Secondary polycythaemia

Overview

Secondary polycythaemia is a true increase in red cell mass driven by elevated EPO - either appropriate (physiological response to hypoxia) or inappropriate (autonomous EPO secretion from tumour or exogenous source) - rather than a primary bone marrow disorder.

Causes

Appropriate vs inappropriate EPO elevation

Feature	Appropriate (hypoxia-driven)	Inappropriate (autonomous)
Mechanism	Chronic hypoxia → HIF-1α → EPO	Tumour secretes EPO regardless of O2
Examples	COPD, OSA, cyanotic heart disease, high altitude, obesity hypoventilation	Renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma; exogenous EPO/testosterone

💡

Erythrocytosis is the most common dose-limiting adverse effect of testosterone replacement therapy - monitor proactively.

Presentation

•Ruddy (plethoric) complexion, conjunctival plethora

•Headache, dizziness, visual disturbances - hyperviscosity reduces cerebral/retinal perfusion

•Hypertension - increased blood viscosity raises vascular resistance

•Features of underlying cause - dyspnoea/cough (COPD), snoring/somnolence (OSA), central cyanosis (cyanotic heart disease), abdominal mass (tumour)

•O2 saturation <92% or clubbing suggests cardiopulmonary aetiology

🎯

Secondary erythrocytosis does NOT cause splenomegaly, aquagenic pruritus, thrombocytosis, or neutrophil leucocytosis. Presence of these features strongly suggests polycythaemia vera instead.

Investigations

Investigate persistent haematocrit >0.52 (males) or >0.48 (females). Immediate investigation if Hct >0.60 (males) or >0.56 (females) without waiting for repeat.

🥇 First-line

•FBC - elevated Hct with normal WBC and platelets; normal/elevated MCV argues against PV

•Serum EPO - elevated supports secondary erythrocytosis; suppressed suggests PV

•JAK2 V617F mutation - if positive, essentially diagnostic of PV; negative favours secondary/apparent cause

•O2 saturation on room air - <92% warrants respiratory/cardiac investigation

•LFTs, U&Es, urine dipstick - screen for hepatic/renal aetiology

🥈 Second-line

•Pulmonary function tests/sleep study (if COPD/OSA suspected); abdominal ultrasound (EPO-secreting tumour or splenomegaly); echocardiography (cyanotic heart disease)

⚠️

Iron deficiency can mask erythrocytosis by limiting RBC size - a normal Hb does not exclude elevated red cell mass if MCV is low.

Differential diagnosis

Secondary erythrocytosis vs polycythaemia vera vs apparent erythrocytosis

Feature	Secondary erythrocytosis	Polycythaemia vera	Apparent erythrocytosis
Red cell mass	Increased	Increased	Normal
EPO	Elevated	Suppressed	Normal
JAK2 V617F	Negative	Positive (~95%)	Negative
WBC/platelets	Normal	Often elevated	Normal
Splenomegaly	Absent	Present	Absent
Aquagenic pruritus	Absent	Present	Absent

Management

•Cornerstone: treat the underlying cause - correcting hypoxia (e.g. long-term oxygen therapy in COPD) or resecting EPO-secreting tumour normalises EPO drive and reduces haematocrit

•Venesection - used symptomatically for hyperviscosity in selected cases; does not treat the disease

⚠️

Venesection in chronic hypoxia carries risk - these patients depend on a higher red cell mass for adequate oxygen delivery. Aggressive venesection can worsen tissue hypoxia. Always treat the cause first.

Complications

•Thrombosis - most important complication; hyperviscosity raises risk of DVT, PE, stroke, MI

•Gout - increased red cell turnover → purine breakdown → uric acid

•Hypertension - raised peripheral vascular resistance from hyperviscosity

•Haemorrhage - extreme hyperviscosity can impair platelet function (less common than in PV)

Prognosis

Unlike PV, secondary erythrocytosis carries no intrinsic risk of transformation to myelofibrosis or AML. Prognosis is entirely determined by the underlying condition.