Polycythaemia

Introduction

Polycythaemia (erythrocytosis) describes a raised haemoglobin concentration or haematocrit above the normal reference range. It is most often picked up incidentally on a full blood count, and the diagnostic task is to work out which of three broad categories is responsible, since management differs completely between them.¹

The essential first distinction is between relative polycythaemia (a normal red cell mass but reduced plasma volume, so the concentration appears high) and absolute (true) polycythaemia (a genuinely increased red cell mass), which is then subdivided into primary and secondary causes.

Classification and aetiology

Relative polycythaemia

Caused by a contracted plasma volume rather than true red cell excess:

• Dehydration - the commonest cause, easily corrected and easily missed if fluid status is not assessed
• Diuretic use
• "Stress" or Gaisbock syndrome - typically middle-aged, overweight, hypertensive smokers with a modestly raised haematocrit and no true red cell excess

Absolute (true) polycythaemia - primary

Polycythaemia vera (PV) is a clonal myeloproliferative neoplasm arising from a haematopoietic stem cell, causing autonomous, EPO-independent overproduction of red cells (and frequently white cells and platelets too). Over 95% of patients carry a JAK2 V617F mutation, which constitutively activates the JAK-STAT signalling pathway normally triggered by the EPO receptor.² Rarer causes include other primary myeloproliferative disorders such as essential thrombocythaemia and primary myelofibrosis.

Absolute (true) polycythaemia - secondary

Driven by a rise in erythropoietin (EPO), which can be either an appropriate physiological response or an inappropriate pathological one:

Clinical features

Many patients, particularly with secondary polycythaemia, are asymptomatic and detected incidentally. Symptomatic patients, especially with PV, may describe:

• Headache, dizziness, tinnitus and visual disturbance - from hyperviscosity
• Aquagenic pruritus - itching, classically after a hot bath or shower, thought to relate to abnormal basophil/mast cell histamine release; a highly characteristic feature of PV
• Erythromelalgia - burning pain and redness/warmth of the hands and feet, from microvascular platelet-mediated occlusion
• Plethoric complexion - a ruddy, red-faced appearance
• Gout - from increased urate turnover with high cell production
• Splenomegaly - common in PV, less so in secondary causes
• Symptoms of thrombosis - the presenting feature in some patients, including at unusual sites (see complications)

Investigations

• FBC - raised haemoglobin/haematocrit; in PV, white cell count and platelets are also often raised, reflecting panmyelosis (overproduction of multiple lineages) rather than an isolated red cell problem
• Assess fluid status and volume history first - excludes relative polycythaemia before further work-up
• JAK2 V617F mutation testing - positive in over 95% of PV; a small remaining fraction have mutations in exon 12 of JAK2
• Serum erythropoietin (EPO) level - typically low or undetectable in PV (since the marrow is producing red cells independent of EPO drive, which suppresses the normal feedback), and raised in secondary polycythaemia
• Further work-up for secondary causes where EPO is raised and JAK2 is negative - pulse oximetry/arterial blood gas, sleep study if OSA is suspected, renal ultrasound/CT to look for a renal mass or cyst, and liver imaging
• Bone marrow biopsy - not always required if JAK2 is positive with a typical picture, but used where the diagnosis is unclear, showing hypercellularity with panmyelosis in PV
• WHO diagnostic criteria combine the raised haemoglobin/haematocrit, JAK2 mutation status and bone marrow appearances to confirm PV in equivocal cases

Management

Polycythaemia vera

• Venesection is first line for most patients, aiming to keep the haematocrit below 45%, a threshold shown to reduce cardiovascular death and major thrombosis compared with looser control³
• Low-dose aspirin for most patients, reducing thrombotic risk unless contraindicated
• Cytoreductive therapy for higher-risk patients (age over 60, prior thrombosis, or poorly controlled counts despite venesection) - hydroxycarbamide is first line; interferon-alpha is an option, particularly in younger patients or during pregnancy; ruxolitinib (a JAK inhibitor) is used second line, including for resistant pruritus
• Manage cardiovascular risk factors aggressively (smoking cessation, blood pressure, lipids), since thrombosis is the dominant driver of morbidity and mortality
• Manage gout if it develops, and treat pruritus symptomatically (antihistamines, and disease-directed therapy if severe)

Secondary polycythaemia

• Treat the underlying cause - long-term oxygen therapy or CPAP for hypoxic lung disease/OSA, smoking cessation, or definitive treatment of an EPO-secreting tumour
• Venesection may be used for symptomatic hyperviscosity, but cytoreductive drug therapy is not generally indicated, since the marrow itself is not intrinsically abnormal

Relative polycythaemia

Managed by correcting the underlying cause - rehydration, reviewing diuretics, and addressing cardiovascular risk factors in Gaisbock syndrome. No venesection or cytoreductive therapy is needed.

Complications

• Arterial thrombosis - stroke, myocardial infarction, peripheral arterial disease - the leading cause of death in PV
• Venous thrombosis, including at unusual sites that should always prompt consideration of an underlying myeloproliferative disorder - Budd-Chiari syndrome (hepatic vein thrombosis), portal vein thrombosis, and cerebral venous sinus thrombosis
• Haemorrhage - paradoxically, very high platelet counts can cause an acquired von Willebrand-like defect, increasing bleeding risk alongside the thrombotic risk
• Transformation to myelofibrosis ("post-polycythaemic myelofibrosis") over years
• Transformation to acute myeloid leukaemia - uncommon but recognised, particularly with certain cytoreductive drug exposures
• Gout and urate nephropathy from increased cell turnover

Red flags

Prognosis

Relative and secondary polycythaemia carry a prognosis determined by the underlying cause; correcting it (rehydration, treating hypoxic lung disease, removing an EPO-secreting tumour) resolves the polycythaemia.

Polycythaemia vera is a chronic condition managed over decades rather than cured. With modern management, particularly maintaining haematocrit below 45% and appropriate cytoreduction, median survival now extends beyond 15-20 years for many patients, though it remains shorter than the general population, driven predominantly by thrombotic events.³ Long-term surveillance continues indefinitely given the risk of transformation to myelofibrosis or, less commonly, acute myeloid leukaemia.