Overview
Autoimmune haemolytic anaemia (AIHA) is a condition in which the immune system mistakenly makes antibodies against the body's own red blood cells. These antibodies mark red cells for destruction, so they are broken down faster than the bone marrow can replace them, causing anaemia.
AIHA can develop suddenly or gradually. Symptoms include tiredness, breathlessness, pale or yellow skin and dark urine. It can occur on its own or alongside other conditions, such as lymphoma, chronic lymphocytic leukaemia, lupus or infections, or as a reaction to medicines. There are two main types, warm and cold, which behave differently and need different treatments. Most people respond well to treatment, though relapses are common.
When to get urgent help
Seek urgent care for severe tiredness or breathlessness, chest pain, fainting, very dark urine, sudden yellow skin, or signs of a blood clot.
Causes and risk factors
- Primary (idiopathic): no underlying cause found
- Secondary, linked to:
- Blood cancers: chronic lymphocytic leukaemia, lymphoma
- Autoimmune diseases: lupus, rheumatoid arthritis, autoimmune thyroid disease
- Infections: Mycoplasma pneumoniae, Epstein-Barr virus, COVID-19 and others (often cold type)
- Medicines: some antibiotics, fludarabine, immune checkpoint inhibitors
- Immune deficiencies
- After stem cell transplant
How it develops (pathophysiology)
Normal red cell life cycle
Red blood cells are made in the bone marrow and live about 120 days. Old cells are removed by macrophages in the spleen and liver. The bone marrow normally replaces them at the same rate, keeping haemoglobin stable. When red cells break down, haemoglobin is converted to bilirubin, which the liver processes.
What goes wrong
In AIHA, autoantibodies bind to proteins on the red cell surface:
Warm AIHA (the most common, about 70 to 80 percent):
- IgG antibodies bind best at body temperature (37°C).
- Coated red cells are recognised by Fc receptors on macrophages in the spleen.
- Macrophages engulf whole cells or bite off parts of the membrane, forming smaller, rounder cells called spherocytes, which are fragile and destroyed quickly.
- This is mainly extravascular haemolysis (destruction outside the bloodstream, in the spleen).
Cold agglutinin disease (cold AIHA):
- IgM antibodies bind best at low temperatures, such as in the fingers, toes, ears and nose.
- They cause red cells to clump (agglutinate) and activate complement, part of the immune system.
- Complement-coated cells are removed mainly in the liver, and sometimes complement punches holes in cells, causing intravascular haemolysis (destruction within blood vessels).
- Often caused by a small clone of abnormal B cells.
Body's response
- The bone marrow increases red cell production, raising the reticulocyte count (young red cells).
- Increased breakdown raises bilirubin and lactate dehydrogenase (LDH), and lowers haptoglobin, a protein that binds free haemoglobin.
Why the symptoms happen
- Tiredness, breathlessness, pale skin and palpitations result from anaemia.
- Yellow skin and eyes (jaundice) result from increased bilirubin.
- Dark urine reflects haemoglobin or bilirubin breakdown products.
- Enlarged spleen reflects increased destruction of cells there in warm AIHA.
- Blue or painful fingers in the cold (acrocyanosis) occur in cold agglutinin disease, as red cells clump in cold extremities.
How treatment acts on the mechanism
Corticosteroids reduce antibody production and macrophage activity in warm AIHA. Rituximab depletes B cells that make antibodies. Splenectomy removes the main site of destruction in warm AIHA. In cold agglutinin disease, keeping warm prevents antibody binding, and sutimlimab blocks complement activation. Transfusions support people with severe anaemia, using warmed blood in cold AIHA.
Types
- Warm AIHA: IgG antibodies; most common
- Cold agglutinin disease: IgM antibodies
- Cold agglutinin syndrome: secondary to infection or lymphoma
- Paroxysmal cold haemoglobinuria: rare, often after viral infections in children
- Mixed AIHA: features of both
- Drug-induced immune haemolytic anaemia
Signs and symptoms
- Tiredness and weakness
- Breathlessness
- Pale skin
- Yellow skin or eyes
- Dark urine
- Fast heartbeat
- Dizziness
- Enlarged spleen
- In cold types: numbness, pain or bluish colour of fingers, toes, ears or nose in the cold
How it is diagnosed
- Full blood count: anaemia
- Blood film: spherocytes in warm AIHA, clumping in cold AIHA
- Reticulocyte count: usually raised
- Markers of haemolysis: raised bilirubin and LDH, low haptoglobin
- Direct antiglobulin test (DAT, Coombs test): shows antibodies or complement on red cells
- Cold agglutinin titre
- Tests for underlying causes: CT scan, lymphoma or leukaemia tests, autoimmune markers, infection tests
Possible complications
- Severe anaemia and heart strain
- Blood clots (thrombosis), especially in warm AIHA
- Gallstones from high bilirubin
- Infections with immunosuppressive treatment
- Relapse
Goals of treatment
Treatment aims to stop red cell destruction, correct anaemia, treat underlying causes and reduce relapse.
Medicines
Warm AIHA:
- Corticosteroids (prednisolone), first-line
- Rituximab, often added early or for relapse
- Other immunosuppressants: azathioprine, mycophenolate, ciclosporin
- Fostamatinib or newer agents in some cases
Cold agglutinin disease:
- Rituximab, alone or with bendamustine
- Sutimlimab (complement C1s inhibitor) where available
- Steroids are usually not effective
General:
- Folic acid supplements
- Blood thinners to prevent clots in some people
Other treatments
- Blood transfusion for severe anaemia
- Splenectomy for warm AIHA not responding to medicines
- Keeping warm, avoiding cold drinks and cold exposure in cold AIHA
- Plasma exchange in severe cold AIHA in emergencies
Living with it and prevention
- Avoid cold exposure if you have cold agglutinin disease
- Take medicines as prescribed and do not stop steroids suddenly
- Get vaccinated, especially before splenectomy or rituximab
- Report symptoms of infection or anaemia early
Monitoring and follow-up
Regular blood tests monitor haemoglobin, reticulocytes and haemolysis markers. Steroids are tapered slowly. Bone health and blood sugar are monitored during steroid treatment.
Outlook
Most people with warm AIHA respond to treatment, though relapses are common. Cold agglutinin disease is usually chronic but manageable. Outcomes depend on underlying causes.
Special considerations
- Children: AIHA is often short-lived after infections
- Older adults: more likely to have an underlying lymphoma or leukaemia
- Pregnancy: needs specialist care
