Diagnosis is Polycythemia vera.
1. Definition
Polycythemia vera (PV) is a chronic BCR::ABL1-negative myeloproliferative neoplasm characterized by clonal erythrocytosis, usually accompanied by varying degrees of leukocytosis and thrombocytosis, and driven by an acquired JAK2 mutation.
2. Etiology and Molecular Basis
1. PV is caused by an acquired somatic activating mutation in JAK2.
2. JAK2 V617F is present in approximately 95% of patients.
3. JAK2 exon 12 mutations account for most remaining JAK2 V617F-negative cases.
4. JAK2 activation causes constitutive signaling through the JAK-STAT pathway, promoting cytokine-independent and cytokine-hypersensitive hematopoiesis.
3. Pathophysiology
1. Clonal proliferation of a hematopoietic stem cell produces panmyelosis involving:
o Erythroid cells
o Granulocytes
o Megakaryocytes
2. Excessive erythrocytosis increases blood viscosity and contributes to hyperviscosity symptoms and thrombosis.
3. Leukocytosis and other disease-related factors may further contribute to thrombotic risk.
4. Marked thrombocytosis may cause acquired von Willebrand syndrome, increasing bleeding risk.
5. Increased cell turnover may cause hyperuricemia and gout.
6. Aquagenic pruritus is characteristic of PV. Its mechanism is incompletely understood but is thought to involve abnormal basophil, mast-cell, and cytokine signaling.
7. Increased red-cell mass suppresses renal erythropoietin production, resulting in low serum erythropoietin.
4. Clinical Features
4.1 Hyperviscosity and Microvascular Symptoms
1. Headache
2. Dizziness
3. Blurred vision
4. Tinnitus
5. Paresthesias
6. Erythromelalgia, characterized by burning pain, warmth, and erythema of the hands or feet
4.2 Thrombotic Manifestations
PV increases the risk of both arterial and venous thrombosis, including:
1. Stroke or transient ischemic attack
2. Myocardial infarction
3. Deep vein thrombosis
4. Pulmonary embolism
5. Splanchnic vein thrombosis, including Budd-Chiari syndrome
4.3 Bleeding Manifestations
1. Epistaxis
2. Easy bruising
3. Gastrointestinal bleeding
4. Bleeding associated with acquired von Willebrand syndrome, particularly with extreme thrombocytosis
4.4 Other Features
1. Aquagenic pruritus, often triggered by a warm bath or shower
2. Splenomegaly
3. Facial plethora
4. Early satiety
5. Constitutional symptoms
6. Hyperuricemia or gout
5. Diagnosis
5.1 Laboratory Findings
Typical findings include:
1. Elevated hemoglobin and hematocrit
2. Leukocytosis
3. Thrombocytosis
4. Subnormal serum erythropoietin
5. JAK2 mutation
Iron deficiency may develop because of increased erythropoiesis or repeated phlebotomy and can sometimes mask the degree of erythrocytosis.
5.2 Bone Marrow
Bone marrow typically demonstrates:
1. Age-adjusted hypercellularity
2. Trilineage proliferation (panmyelosis)
3. Prominent erythroid and granulocytic proliferation
4. Increased pleomorphic, mature megakaryocytes
5.3 Molecular Testing
1. A JAK2 V617F or JAK2 exon 12 mutation is present in virtually all patients with PV.
2. JAK2 testing is therefore central to the diagnostic evaluation.
6. WHO 5th-Edition Diagnostic Criteria
Major Criteria
1. Elevated:
o Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, or
o Hematocrit >49% in men or >48% in women
2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation (panmyelosis), including erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic mature megakaryocytes
3. Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor Criterion
1. Subnormal serum erythropoietin level
Diagnosis requires:
1. All three major criteria, or
2. The first two major criteria plus the minor criterion
Measured red-cell mass is no longer included as a WHO 5th-edition diagnostic criterion.
7. Risk Stratification
The conventional thrombotic risk categories are:
7.1 Low Risk
1. Age <60 years
2. No previous thrombosis
7.2 High Risk
Either:
1. Age ≥60 years, or
2. History of thrombosis
Cardiovascular risk factors such as hypertension, smoking, diabetes, and hyperlipidemia should also be actively managed.
This 55-year-old patient with no reported previous thrombosis would be classified as low risk for thrombosis by the conventional risk model.
8. Management
The primary treatment goal is prevention of thrombosis and hemorrhage while controlling erythrocytosis and disease-related symptoms.
8.1 Treatment for All Patients
1. Phlebotomy to maintain hematocrit below 45%
2. Low-dose aspirin, typically 81 to 100 mg daily, unless contraindicated
3. Aggressive management of cardiovascular risk factors
Low-dose aspirin may need to be withheld in patients with active bleeding or clinically significant acquired von Willebrand syndrome, particularly in the setting of extreme thrombocytosis.
Maintaining hematocrit below 45% significantly reduces cardiovascular death and major thrombosis.
8.2 Low-Risk PV
Standard therapy consists of:
1. Phlebotomy
2. Low-dose aspirin
Cytoreductive therapy may be considered despite low-risk status when there is:
1. Poor tolerance of or excessive requirement for phlebotomy
2. Progressive or symptomatic splenomegaly
3. Persistent leukocytosis >15 × 10⁹/L
4. Progressive leukocytosis
5. Extreme thrombocytosis >1500 × 10⁹/L
6. Persistent high symptom burden
7. Persistently high cardiovascular risk
When cytoreduction is required in a low-risk patient, preferred interferon-based options include:
1. Ropeginterferon alfa-2b
2. Pegylated interferon alfa-2a
8.3 High-Risk PV
High-risk patients generally receive:
1. Phlebotomy to maintain hematocrit below 45%
2. Low-dose aspirin
3. Cytoreductive therapy
First-line cytoreductive options include:
1. Hydroxyurea
2. Ropeginterferon alfa-2b
3. Pegylated interferon alfa in appropriate patients
8.4 Additional Therapy
1. Ruxolitinib, a JAK1/JAK2 inhibitor, is an important option for patients who are resistant or intolerant to hydroxyurea and can improve hematocrit control, splenomegaly, and disease-related symptoms.
2. Rusfertide, a hepcidin mimetic, is FDA-approved for the treatment of erythrocytosis in adults with PV.
3. Rusfertide restricts iron availability for erythropoiesis and can reduce the need for therapeutic phlebotomy.
4. Treatment selection should be individualized according to thrombotic risk, symptom burden, phlebotomy requirement, prior therapy, and comorbidities.
8.5 Symptom Management
1. Erythromelalgia often responds rapidly to low-dose aspirin.
2. Management of aquagenic pruritus begins with adequate control of the underlying PV.
3. Additional therapies for persistent pruritus may be individualized.
4. Allopurinol may be used for gout or clinically significant hyperuricemia when indicated.
9. Complications
1. Arterial and venous thrombosis
2. Hemorrhage
3. Acquired von Willebrand syndrome
4. Hyperuricemia and gout
5. Progression to post-PV myelofibrosis
6. Transformation to acute myeloid leukemia
Thrombotic complications are a major cause of morbidity and mortality in PV.
10. Key Clinical Insight
Aquagenic pruritus + erythromelalgia + splenomegaly + erythrocytosis + low erythropoietin + panmyelosis + JAK2 mutation = polycythemia vera.
In this patient, the markedly elevated hemoglobin and hematocrit, leukocytosis, thrombocytosis, low erythropoietin, bone marrow panmyelosis, JAK2 mutation, splenomegaly, aquagenic pruritus, and microvascular symptoms establish the diagnosis of polycythemia vera.
References
1. Loghavi S, Kanagal-Shamanna R, Khoury JD, et al. Fifth Edition of the World Health Classification of Tumors of the Hematopoietic and Lymphoid Tissue: Myeloid Neoplasms. Mod Pathol. 2024;37(2):100397. doi:10.1016/j.modpat.2023.100397.
2. Ellis MH, Barbui T, Tefferi A. Polycythemia vera. Mayo Clin Proc. 2026;101(5):826-845. doi:10.1016/j.mayocp.2026.01.008.
3. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular Events and Intensity of Treatment in Polycythemia Vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500.
4. U.S. Food and Drug Administration. MIMRYLO (rusfertide) for injection: Prescribing Information. 2026. NDA 220605.
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