Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs (RBCs originating from outside the person themselves, e.g. in the case of a blood transfusion) AIHA is a relatively rare condition, affecting one to three people per 100,000 per year. There are two main types of autoimmune hemolytic anemia:warm antibody hemolytic anemia and cold antibody hemolytic anemia.
Symptoms may include unusual weakness and fatigue with tachycardia and breathing difficulties, jaundice, dark urine and/or splenomegaly. AIHA can be primary (idiopathic) or result from an underlying disease or medication. The condition may develop gradually or occur suddenly.
The causes of AIHA are poorly understood. The disease may be primary, or secondary to another underlying illness. The primary illness is idiopathic (the two terms used synonymously). Idiopathic AIHA accounts for approximately 50% of cases. Secondary AIHA can result from many other illnesses. Warm and cold type AIHA each have their own more common secondary causes. The most common causes of secondary warm-type AIHA include lymphoproliferative disorders (e.g., chronic lymphocytic leukemia, lymphoma) and other autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma, ulcerative colitis). Less common causes of warm-type AIHA include neoplasms other than lymphoid, and infection. Secondary cold type AIHA is also caused primarily by lymphoproliferative disorders, but is also commonly caused by infection, especially by mycoplasma, viral pneumonia, infectious mononucleosis, and other respiratory infections. Less commonly, it can be caused by concomitant autoimmune disorders.
Drug-induced AIHA, though rare, can be caused by a number of drugs, including α-methyldopa and penicillin. This is a type II immune response in which the drug binds to macromolecules on the surface of the RBCs and acts as an antigen. Antibodies are produced against the RBCs, which leads to complement activation. Complement fragments, such as C3a, C4a and C5a, activate granular leukocytes (e.g., neutrophils), while other components of the system (C6, C7, C8, C9) either can form the membrane attack complex (MAC) or can bind the antibody, aiding phagocytosis by macrophages (C3b). This is one type of "penicillin allergy".
Diagnosis is made by first ruling out other causes of hemolytic anemia, such as G6PD, thalassemia, sickle-cell disease, etc. Clinical history is also important to elucidate any underlying illness or medications that may have led to the disease.
Following this, laboratory investigations are carried out to determine the etiology of the disease. A positive DAT test has poor specificity for AIHA (having many differential diagnoses); so supplemental serological testing is required to ascertain the cause of the positive reaction. Hemolysis must also be demonstrated in the lab. The typical tests used for this are a CBC with peripheral smear, bilirubin, LDH (in particular with isoenzyme 1), haptoglobin and urine hemoglobin.
Evidence for hemolysis
- Increased red cell breakdown
- Elevated serum bilirubin (unconjugated)
- Excess urinary urobilinogen
- Reduced plasma haptoglobin
- Raised serum lactic dehydrogenase (LDH)
- Increased red cell production:
- Erythroid hyperplasia of the bone marrow
Treatment may include corticosteroids such as prednisone, splenectomy, immunosuppressive drugs and/or blood transfusions.
Efficacy of treatment depends on the correct diagnosis of either warm- or cold-type AIHA.
Warm-type AIHA is usually a more insidious disease, not treatable by simply removing the underlying cause. First-line therapy for this is usually with corticosteroids, such as prednisolone. Following this, other immunosuppressants are considered, such as rituximab, danazol, cyclophosphamide, azathioprine, or cyclosporine.
Cold agglutinin disease is treated by avoiding the cold or sometimes with rituximab. Removal of the underlying cause is also important.
Paroxysmal cold hemoglobinuria is treated by removing the underlying cause, such as infection.