Autoimmune Haemolytic Anaemia
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Direct answer
Autoimmune haemolytic anaemia is destruction of red cells by autoantibodies, confirmed by a positive direct antiglobulin (Coombs) test and classified by the temperature at which the antibody binds. Warm antibody disease, usually IgG, causes extravascular haemolysis in the spleen and may be idiopathic or secondary to lupus or lymphoma. Cold agglutinin disease, usually IgM, causes complement-mediated haemolysis that worsens with cold exposure. Corticosteroids are first-line for warm disease, while rituximab is the mainstay for cold agglutinin disease.
What you must remember
- Warm antibody type: IgG, optimal at body temperature, with spherocytes on smear and extravascular haemolysis; the direct Coombs test is typically positive for IgG with or without C3.
- Cold agglutinin type: IgM, active below about 30 degrees Celsius, causing acrocyanosis, complement-mediated haemolysis and haemoglobinuria; the Coombs test is positive for C3d.
- Mycoplasma link: transient cold autoimmune haemolysis can follow Mycoplasma pneumoniae infection, usually resolving with the infection.
- Warm disease treatment: high-dose oral prednisolone with taper is first-line, with rituximab, splenectomy or other immunosuppression as later options.
- Transfusion: reserved for life-threatening anaemia, because the autoantibody complicates cross-matching and transfused cells are also destroyed.
- Drug-induced immune haemolysis: methyldopa is the classic cause of a warm IgG antibody, and penicillin and quinine can also produce immune haemolysis.
- Evans syndrome: autoimmune haemolysis coexisting with immune thrombocytopenia.
A worked case: fatigue and jaundice with a positive Coombs
A 40-year-old woman presents with fatigue and jaundice, with haemoglobin of 7.4 g/dL, a reticulocyte count of 14 percent, raised lactate dehydrogenase and low haptoglobin. The smear shows spherocytes, and the direct Coombs test is positive for IgG.
- Establish warm disease: A positive IgG direct Coombs test in a patient who is haemolysing establishes warm autoimmune haemolysis.
- Search for a cause: Lupus serology, lymphoma screening, hepatitis and HIV testing are sent, along with a drug history for methyldopa or penicillin.
- Start steroids: High-dose prednisolone with taper is started, and transfusion is avoided unless the anaemia becomes life-threatening.
- Contrast cold disease: A 65-year-old with acrocyanosis, fatigue after cold exposure, a haemoglobin of 9 g/dL and an IgM cold agglutinin with C3d on the Coombs test has cold agglutinin disease. Management centres on keeping warm, avoiding cold exposure and considering rituximab, since steroids are much less effective here.
- Look for a trigger: Mycoplasma serology or a recent infection history may explain a transient picture, and the cause is sought in every case.
Where the examiner sets the trap
Four traps recur in examination questions on this condition.
- Trap: treating any positive direct Coombs test as diagnostic. Correct: a positive result with no haemolysis may reflect a drug effect, transfusion or a benign finding, so it does not by itself make the diagnosis.
- Trap: trusting the MCV and red cell count in cold agglutinin disease. Correct: cold agglutinins falsely raise the MCV and lower the red cell count on automated analysers, so a warm smear review avoids a misleading result.
- Trap: steroids as the answer for every case. Correct: steroids are the answer for warm disease but rarely the right answer for cold agglutinin disease.
- Trap: ignoring the drug history in a warm IgG picture. Correct: methyldopa is the classic viva cause, and its warm IgG antibody settles once the drug is withdrawn.
Frequently asked questions
What does a positive direct Coombs test indicate?
A positive direct antiglobulin test shows that immunoglobulin or complement is attached to red cells in vivo, supporting autoimmune haemolytic anaemia when haemolysis is present. Drug-induced immune haemolysis, transfusion reactions and haemolytic disease of the newborn also give positive results.
Which drug is the classic cause of immune haemolytic anaemia?
Methyldopa is the classic drug cause, producing a warm IgG antibody that mimics autoimmune haemolytic anaemia. Stopping the drug is the first step, although the direct Coombs test may remain positive for some time afterwards.
Why is cold agglutinin disease treated differently from warm antibody disease?
Cold agglutinin disease is driven by IgM antibodies that fix complement, so it responds poorly to corticosteroids and is managed by avoiding cold and using rituximab. Warm antibody disease responds to corticosteroids as first-line therapy.
When is transfusion justified in autoimmune haemolytic anaemia?
Transfusion is reserved for life-threatening anaemia, because the autoantibody makes cross-matching difficult and transfused red cells are also destroyed. When it is needed, compatible or least-incompatible blood is chosen with blood bank expertise.