Polycythemia vera

A 55 year old male presents to his primary care physician with persistent headaches, dizziness, and episodic blurred vision over the past few months. He also reports a burning sensation in his hands and feet and generalized pruritus after hot showers. On examination, splenomegaly is noted. Vital signs show blood pressure 140/90 mmHg. Laboratory studies reveal hemoglobin 20 g/dL, hematocrit 56 percent, leukocytosis, and thrombocytosis. Serum erythropoietin is low. Bone marrow biopsy shows hypercellularity with trilineage proliferation (panmyelosis). Molecular testing reveals a JAK2 mutation. Diagnosis?

Diagnosis is Polycythemia vera.

1. Definition

Polycythemia vera is a chronic myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic stem cells, leading to increased red cell mass, often with leukocytosis and thrombocytosis, and is strongly associated with a JAK2 mutation.

2. Etiology

1. Somatic mutation in JAK2 (V617F or exon 12)
2. Causes constitutive activation of the JAK STAT pathway
3. Leads to growth factor independent hematopoiesis

3. Pathophysiology

1. Clonal expansion of hematopoietic stem cells
2. Results in panmyelosis
3. Increased red cell mass causes hyperviscosity
4. Leukocytosis and thrombocytosis contribute to thrombosis risk
5. Very high platelet counts may cause acquired von Willebrand disease, leading to bleeding
6. Increased cell turnover leads to hyperuricemia
7. Histamine release contributes to aquagenic pruritus

4. Clinical Features

4.1 Hyperviscosity Symptoms

1. Headache
2. Dizziness
3. Blurred vision

4.2 Thrombotic Manifestations

1. Deep vein thrombosis
2. Stroke
3. Myocardial infarction
4. Budd Chiari syndrome
5. Erythromelalgia

4.3 Bleeding Manifestations

1. Epistaxis
2. Easy bruising
3. Gastrointestinal bleeding

4.4 Other Features

1. Aquagenic pruritus
2. Splenomegaly
3. Plethora
4. Early satiety
5. Gout due to hyperuricemia

5. Diagnosis

5.1 Laboratory Findings

1. Elevated hemoglobin and hematocrit
2. Increased red cell mass
3. Leukocytosis
4. Thrombocytosis
5. Low serum erythropoietin

5.2 Bone Marrow

1. Hypercellular marrow
2. Panmyelosis
3. Pleomorphic megakaryocytes

5.3 Molecular Testing

1. JAK2 mutation present in more than 95 percent of cases

6. WHO Diagnostic Criteria

Major Criteria

1. Elevated hemoglobin or hematocrit
2. Bone marrow biopsy showing panmyelosis
3. Presence of JAK2 mutation

Minor Criterion

1. Low serum erythropoietin

Diagnosis requires:

1. All three major criteria, or
2. Two major criteria and one minor criterion

7. Management

7.1 Low Risk Patients

1. Phlebotomy targeting hematocrit less than 45 percent
2. Low dose aspirin

7.2 High Risk Patients

1. Age greater than or equal to 60 years or history of thrombosis
2. Phlebotomy and aspirin
3. Hydroxyurea

7.3 Additional Therapy

1. Ruxolitinib in refractory cases
2. Antihistamines or SSRIs for pruritus
3. Allopurinol for hyperuricemia

8. Complications

1. Thrombosis is the leading cause of morbidity and mortality
2. Hemorrhage
3. Progression to myelofibrosis
4. Transformation to acute leukemia

9. Key Clinical Insight

Aquagenic pruritus + erythromelalgia + splenomegaly + elevated hemoglobin with low erythropoietin + JAK2 mutation = Polycythemia vera

10. Exam Level Pearls

1. JAK2 mutation is present in more than 95 percent of cases
2. Low erythropoietin distinguishes PV from secondary polycythemia
3. Phlebotomy to hematocrit less than 45 percent reduces thrombosis risk
4. Erythromelalgia responds to aspirin
5. Aquagenic pruritus is a classic clue