Summary
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is characterized by an erythropoietin-independent, irreversible increase in erythrocyte, granulocyte, and platelet counts. The elevated blood cell mass results in hyperviscosity, which is associated with slow blood flow and an increased risk of thrombosis. The disorder typically initially has a long asymptomatic period, then assumes a chronic, insidious course. Clinical features include facial flushing, pruritus, erythromelalgia, headaches, and dizziness. Severe complications such as thrombotic events (e.g., stroke, Budd-Chiari syndrome) may occur. Since PV is an incurable disorder, the primary goals of management involve controlling RBC mass and reducing the risk of thrombotic complications. Periodic phlebotomy reduces the amount of circulating cells and is therefore the treatment of choice.
Pathophysiology
- The JAK2 (Janus kinase 2) oncogene codes for a non-receptor tyrosine kinase in hematopoietic progenitor cells. JAK2 is essential for the regulation of erythropoiesis, thrombopoiesis (megakaryopoiesis), and granulopoiesis.
- 95% of primary PV patients have a mutation in the JAK2 gene (gain of function) → ↑ tyrosine kinase activity → erythropoietin-independent proliferation of the myeloid cell lines → ↑ blood cell mass (erythrocytosis, thrombocytosis, and granulocytosis) → hyperviscosity and slow blood flow → ↑ risk of thrombosis and poor oxygenation.
References:[1]
Clinical features
- Often asymptomatic (incidental finding on routine blood tests)
- Constitutional symptoms: weight loss, fatigue, sweating
- Hyperviscosity syndrome (triad of mucosal bleeding, neurological symptoms, and visual changes)
- Plethora
- Pruritus: Itching typically worsens when the skin comes into contact with warm water (aquagenic pruritus).
- Erythromelalgia [2]
- Nonspecific neurological symptoms : dizziness, headache, visual disturbances, tinnitus
- Hypertension
- Splenomegaly : associated with early satiety and abdominal discomfort; less commonly hepatomegaly
- Peptic ulcer disease
- Symptoms of thrombotic and hemorrhagic complications (see “Complications” below)
Patients with PV are at increased risk of thrombosis and bleeding.
References:[3][4][5]
Diagnostics
Laboratory findings
- ↑ Hb/Hct, ↑ RBCs
- ↑ Platelets (> 450,000/μL)
- ↑ Leukocytes (> 12,000/μL)
- ↑ Uric acid, ↑ LDH
- ↑ Leukocyte alkaline phosphatase
- ↓ Serum iron levels
- ↓ ESR
- ↓ EPO
- Arterial O2 saturation: normal
Diagnostic criteria (WHO 2016) [6][7]
A diagnosis of polycythemia vera requires:
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All three major criteria
OR - The first two major criteria AND the minor criterion
| Major criteria |
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| Minor criterion |
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References:[8][9]
Differential diagnoses
| Differential diagnoses of secondary erythrocytosis | ||||||
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| EPO | Expected plasma volume | RBC mass | Oxygen saturation | Underlying conditions | ||
| Relative polycythemia |
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| Absolute polycythemia | ||||||
| Appropriate absolute polycythemia |
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| Inappropriate absolute polycythemia |
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- Other causes may present with normal or even decreased endogenous EPO levels.
The differential diagnoses listed here are not exhaustive.
Treatment
-
Phlebotomy
- Periodic removal of blood via venapuncture temporarily reduces cell counts and hyperviscosity.
- 250–500 mL in intervals of 2–3 days until a HCT of ≤ 0.45 is established [10]
- Antiplatelet prophylaxis: aspirin
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Cytoreductive therapy: determined on an individual basis; recommended if risk factors are present
- Hydroxyurea
- Interferon alpha
- JAK2 inhibitor: ruxolitinib
If platelet count is > 1 million/μL, platelet function is very likely to be impaired, and the risk of bleeding is significantly increased. Aspirin should be discontinued!
Complications
Polycythemia vera is a life-threatening disease because of the numerous complications associated with it.
Thrombotic complications
- Venous thrombosis
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Arterial thrombosis
- Stroke
- Peripheral arterial emboli
- Myocardial infarction (MI)
Hemorrhagic complications
Late stages
- Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS): Additional genetic mutations may cause polycythemia vera to transition to other hematological diseases.
- Myelofibrosis: fibrotic transformation of the bone marrow
References:[3]
We list the most important complications. The selection is not exhaustive.