Medicine chapters
Haemolytic anaemias: autoimmune, drug-induced and cold agglutinin disease
How to recognise haemolysis, tell intravascular from extravascular and acute from chronic causes, confirm it with the direct Coombs test, and manage warm, cold and drug-induced immune haemolytic anaemias.
- Haemolysis shows anaemia + reticulocytosis + raised unconjugated bilirubin and LDH + low haptoglobin.
- The direct Coombs (antiglobulin) test confirms immune haemolysis: warm AIHA is IgG at 37°C with spherocytes; cold agglutinin disease is IgM with C3d only and acrocyanosis.
- Warm AIHA: prednisolone first, then rituximab or splenectomy; cold disease: keep warm, rituximab, and avoid steroids and splenectomy (they rarely help).
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Overview
Haemolytic anaemia is anaemia caused by shortened red cell survival (normally about 120 days). The marrow can increase output by 6–8 times, so mild haemolysis may cause no anaemia (compensated haemolysis).
This chapter covers the general approach to haemolysis and the acquired immune types: warm autoimmune, cold agglutinin disease and drug-induced haemolysis. Hereditary spherocytosis, G6PD deficiency, sickle cell disease and thalassaemia have their own chapters.
Classification
| Group | Examples |
|---|---|
| Inherited: membrane | Hereditary spherocytosis, elliptocytosis |
| Inherited: enzyme | G6PD deficiency, pyruvate kinase deficiency |
| Inherited: haemoglobin | Sickle cell disease, thalassaemia |
| Acquired: immune | Warm AIHA, cold AIHA, drug-induced, alloimmune (transfusion reaction, haemolytic disease of the newborn) |
| Acquired: non-immune | Microangiopathic (TTP, HUS, DIC, HELLP), prosthetic valves, march haemoglobinuria, PNH, malaria, Clostridium perfringens sepsis, burns, snake venom, hypersplenism, liver and kidney failure |
Acute versus chronic causes
| Acute haemolysis | Chronic haemolysis |
|---|---|
| G6PD deficiency after oxidant drugs, infection or fava beans | Hereditary spherocytosis |
| Incompatible blood transfusion | Sickle cell disease, thalassaemia |
| Falciparum malaria (blackwater fever) | Warm AIHA (often relapsing) |
| Drug-induced immune haemolysis | Cold agglutinin disease |
| Microangiopathic (HUS, TTP, DIC) | Pyruvate kinase deficiency |
| Paroxysmal cold haemoglobinuria after viral infection | PNH (chronic with acute bouts) |
| Burns, Clostridium sepsis, snake bite | Prosthetic heart valve |
Intravascular versus extravascular haemolysis
| Feature | Extravascular (commoner) | Intravascular |
|---|---|---|
| Where | Macrophages in spleen and liver | Inside blood vessels |
| Examples | Spherocytosis, warm AIHA, thalassaemia, sickle cell | Mismatched transfusion, G6PD crisis, PNH, malaria, MAHA, cold agglutinins (severe) |
| Spleen | Often enlarged | Usually not |
| Plasma haemoglobin | Normal | Raised (haemoglobinaemia) |
| Haptoglobin | Reduced | Absent |
| Urine | Urobilinogen up | Haemoglobinuria (red-brown urine); haemosiderinuria after a few days |
| Other | Pigment gallstones | Methaemalbumin (Schumm's test); risk of acute kidney injury |
Haemosiderinuria (iron in shed tubular cells, Perls' stain on spun urine) proves chronic intravascular haemolysis. Chronic intravascular loss (PNH, valve haemolysis) can cause iron deficiency.
Presentation
- Symptoms of anaemia.
- Jaundice (acholuric: bilirubin is unconjugated, so urine has no bilirubin but is dark from urobilinogen; or red-brown from haemoglobin in intravascular cases).
- Splenomegaly (extravascular, chronic).
- Pigment (bilirubin) gallstones in chronic haemolysis.
- Leg ulcers (sickle cell, spherocytosis).
- Crises: aplastic (parvovirus B19), haemolytic (sudden worsening) and megaloblastic (folate exhaustion).
- Intravascular: loin pain, fever, rigors, dark urine, shock, kidney injury.
- Cold disease: acrocyanosis, Raynaud-like changes on cold exposure.
Lab investigations
Evidence of increased breakdown
- Raised unconjugated bilirubin.
- Raised LDH.
- Low haptoglobin (it binds released haemoglobin and is cleared).
- Raised urinary urobilinogen.
Evidence of increased production
- Reticulocytosis (normal below about 2.5%); seen on the film as polychromasia; raised MCV from large young cells.
- Erythroid hyperplasia in the marrow.
Correcting the reticulocyte count
The reticulocyte percentage looks higher simply because there are fewer red cells. A common correction multiplies it by the patient's haematocrit divided by 45 (normal haematocrit). A corrected count above about 3% shows a good marrow response.
Reticulocytes 9%, haematocrit 20%
Corrected = 9 × 20 ÷ 45 = 4% → above 3%, marrow responding (suggests haemolysis or bleeding)
Blood film clues
| Film finding | Points to |
|---|---|
| Spherocytes | Hereditary spherocytosis, warm AIHA |
| Bite and blister cells, Heinz bodies | G6PD deficiency |
| Schistocytes (fragments) | Microangiopathic haemolysis (TTP, HUS, DIC), valves |
| Sickle cells | Sickle cell disease |
| Target cells | Thalassaemia, HbC, liver disease |
| Red cell agglutination | Cold agglutinin disease |
| Parasites | Malaria |
Confirmatory tests
- Direct antiglobulin (Coombs') test (DAT): detects antibody or complement already on the patient's red cells (sensitised in the body). Positive in autoimmune, drug-induced, alloimmune (transfusion reaction, haemolytic disease of the newborn) haemolysis.
- Indirect antiglobulin test: detects antibodies in the patient's serum using test red cells; used in antenatal antibody screening and cross-matching.
- Others as indicated: osmotic fragility or EMA test (spherocytosis), G6PD assay, haemoglobin electrophoresis, flow cytometry for CD55/CD59 (PNH), malaria film, cold agglutinin titre, Donath–Landsteiner test.
Spherocytes occur in both hereditary spherocytosis and warm AIHA. The DAT separates them: negative in hereditary spherocytosis, positive in AIHA.
Autoimmune haemolytic anaemia (AIHA)
Autoantibodies against the patient's own red cells, defined by a positive DAT. About 65% warm, 30% cold, 5% mixed. About half are primary (idiopathic) and half secondary.
Warm AIHA
- Antibody: IgG, binds best at 37°C; often has Rh specificity.
- Mechanism: extravascular haemolysis in the spleen. Macrophages nibble the coated membrane, leaving spherocytes.
- DAT: positive with IgG alone, IgG plus complement, or complement alone.
- Commonest in middle-aged women.
- Secondary causes:
- Lymphoproliferative disease: CLL (most common), lymphomas.
- Autoimmune disease: SLE, rheumatoid arthritis.
- Other cancers; drugs (see below); HIV.
- Evans syndrome: AIHA together with immune thrombocytopenia (and sometimes neutropenia).
- Look for an underlying cause: CT of chest and abdomen for lymphoma, ANA, blood film for CLL.
Treatment:
- Prednisolone 1 mg/kg daily (remission in about 80%), tapered slowly over months.
- Rituximab (anti-CD20) if steroids fail or relapse.
- Splenectomy (most effective second-line option; vaccinate first).
- Other immunosuppressants: azathioprine, ciclosporin, mycophenolate, cyclophosphamide.
- Folic acid; treat the underlying cause.
- Transfusion for life-threatening anaemia; cross-matching is difficult because the autoantibody reacts with all donor cells, so use the "least incompatible" blood.
- IV immunoglobulin has a limited role.
Cold AIHA
- Antibody: IgM, binds best in the cold (peripheries).
- IgM agglutinates cells and fixes complement; the IgM falls off when warmed, leaving C3d on the cells.
- DAT positive for complement (C3d) only.
- Antibody specificity: usually anti-I.
Types:
| Type | Features |
|---|---|
| Chronic cold agglutinin disease | Elderly; monoclonal IgM from a low-grade B-cell clone (lymphoma, Waldenström); gradual onset; worse in winter |
| Post-infectious (polyclonal) | After Mycoplasma pneumoniae (anti-I) or infectious mononucleosis/EBV, CMV; transient |
| Paroxysmal cold haemoglobinuria (PCH) | Children after viral infections (measles, mumps, chickenpox), historically syphilis; IgG biphasic Donath–Landsteiner antibody against the P antigen; binds in the cold and lyses on warming; intravascular haemolysis |
Features of cold agglutinin disease:
- Acrocyanosis: purple, painful fingers, toes, ears and nose in the cold, like Raynaud's.
- Haemoglobinuria after cold exposure.
- Film: red cell clumping, which reverses on warming.
- Falsely high MCV and low red cell count on automated counters (clumps counted as single large cells).
- Cold agglutinin titre markedly raised (above 1 : 512 in chronic disease).
Treatment:
- Avoid cold; keep the patient warm, warm all IV fluids and blood.
- Treat the cause (lymphoma, infection).
- Rituximab is the main drug for chronic disease.
- Steroids and splenectomy usually do not help (the liver, not the spleen, removes C3b-coated cells).
- Transfuse with a blood warmer if needed.
| Feature | Warm AIHA | Cold AIHA |
|---|---|---|
| Antibody | IgG | IgM |
| Temperature | 37°C | Below 37°C (peripheries) |
| DAT | IgG ± C3d | C3d only |
| Site of destruction | Spleen (extravascular) | Liver and intravascular |
| Film | Spherocytes | Agglutination |
| Causes | Idiopathic, CLL, lymphoma, SLE, drugs | Idiopathic, lymphoma, Mycoplasma, EBV |
| First-line treatment | Steroids | Avoid cold, rituximab |
| Splenectomy | Helps | Rarely helps |
"Warm G, cold M." Warm antibodies are IgG (G for "Get to the spleen"); cold antibodies are IgM (M for "Mycoplasma" and "Monoclonal").
PCH is a cold antibody but it is IgG, not IgM. The Donath–Landsteiner antibody is the exception.
Drug-induced immune haemolytic anaemia
Over 100 drugs are implicated, though it is rare. Mechanisms:
| Mechanism | Classic drug | Notes |
|---|---|---|
| Hapten (drug adsorption): drug sticks to the red cell, antibody binds the drug–cell complex | Penicillin (high dose), cephalosporins | Extravascular; DAT positive (IgG) |
| Immune complex: drug–antibody complexes land on the red cell and fix complement | Quinine, quinidine, some cephalosporins (ceftriaxone) | Acute intravascular haemolysis, kidney injury; DAT positive for C3d |
| True autoantibody induced by the drug | Methyldopa; also fludarabine | Behaves like warm AIHA; DAT IgG; persists for weeks after stopping |
- Diagnosis rests on: a time link to the drug, a positive DAT and recovery when the drug is stopped.
- Do not rechallenge.
- Treatment: stop the drug; transfuse if needed; steroids in severe autoantibody cases.
Methyldopa can make the DAT positive in many patients, but only a few actually haemolyse. Oxidant drugs in G6PD deficiency (primaquine, dapsone, sulphonamides) cause non-immune, DAT-negative haemolysis with Heinz bodies.
Non-immune acquired causes in brief
- Microangiopathic haemolytic anaemia: schistocytes with low platelets in TTP, HUS, DIC, malignant hypertension, HELLP.
- Mechanical: leaking prosthetic valves; long-distance running (march haemoglobinuria).
- PNH: loss of the GPI anchor (CD55, CD59) makes cells sensitive to complement; intravascular haemolysis, venous thrombosis at unusual sites (hepatic vein), pancytopenia; diagnosed by flow cytometry.
- Infection: malaria, Clostridium perfringens.
Expect: the lab signs of haemolysis (reticulocytes, unconjugated bilirubin, LDH, low haptoglobin) and the extra signs of intravascular haemolysis (haemoglobinuria, haemosiderinuria); direct versus indirect Coombs test; spherocytes in warm AIHA and how DAT separates it from hereditary spherocytosis; IgG warm versus IgM cold antibodies, C3d-only DAT, anti-I and Mycoplasma; secondary causes such as CLL and SLE; Evans syndrome; methyldopa, penicillin and quinine mechanisms; the Donath–Landsteiner IgG antibody; and first-line treatment (steroids for warm, warmth and rituximab for cold).
Quick revision
- Haemolysis = anaemia + reticulocytes + unconjugated bilirubin + LDH + low haptoglobin.
- Intravascular adds haemoglobinaemia, haemoglobinuria, haemosiderinuria, methaemalbumin.
- DAT positive = antibody or complement on the patient's own cells.
- Warm AIHA: IgG, spherocytes, spleen; CLL and SLE; prednisolone, then rituximab or splenectomy.
- Cold disease: IgM, C3d, anti-I, acrocyanosis, agglutination; Mycoplasma and EBV; keep warm, rituximab.
- PCH: IgG anti-P, Donath–Landsteiner, children after viral illness.
- Drugs: penicillin (hapten), quinine (immune complex), methyldopa (autoantibody).
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
What is the most useful single test to confirm autoimmune haemolysis?
The direct antiglobulin (Coombs') test, which shows antibody or complement coating the patient's red cells.
Why are spherocytes seen in warm AIHA?
Splenic macrophages remove pieces of IgG-coated membrane, so the cells lose surface area and become round.
Why is steroid treatment less useful in cold agglutinin disease?
Cells coated with complement are cleared mainly in the liver, and the IgM-producing clone responds poorly to steroids; rituximab and avoiding cold work better.
Which pneumonia is linked to haemolytic anaemia?
Mycoplasma pneumoniae, which induces cold IgM antibodies against the I antigen.
What is Evans syndrome?
Autoimmune haemolytic anaemia occurring together with immune thrombocytopenia.