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This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
The Bottom Line
- Hallmarks of haemolysis: raised LDH, raised unconjugated bilirubin, raised reticulocyte count, low haptoglobin, fragmented red cells or spherocytes on film
- Direct antiglobulin test (DAT/Coombs) positive = autoimmune haemolytic anaemia (AIHA); negative = non-immune cause
- Warm AIHA (IgG, 37°C): idiopathic, SLE, CLL, lymphoma, drugs (methyldopa). Treat with prednisolone ± rituximab
- Cold AIHA (IgM, <37°C): idiopathic, lymphoma, Mycoplasma, EBV. Avoid cold exposure; rituximab if treatment needed
- Inherited causes: hereditary spherocytosis (AD, Northern European), G6PD deficiency (X-linked, oxidative stress triggers), sickle cell disease, thalassaemia
Overview
Haemolytic anaemia encompasses a wide group of conditions characterised by premature destruction of red blood cells, either within the circulation (intravascular) or within the reticuloendothelial system — liver and spleen (extravascular). The classification is broadly into immune-mediated (autoimmune, alloimmune, drug-induced) and non-immune (inherited red cell defects, mechanical causes). The direct antiglobulin test (DAT/Coombs test) is the key test that distinguishes immune from non-immune haemolysis.
Epidemiology
Autoimmune haemolytic anaemia (AIHA) has an incidence of approximately 1–3 per 100,000 per year. Warm AIHA (IgG-mediated) accounts for ~70% of cases and is more common in women. Cold AIHA (IgM-mediated) accounts for ~20%. Hereditary spherocytosis is the commonest inherited haemolytic anaemia in Northern Europeans (1 in 5,000). G6PD deficiency is the commonest enzyme disorder worldwide, affecting ~400 million people, predominantly males of Mediterranean, African, and Asian descent.
Clinical Features
Symptoms
Fatigue, pallor, and breathlessness (anaemia)
Jaundice — often intermittent, related to haemolytic episodes
Dark urine (haemoglobinuria — suggests intravascular haemolysis)
Back or loin pain (intravascular haemolysis)
Acrocyanosis or Raynaud-like symptoms (cold AIHA — red cell agglutination in cold extremities)
Acute onset with triggers: fava beans, infections, oxidant drugs in G6PD deficiency
Signs
Pallor and jaundice (combination is characteristic of haemolysis)
Splenomegaly (extravascular haemolysis — spleen removes opsonised RBCs)
Hepatomegaly (extramedullary haemopoiesis in chronic haemolysis)
Leg ulcers (chronic haemolysis — sickle cell, hereditary spherocytosis)
Gallstones (pigment gallstones from chronic bilirubin excess)
Investigations
First-line
FBC and blood filmAnaemia with raised reticulocyte count (>2% or absolute >100 × 10⁹/L). Film: spherocytes (AIHA, hereditary spherocytosis), fragmented red cells/schistocytes (MAHA, DIC), target cells (thalassaemia), Heinz bodies/bite cells (G6PD)
Reticulocyte countRAISED — the bone marrow response to haemolysis. Key distinguishing feature from other anaemias
LDH, bilirubin, haptoglobinRaised LDH, raised unconjugated bilirubin, LOW haptoglobin (consumed binding free haemoglobin) — the classic haemolysis triad
Second-line
Direct antiglobulin test (DAT/Coombs)POSITIVE = antibodies or complement on RBC surface = autoimmune haemolysis. NEGATIVE = non-immune cause
UrinalysisHaemoglobinuria (intravascular haemolysis), urobilinogen raised
Blood film review by haematologistEssential to identify specific morphology: spherocytes, elliptocytes, sickle cells, fragmented cells
Specialist
Haemoglobin electrophoresisIf haemoglobinopathy suspected (sickle cell, thalassaemia)
G6PD enzyme assayCheck BETWEEN crises (reticulocytes have higher G6PD — may give false normal during acute haemolysis)
Osmotic fragility test / EMA binding testFor hereditary spherocytosis (increased fragility/reduced EMA binding)
Flow cytometry for GPI-anchored proteinsFor paroxysmal nocturnal haemoglobinuria (PNH) — absent CD55/CD59
Management
BSH Guidelines on AIHA (2017)1
Warm AIHA (DAT positive, IgG)
- First-line: prednisolone 1 mg/kg/day — taper slowly over weeks once Hb stabilising
- Second-line: rituximab (anti-CD20) — now preferred over splenectomy in many centres
- Third-line: splenectomy, mycophenolate, azathioprine, or ciclosporin
- Folic acid 5 mg daily (increased demand from chronic haemolysis)
- Transfuse only if life-threatening anaemia — least incompatible blood; inform blood bank of AIHA
2
Cold AIHA (DAT positive, complement/C3d)
- Avoid cold exposure — keep extremities warm
- Rituximab is first-line pharmacological treatment if intervention needed
- Steroids are generally INEFFECTIVE in cold AIHA (unlike warm)
- Warm blood products before transfusion
3
Non-immune haemolysis
- Treat underlying cause: G6PD — avoid triggers (fava beans, dapsone, primaquine, ciprofloxacin); hereditary spherocytosis — folic acid, splenectomy if severe
- MAHA (TTP, HUS): see specific condition — plasma exchange for TTP
- Supportive: folic acid supplementation in all chronic haemolytic conditions
Complications
- Acute haemolytic crisis: Rapid anaemia requiring emergency transfusion — can cause cardiovascular collapse
- Pigment gallstones: Chronic haemolysis leads to bilirubin-rich gallstones — may present with biliary colic or cholecystitis
- Aplastic crisis: Parvovirus B19 infection in chronic haemolysis causes temporary red cell aplasia — sudden severe anaemia
- Folate deficiency: Increased folate demand from chronic erythropoiesis — supplement all chronic haemolytic conditions
- Iron overload: From chronic transfusions in severe haemolytic anaemias
UKMLA Exam Tips
- 1The haemolysis screen: raised LDH + raised unconjugated bilirubin + low haptoglobin + raised reticulocytes = HAEMOLYSIS
- 2DAT positive = autoimmune. DAT negative = think inherited (spherocytosis, G6PD, sickle cell) or mechanical (MAHA)
- 3Warm AIHA = IgG = steroids work. Cold AIHA = IgM/complement = steroids DON'T work, use rituximab
- 4G6PD assay must be done BETWEEN crises — reticulocytes have higher enzyme levels giving false negatives during acute episodes
- 5Spherocytes on film: think AIHA (DAT positive) or hereditary spherocytosis (DAT negative, family history)
- 6Fragmented red cells (schistocytes) = mechanical haemolysis: TTP, HUS, DIC, mechanical heart valves, pre-eclampsia
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