Key Facts

Autoimmune haemolytic anaemia (AIHA) is an acquired condition in which autoantibodies directed against RBCs cause haemolysis. It is classified by the thermal reactivity of the autoantibody.

Epidemiology

• Incidence: ~1–3 per 100,000 per year
• Warm AIHA: ~70%; cold AIHA: ~20%; mixed: ~10%
• All ages; warm AIHA peaks in middle age; cold more common in elderly

Aetiology

Warm AIHA (IgG):

• Idiopathic (~50%)
• Secondary: SLE, CLL, lymphoma, drugs (methyldopa, fludarabine), autoimmune disorders

Cold AIHA (IgM):

• Post-infectious: Mycoplasma pneumoniae, EBV (usually transient)
• Chronic cold agglutinin disease: lymphoproliferative disorder (underlying clonal B-cell)

Pathophysiology

Warm:

• IgG coats RBCs → splenic macrophages recognise Fc portion → partial phagocytosis → microspherocytes → extravascular haemolysis

Cold:

• IgM binds RBCs at low temperatures (periphery) → complement activation (C3b) → intravascular haemolysis + hepatic clearance of C3b-coated RBCs
• Agglutination in peripheral circulation → acrocyanosis, livedo

Warm AIHA

• Gradual onset anaemia: fatigue, pallor, dyspnoea
• Jaundice
• Splenomegaly
• Dark urine
• May be precipitated by drug exposure or underlying disease flare

Cold AIHA

• Anaemia + jaundice (often mild)
• Acrocyanosis: blue/purple discolouration of fingers, toes, ears, nose in cold
• Raynaud-like symptoms
• Haemoglobinuria after cold exposure

Red Flags

• Severe acute haemolysis (Hb <60 g/L)
• Evans syndrome (AIHA + ITP — cytopenias)
• Underlying malignancy (CLL, lymphoma)
• Drug-induced (stop offending drug)

Bloods

• FBC: anaemia (severity varies), raised MCV (reticulocytosis)
• Reticulocyte count: raised (usually markedly)
• Blood film: spherocytes (warm), RBC agglutination (cold), polychromasia
• DAT (direct Coombs test): POSITIVE
  • Warm AIHA: IgG ± C3d
  • Cold AIHA: C3d alone (IgM dissociates at lab temperature)
• LDH: raised
• Bilirubin (unconjugated): raised
• Haptoglobin: low/undetectable
• Urinalysis: haemoglobinuria (intravascular haemolysis)

Special Tests

• Cold agglutinin titre: if cold AIHA suspected (high titre >1:64 at 4°C)
• ANA, anti-dsDNA: screen for SLE
• Serum immunoglobulins, SPEP: lymphoproliferative disorder
• CT CAP: lymphoma staging if suspected
• Flow cytometry (peripheral blood): CLL screen
• Bone marrow: if underlying haematological malignancy suspected

Warm AIHA

First-line:

• Prednisolone 1mg/kg/day (max 60mg) for 1–3 weeks; taper over 4–6 months
• Response in ~70–80%

Second-line:

• Rituximab 375mg/m² × 4 weekly (anti-CD20): ~60–80% response

Third-line:

• Splenectomy: ~65–70% response; reserved for refractory
• Mycophenolate, azathioprine, ciclosporin: steroid-sparing alternatives

Drug-induced: Stop offending drug; usually resolves

Cold AIHA

• Avoid cold exposure (most important)
• Corticosteroids usually INEFFECTIVE (not IgG-mediated)
• Rituximab: first-line for chronic cold agglutinin disease
• Sutimlimab (anti-C1s complement inhibitor): NICE TA985 — for cold agglutinin disease
• Transfusion: use blood warmer; crossmatch difficulties (warm sample to 37°C)

Supportive

• Folic acid 5mg daily: increased erythropoiesis
• Thromboprophylaxis: AIHA is prothrombotic
• Transfusion: if severe/symptomatic; crossmatch may be difficult (least incompatible units)

Referral Criteria

• Haematology: all confirmed AIHA
• Emergency: severe acute haemolysis
• Rheumatology: if SLE suspected

• Warm AIHA: ~70–80% respond to steroids; ~50% relapse on taper
• Rituximab: durable remission in ~60% at 2 years
• Chronic relapsing course in ~30–40%
• Cold agglutinin disease: chronic; rituximab effective
• Drug-induced: excellent prognosis on drug withdrawal
• Evans syndrome: more difficult to treat; consider underlying SLE or lymphoma
• Mortality: ~5–10% in severe cases (thromboembolic complications)

Warm vs Cold AIHA