Key Facts

Polycythaemia vera is a chronic myeloproliferative neoplasm characterised by uncontrolled production of red blood cells, often accompanied by leucocytosis and thrombocytosis. It carries a significant risk of thrombotic events.

Epidemiology

• Incidence: 2 per 100,000/year in the UK
• Median age at diagnosis: 60 years
• Slight male predominance
• Prevalence approximately 22 per 100,000

Aetiology

• JAK2 V617F mutation in >95% of PV cases (exon 14)
• JAK2 exon 12 mutations in ~3% of JAK2 V617F-negative PV
• Gain-of-function mutation → constitutive activation of JAK-STAT signalling
• Results in cytokine-independent erythroid proliferation

Pathophysiology

• Mutant JAK2 → constitutive activation of erythropoietin receptor signalling
• Uncontrolled erythropoiesis → raised haematocrit → hyperviscosity → increased thrombotic risk
• Leucocytosis and thrombocytosis also common (trilineage proliferation)
• Raised haematocrit → reduced blood flow, endothelial damage → arterial and venous thrombosis
• Platelet dysfunction → paradoxical bleeding risk (especially if platelets >1500 × 10⁹/L due to acquired von Willebrand disease)
• Late-phase: bone marrow fibrosis (post-PV myelofibrosis) or leukaemic transformation

Common Presentations

• Incidental finding on FBC (raised Hb/Hct)
• Facial plethora (ruddy complexion)
• Aquagenic pruritus (itch after bathing – highly characteristic)
• Headache, dizziness, visual disturbance (hyperviscosity)
• Splenomegaly (present in ~70%)
• Erythromelalgia (burning pain and redness of extremities)

Thrombotic Complications

• Stroke, TIA
• MI, angina
• DVT/PE
• Budd-Chiari syndrome (hepatic vein thrombosis) – consider PV in young patients
• Portal/splenic vein thrombosis

Late-Phase Disease

• Progressive splenomegaly (post-PV myelofibrosis)
• Worsening cytopenias
• Constitutional symptoms (weight loss, night sweats)

Red Flags

• Budd-Chiari syndrome in young patient → test JAK2
• Erythrocytosis with low EPO → strongly suggests PV
• Rapidly increasing spleen size → transformation to myelofibrosis
• New pancytopenia in known PV → leukaemic transformation

Bedside

• SpO₂: exclude hypoxic secondary polycythaemia
• Weight/BMI: obesity associated with apparent polycythaemia

Bloods

• FBC: raised Hb (>165 g/L males, >160 g/L females), raised Hct (>0.49 males, >0.48 females); often WCC and platelets also raised
• JAK2 V617F mutation: positive in >95%
• JAK2 exon 12: if V617F negative but PV still suspected
• Serum erythropoietin (EPO): low or low-normal in PV (raised in secondary causes)
• Serum ferritin: often low (iron depletion from erythrocytosis or venesection)
• LDH: may be elevated
• Uric acid: often raised

Imaging

• Abdominal ultrasound: splenomegaly, hepatomegaly
• CT abdomen: if Budd-Chiari or splanchnic thrombosis suspected

Special Tests

• Bone marrow biopsy: hypercellular with trilineage proliferation, pleomorphic megakaryocytes; confirms diagnosis if EPO and JAK2 equivocal
• Cytogenetics: for risk stratification
• Red cell mass study: rarely performed now; replaced by JAK2 testing

Non-pharmacological

• Venesection: target haematocrit <0.45 (regardless of sex) – CYTO-PV trial demonstrated reduced thrombotic events
• Initially weekly 400-500mL until target achieved, then as needed
• Cardiovascular risk factor management: smoking cessation, BP control

Pharmacological

All patients:

• Aspirin 75mg OD (unless contraindicated) – reduces thrombotic risk
• Avoid aspirin if platelets >1500 × 10⁹/L (acquired vWD risk)

High-risk patients (age >60 OR prior thrombosis):

• Hydroxycarbamide (hydroxyurea) 500mg-2g OD – first-line cytoreductive therapy
• Titrate to maintain Hct <0.45, WCC <10, platelets <400

Hydroxycarbamide-intolerant/resistant:

• Ruxolitinib 10mg BD (JAK1/2 inhibitor) – RESPONSE trial: superior to best available therapy
• Interferon alfa (ropeginterferon alfa-2b): preferred in younger patients, pregnancy-safe
• Busulfan 2-4mg OD – in elderly/frail patients

Aquagenic pruritus:

• Antihistamines, SSRIs, narrow-band UVB phototherapy, ruxolitinib

Referral Criteria

• All patients with confirmed/suspected PV → haematology
• Splanchnic thrombosis with erythrocytosis → urgent haematology + hepatology

• Median survival: 14-20 years (near-normal life expectancy with good control)
• Major cause of death: thrombotic events (30-40% of deaths)
• Risk of myelofibrotic transformation: 10-20% at 20 years
• Risk of AML transformation: 5-10% at 20 years (increased with alkylating agents)
• CYTO-PV trial: maintaining Hct <0.45 reduces cardiovascular death and major thrombosis by 60%
• Prognosis significantly worse with high-risk cytogenetics or leukaemic transformation

WHO Diagnostic Criteria for PV (2016)

Major criteria (all 3 required, or first 2 + minor criterion):

Minor criterion: Low serum EPO

Risk Stratification

Landmark Trials