Haematology: Autoimmune haemolytic anaemia

Diagnosing and managing autoimmune haemolytic anaemia. By Professor David Roberts

Autoimmune haemolysis: large, bluish reticulocytes and damaged, rounded or spherocytic red cells (Photograph: David Roberts and John Burthem)
Autoimmune haemolysis: large, bluish reticulocytes and damaged, rounded or spherocytic red cells (Photograph: David Roberts and John Burthem)

Autoimmune haemolytic anaemia (AIHA) is due to shortened red cell survival that is not fully compensated for by increased bone marrow production. It is caused by binding of autoantibodies to red cell membrane antigens and the destruction or removal of red cells.

There are two main types. Warm AIHA (80-90% of cases) is usually caused by IgG autoantibodies binding to red cells at 37 degsC, activating complement and causing removal of cells by macrophages (known as extravascular haemolysis).

Cold AIHA (10-15% of cases) is caused by IgM or occasionally IgG autoantibodies that bind strongly to red cells at <37°C, giving rise predominantly to intravascular haemolysis with or without acrocyanosis (purplish discoloration of the distal limbs, fingers and toes) due to occlusion of peripheral blood vessels in the cold.

Two forms of cold AIHA are cold haemagglutinin disease (CHAD) and paroxysmal cold haemoglobinuria (PCH), which is caused by antibody binding to erythrocytes in the cold, but activating complement and causing haemolysis at 37°C.

Mixed AIHA, which is caused by both warm IgG and cold IgM autoantibodies, is uncommon. All forms of AIHA can occur in association with other disorders and may be induced by a variety of drugs.

Most cases of AIHA have no underlying cause, but it has been associated with a variety of conditions that disturb immune function. These include lymphoma, chronic lymphatic leukaemia, other autoimmune disorders or secondary immunodeficiency, and infections (for example, Mycoplasma pneumoniae, infectious mononucleosis).

AIHA may be the presenting feature of underlying disease, or it may precede the disease by months to years. Many drugs have also been linked with AIHA, for example, penicillin and cephalosporins, quinine and L-dopa.

Onset may be acute or insidious with pallor and fatigue, dyspnoea, jaundice, some splenomegaly and mild fever. Severity ranges from mild to hyperacute haemolysis. Patients with cardiovascular or cerebrovascular disease can present with angina, TIA or stroke.

Presenting symptoms and a history, including drug history, are crucial to distinguish primary from secondary AIHA.

MCV may be mildly raised and the blood film may have a bluish tinge (polychromasia); some red cells may become rounded (spherocytosis). Autoantibodies and/or complement binding to the red cell membrane may be detected by the direct antiglobulin test (DAT) or direct Coombs' test.

Platelets may be low in systemic lupus erythematosus or chronic lymphatic leukaemia, and red cell breakdown products, such as bilirubin or lactate dehydrogenase (LDH), may be elevated. Serum immunoglobulin levels or an HIV test may reveal causes of immunodeficiency, while bone marrow tests may indicate chronic lymphoproliferative disease, particularly in older patients or those with CHAD.

The mainstay of treatment for warm AIHA is corticosteroids. Many patients respond well to high-dose prednisolone (1mg/kg) for two weeks, given with an H2-blocker to reduce risk of dyspepsia or ulceration and folic acid to prevent deficiency secondary to high cell turnover.

Common side-effects of high-dose steroids are mood swings, bad dreams and weight gain. Dyspepsia or oral thrush may require treatment.

If a response is seen, the steroid dose can be reduced steadily and stopped. About one-third of patients respond quickly with few recurrences, one-third may relapse and one-third do not respond or have a partial response but cannot reduce the dose without haemolysis returning. Azathioprine may be used to spare the use of steroids.

None of the second-line treatments has a clear superiority. High-dose IV immunoglobulin, anti-D, splenectomy by keyhole surgery and rituximab have all been successfully used. Transfusions may be life-saving if haemolysis is severe.

Warm AIHA requires careful follow-up, measuring Hb, reticulocytes and LDH to detect incipient relapses and monitor for any underlying disease.

Types of AIHA
  • Warm Idiopathic or secondary to systemic lupus erythematosus, lymphoma, chronic lymphatic leukaemia, Evans syndrome.
  • Cold CHAD or PCH; may be idiopathic or secondary to M pneumoniae, lymphoma, infectious mononucleosis or other viral infection.
  • Drug-related Drug absorbed on red cell surface, for example, penicillins, cephalosporins; or immune complex mediated, for example, sulfonamides, sulfasalazine.

Primary CHAD is often due to a monoclonal autoantibody in patients with lymphoproliferative disorders. CHAD may be secondary to infection with Epstein-Barr virus, cytomegalovirus or M pneumoniae.

Patients present with a mild haemolytic anaemia made worse by the cold. They may show acrocyanosis, skin ulceration, Raynaud's phenomenon, or haemoglobinuria secondary to intravascular haemolysis.

Acute transient PCH is characterised by sudden onset acute intravascular haemolysis and is seen in young children after measles, mumps, chickenpox or unidentified viral illness. Chronic PCH with intermittent haemolysis is a rare manifestation of syphilis.

FBC will show anaemia and a blood film at room temperature may show gross agglutination of red cells, reticulocytosis, polychromasia and occasional spherocytes. Bilirubin and LDH are raised and urine examination may show haemoglobinuria or haemosiderinuria.

Complement binding
A positive DAT with complement only is the usual finding in CHAD because IgM autoantibodies cause complement binding, but the antibody no longer binds to red cells at 37 degsC. In PCH, the biphasic antibody binding to red cells at 37 degsC and lysing them at 20 degsC is detected by the Donath-Landsteiner test.

Some patients have warm and cold autoantibodies and have a positive DAT with IgG, IgM and complement, and should be identified because they respond well to steroids. For CHAD, further investigation for lymphoproliferative disease would include serum immunoglobulin electrophoresis, CT scan, bone marrow biopsy and appropriate serological testing.

Many patients with chronic mild haemolysis in cold AIHA only require advice to avoid the cold, dress warmly and take folic acid. Any underlying condition should be treated.

Steroids and splenectomy rarely help. Chlorambucil, alkylating agents and other chemotherapeutic agents have been used in difficult cases. Rituximab may be effective but carries a considerable risk of immunosuppression.

Awareness and a high index of suspicion of sudden intravascular haemolysis are needed to spot acute PCH. These children should be kept warm and transfused only if haemolysis is severe, using blood warmers to reduce risk of haemolysis.

Cold AIHA also requires close supervision, to minimise haemolysis and treat any underlying condition.

  • Professor Roberts is a consultant haematologist at NHS Blood and Transplant and University of Oxford

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