treatment to maintain hematocrit below 45% in men and 42% in women.
• Low-dose aspirin: To reduce the risk of thrombotic events.
• Cytoreductive therapy: Considered in high-risk patients with a history of thrombosis or age >60 years. Hydroxyurea is the mainstay of cytoreductive therapy.
• JAK inhibitors: Ruxolitinib, a JAK1/2 inhibitor, is approved for patients who are resistant or intolerant to hydroxyurea.
• Supportive care: Adequate hydration and control of cardiovascular risk factors (e.g., smoking cessation, blood pressure management).

Prognosis

The natural history of PV is highly variable. The risk of thrombotic complications and transformation to myelofibrosis or acute leukemia increases with age and other risk factors. Regular monitoring and appropriate management can significantly improve outcomes.

Conclusion

Polycythemia Vera is a chronic myeloproliferative neoplasm characterized by abnormal proliferation of blood cells. Understanding the pathogenesis, clinical presentation, diagnosis, and management of PV is crucial for physicians preparing for USMLE exams. Early diagnosis, risk stratification, and appropriate management can significantly improve patient outcomes and reduce the risk of complications associated with PV.