Secondary Polycythaemia

Secondary polycythaemia is an increase in red cell mass driven by raised erythropoietin, either as an appropriate response to chronic tissue hypoxia or as inappropriate production by tumours and drugs. It differs from polycythaemia vera, which is a clonal myeloproliferative neoplasm with low erythropoietin.

• Definition (persistent): haemoglobin over 165 g/L or haematocrit over 49 percent in men, and over 160 g/L or over 48 percent in women.
• Hypoxic (appropriate) causes: chronic lung disease (chronic obstructive pulmonary disease), obstructive sleep apnoea and obesity hypoventilation, cyanotic congenital heart disease, right-to-left shunts, residence at high altitude, smoking and carbon monoxide exposure (carboxyhaemoglobin), high oxygen affinity haemoglobin variants, and chronic kidney hypoxia.
• Non-hypoxic (inappropriate erythropoietin) causes: renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma, uterine fibroids, phaeochromocytoma, renal cysts, renal artery stenosis, hydronephrosis, post-renal transplant erythrocytosis, androgens and anabolic steroids, testosterone therapy, erythropoietin doping, and sodium glucose cotransporter 2 inhibitors (mild).
• Relative polycythaemia (stress or Gaisbock syndrome): reduced plasma volume from dehydration, diuretics, obesity, and alcohol, with a normal red cell mass.
• Congenital: VHL, EPAS1, EGLN1 and EPOR mutations.

• Plethora, ruddy face, headache, dizziness, tinnitus, visual disturbance, fatigue, difficulty concentrating, and hypertension.
• Hyperviscosity: thrombosis, stroke, transient ischaemic attacks, peptic ulcer, gout, bleeding, and rarely pruritus after bathing (more typical of polycythaemia vera).
• Features of the cause: central cyanosis, finger clubbing, cough, breathlessness, snoring, daytime sleepiness, obesity, heart murmur (shunt), loin pain, haematuria, abdominal mass (renal tumour), and drug and testosterone history.
• Splenomegaly is typically absent (suggests polycythaemia vera).
• Examination: oxygen saturation at rest and on exertion, blood pressure, cyanosis, lungs, heart, abdomen, and kidneys.

• Repeat FBC with haematocrit after rehydration (2 occasions, 2 to 4 weeks apart) and review the film.
• Serum erythropoietin: raised or normal in secondary polycythaemia, low in polycythaemia vera.
• JAK2 V617F mutation (positive in about 95 percent of polycythaemia vera): if positive refer to haematology; if negative with a low erythropoietin, test JAK2 exon 12.
• Oxygen saturation (pulse oximetry), arterial blood gas, carboxyhaemoglobin level, spirometry, chest X-ray, sleep study or overnight oximetry, echocardiogram (shunt), and P50 or haemoglobin electrophoresis for high affinity variants.
• Abdominal ultrasound for kidneys, liver, spleen and uterus; CT or MRI if tumour suspected; urine analysis for haematuria.
• Other tests: ferritin (iron deficiency can mask), renal and liver function, urate, testosterone and drug review.
• Bone marrow biopsy if the JAK2 result is negative with a low erythropoietin or the diagnosis is unclear.

Find and treat the cause

• Stop smoking (carboxyhaemoglobin and haematocrit fall within weeks to months), treat obstructive sleep apnoea with continuous positive airway pressure, optimise chronic obstructive pulmonary disease with long term oxygen when criteria are met (PaO2 under 7.3 kPa, or under 8.0 with cor pulmonale or polycythaemia), manage obesity, and correct cardiac shunts if feasible.
• Stop or reduce androgens and erythropoiesis stimulating agents; reduce testosterone dose or change route if haematocrit exceeds 54 percent (testosterone gel rather than injections); post-transplant erythrocytosis: enalapril 2.5 to 5 mg daily or losartan 25 to 50 mg daily.
• Remove erythropoietin secreting tumours (nephrectomy, hepatic resection, haemangioblastoma excision).

Phlebotomy (selectively)

• Not needed for most hypoxic polycythaemia, since the raised red cell mass compensates for hypoxia and venesection can worsen symptoms and reduce oxygen delivery.
• Consider cautious venesection of 250 to 500 mL with isovolaemic fluid replacement (500 mL saline) when haematocrit is over 65 percent or hyperviscosity symptoms are present, aiming for a haematocrit of 55 to 60 percent in cyanotic congenital heart disease and under 55 percent otherwise; avoid iron deficiency (keep ferritin over 30 micrograms/L).
• Haematocrit target for testosterone related erythrocytosis: under 50 to 54 percent.

Cardiovascular risk

• Control blood pressure, lipids, and diabetes; aspirin 75 mg daily for those with cardiovascular disease or high risk; counsel on hydration, avoid dehydration, and avoid long immobile travel.
• Treat gout with allopurinol 100 mg increasing to 300 mg daily.

Polycythaemia vera (if JAK2 positive, low erythropoietin)

• Haematology care: venesection to haematocrit under 45 percent, aspirin 75 to 100 mg daily, hydroxycarbamide for high risk disease (age over 60 or previous thrombosis), ruxolitinib for intolerance.

Follow up

• FBC and haematocrit every 3 to 6 months once stable; refer to haematology if unexplained, JAK2 positive, splenomegaly, thrombosis, or persistently over 60 percent haematocrit.