Polycythaemia Vera

A clonal myeloproliferative neoplasm characterised by autonomous, erythropoietin-independent overproduction of red blood cells (typically with accompanying granulocytosis and thrombocytosis), driven in the overwhelming majority by the JAK2 V617F mutation (or, less commonly, JAK2 exon 12 mutations), which constitutively activates the JAK-STAT signalling pathway.

Pathophysiology

The JAK2 mutation renders erythroid precursors hypersensitive to, or independent of, erythropoietin, driving unregulated proliferation. This distinguishes true (clonal) polycythaemia vera from secondary polycythaemia (appropriate or inappropriate erythropoietin-driven, from hypoxia, erythropoietin-secreting tumours, or exogenous erythropoietin/androgen use) and from relative/spurious polycythaemia (plasma volume contraction, e.g. dehydration, diuretic use, obesity --- "Gaisböck syndrome").

Clinical consequences

The elevated red cell mass increases blood viscosity, driving the major complications: arterial and venous thrombosis (the principal cause of morbidity and mortality), and, over years, progression to myelofibrosis (post-polycythaemic myelofibrosis) or, less commonly, acute myeloid leukaemia.

• Often discovered incidentally on routine blood count before symptoms develop.
• Hyperviscosity symptoms: headache, dizziness, visual disturbance, tinnitus, and erythromelalgia (burning pain and redness of the extremities, characteristic and often dramatically responsive to aspirin).
• Pruritus, classically aquagenic (triggered or worsened by warm water/bathing), a distinctive and often severely troublesome symptom related to histamine/serotonin release from increased basophil mass.
• Plethora (facial redness), conjunctival injection.
• Splenomegaly, present in the majority, from extramedullary haematopoiesis; can cause early satiety and abdominal discomfort.
• Thrombotic events, arterial (stroke, myocardial infarction, peripheral arterial occlusion) or venous (deep vein thrombosis, pulmonary embolism, and characteristically unusual-site thromboses --- Budd-Chiari syndrome, portal/splenic/mesenteric vein thrombosis), sometimes the presenting feature before the diagnosis is made.
• Gout from increased cell turnover and uric acid production.
• Bleeding tendency paradoxically can occur with marked thrombocytosis (acquired von Willebrand syndrome from high platelet counts adsorbing high-molecular-weight von Willebrand multimers).
• Constitutional symptoms (fatigue, night sweats, weight loss) more prominent with progression toward myelofibrosis.

Requires a combination of major and minor criteria (WHO):

Major criteria: haemoglobin above 165 g/L (men) or 160 g/L (women), or haematocrit above 49% (men) or 48% (women), or increased red cell mass; bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) and pleomorphic mature megakaryocytes; presence of JAK2 V617F or JAK2 exon 12 mutation.

Minor criterion: subnormal serum erythropoietin level.

Diagnosis requires all three major criteria, or the first two major criteria plus the minor criterion.

• Full blood count typically shows elevated haemoglobin/haematocrit, often with accompanying leucocytosis and thrombocytosis.
• JAK2 mutation testing, positive in over 95% (V617F) with most of the remainder having exon 12 mutations --- a negative result makes the diagnosis very unlikely but does not entirely exclude it.
• Serum erythropoietin, characteristically low/suppressed (distinguishing from secondary causes where it is normal or elevated).
• Bone marrow biopsy, generally recommended for full WHO diagnostic confirmation and to assess for fibrosis (prognostic).
• Exclude secondary causes if clinically indicated: arterial blood gas/pulse oximetry (chronic hypoxia), abdominal imaging (renal or hepatic pathology, erythropoietin-secreting tumour), and a careful drug/exposure history (androgens, erythropoietin misuse, smoking).

• Risk stratification drives treatment intensity: high risk defined as age over 60 or prior thrombosis; low risk is age under 60 with no prior thrombosis.
• Therapeutic phlebotomy to maintain haematocrit below 45% (both risk groups), which is proven to reduce cardiovascular events and is the cornerstone of management.
• Low-dose aspirin (75-100mg daily) for all patients without contraindication, reducing thrombotic risk.
• Cytoreductive therapy for high-risk patients (and low-risk patients with progressive disease, poor phlebotomy tolerance, symptomatic/progressive splenomegaly, or significant thrombocytosis/leucocytosis): hydroxyurea is first-line; interferon alfa (particularly pegylated formulations) is preferred in younger patients and during pregnancy given lack of leukemogenic/teratogenic concern; ruxolitinib (JAK inhibitor) is second-line for hydroxyurea-resistant or intolerant disease, also effective for pruritus and splenomegaly.
• Manage pruritus: antihistamines (often disappointing), selective serotonin reuptake inhibitors (paroxetine has evidence), phototherapy (UVB), and ruxolitinib in refractory cases.
• Manage erythromelalgia and microvascular symptoms with aspirin, usually highly effective.
• Aggressive cardiovascular risk factor management (smoking cessation, blood pressure, lipids, diabetes control), which is at least as important as haematocrit control for thrombotic risk reduction.
• Manage hyperuricaemia/gout with allopurinol if symptomatic or significantly elevated.
• Treat acute thrombotic events per standard protocols, with anticoagulation duration and cytoreductive intensification individualised given ongoing thrombotic risk.
• Monitor for progression to myelofibrosis (worsening cytopenias, increasing splenomegaly, constitutional symptoms, marrow fibrosis) and to acute leukaemia (occurring in a minority over decades, with risk influenced by cytoreductive agent choice), with regular long-term haematology follow-up.