Autoimmune hemolytic anemia

Autoimmune hemolytic anemia is caused by antibodies that interact with red blood cells at temperatures of 37°C (warm antibody hemolytic anemia) or temperatures <37°C (cold agglutinin hemolytic anemia).

Hemolysis is usually extravascular. The direct antiglobulin (Coombs) test establishes the diagnosis and may suggest the cause of hemolysis. Treatment depends on the cause of hemolysis and includes glucocorticoids, intravenous immunoglobulin, immunosuppressants, splenectomy, avoidance of blood transfusions, and/or drug withdrawal.

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Causes of autoimmune hemolytic anemia

Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia (AIHA), affecting women more often with this type of anemia. Autoantibodies usually react at a temperature of 37 °C. They can occur spontaneously or in combination with some other diseases (SLE, lymphoma, chronic lymphocytic leukemia). Certain drugs (eg, methyldopa, levodopa) stimulate the production of autoantibodies against Rh antigens (methyldopa type AIHA). Some drugs stimulate the production of autoantibodies against the antibiotic-erythrocyte membrane complex as part of a transient hapten mechanism; the hapten may be stable (eg, high doses of penicillin, cephalosporins) or unstable (eg, quinidine, sulfonamides). In warm antibody hemolytic anemia, hemolysis occurs predominantly in the spleen, the process is often intense and can be fatal. Most autoantibodies in this type of hemolysis are IgG, a significant portion are panagglutinins and have limited specificity.

Drugs that can cause warm antibody hemolytic anemia

Autoantibodies	Stable	Unstable or unknown mechanism
Cephalosporins Diclofenac Ibuprofen Interferon Levodopa Mefenamic acid Methyldopa Procainamide Teniposide Thioridazine Tolmetin	Cephalosporins Penicillins Tetracycline Tolbutamide	Amphotericin B Antazoline Cephalosporins Chlorpropamide Diclofenac Diethylstilbestrol Doxepin Hydrochlorothiazide Isoniazid Beta-aminosalicylic acid Probenecid Quinidine Quinine Rifampicin Sulfonamides Thiopental Tolmetin

Cold agglutinin disease (Cold antibody disease) is caused by autoantibodies that react at temperatures below 37°C. It is sometimes seen in infections (especially mycoplasmal pneumonia or infectious mononucleosis) and lymphoproliferative disorders; about 1/3 of all cases are idiopathic. Cold agglutinin disease is the main form of hemolytic anemia in elderly patients. Infections usually cause the acute form of the disease, while idiopathic forms tend to be chronic. Hemolysis occurs mainly in the extravascular mononuclear phagocytic system of the liver. Anemia is usually moderate (hemoglobin > 75 g/L). Antibodies in this form of anemia are IgM. The degree of hemolysis is more pronounced, the higher the temperature (closer to normal body temperature) at which these antibodies react with erythrocytes.

Paroxysmal cold hemoglobinuria (PCH, Donath-Landsteiner syndrome) is a rare type of cold agglutinin disease. Hemolysis is provoked by cooling, which can even be local (for example, when drinking cold water, washing hands with cold water). Autohemolysins IgG bind to erythrocytes at low temperatures and cause intravascular hemolysis after warming. This occurs most often after a non-specific viral infection or in healthy people, and is found in patients with congenital or acquired syphilis. The severity and speed of development of anemia varies and can have a fulminant course.

Symptoms of autoimmune hemolytic anemia

Symptoms of warm antibody hemolytic anemia are due to the presence of anemia. In severe cases, there is an increase in body temperature, chest pain, fainting, and signs of heart failure. Moderate splenomegaly is typical.

Cold agglutinin disease occurs in acute or chronic forms. Other cryopathic symptoms may be present (eg, acrocyanosis, Raynaud's phenomenon, cold-associated occlusive disorders). Symptoms of PNH may include severe back and leg pain, headache, nausea, diarrhea, dark brown urine; splenomegaly may occur.

Diagnosis of autoimmune hemolytic anemia

AIHA is suspected in patients with hemolytic anemia, particularly if symptoms are severe and other characteristic features are present. Routine laboratory tests usually confirm the presence of extravascular hemolysis (eg, absence of hemosiderinuria, normal haptoglobin levels) unless the anemia is sudden and severe or is due to PNH. Spherocytosis and a high MCHC are typical features.

AIHA is diagnosed by detecting autoantibodies with the direct antiglobulin (Coombs) test. Antiglobulin serum is added to washed red blood cells from the patient; the presence of agglutination indicates the presence of immunoglobulin, usually IgG, or complement component C3 bound to the red cell surface. The sensitivity of the test for AIHA is about 98%. If the antibody titer is very low or if the antibodies are IgA and IgM, false-negative tests are possible. In general, the intensity of the direct antiglobulin test correlates with the number of IgG or complement component C3 molecules bound to the red cell membrane and approximately with the degree of hemolysis. The indirect antiglobulin (Coombs) test involves mixing the patient's plasma with normal red cells to detect the presence of antibodies in the plasma. A positive indirect antiglobulin test and a negative direct test usually indicate the presence of alloantibodies caused by pregnancy, previous transfusions, or lectin cross-reactivity, rather than the presence of autoimmune hemolysis. It should be noted that the detection of warm antibodies alone does not determine the presence of hemolysis, since 1/10,000 normal blood donors test positive for these antibodies.

When establishing a diagnosis of autoimmune hemolytic anemia using the Coombs test, it is necessary to differentiate between warm antibody hemolytic anemia and cold agglutinin disease, as well as to determine the mechanism responsible for warm antibody hemolytic anemia. This diagnosis can often be made using the direct antiglobulin reaction. Three options are possible:

1. the reaction is positive with anti-IgG and negative with anti-C3. This pattern is typical in idiopathic autoimmune hemolytic anemia, as well as in drug-induced or methyldopa-induced autoimmune hemolytic anemia, usually in warm antibody hemolytic anemia;
2. the reaction is positive with anti-IgG and anti-C3. This pattern is typical in cases of SLE or idiopathic autoimmune hemolytic anemia with warm antibodies and less commonly in drug-associated cases;
3. the reaction is positive with anti-C3 and negative with anti-IgG. This is seen in idiopathic autoimmune hemolytic anemia with warm antibodies, when there are low-affinity IgG, in individual drug-associated cases, in Cold agglutinin disease, paroxysmal cold hemoglobinuria.

Other diagnostic tests used in autoimmune hemolytic anemia are usually inconclusive. In cold agglutinin disease, red blood cells agglutinate in blood smears, and automated analyzers often detect an elevated MCV and falsely low hemoglobin levels. After warming the hands and recalculating the results, the values change toward normal. Differential diagnosis between warm antibody hemolytic anemia and cold agglutinin disease can be made by determining the temperature at which the direct antiglobulin test is positive. A positive test at a temperature > 37 °C indicates warm antibody hemolytic anemia, while a positive test at low temperatures indicates cold agglutinin disease.

If the presence of UCH is suspected, the Donath-Landsteiner test, which is specific for UCH, should be performed. Laboratory tests for syphilis are recommended.

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Treatment of autoimmune hemolytic anemia

In drug-induced hemolytic anemia with warm antibodies, drug withdrawal reduces the intensity of hemolysis. In methyldopa-type autoimmune hemolytic anemia, hemolysis usually stops within 3 weeks, but a positive Coombs test may persist for more than 1 year. In hapten-associated autoimmune hemolytic anemia, hemolysis stops after the blood plasma is cleared of the drug. Glucocorticoids have a moderate effect in drug-induced hemolysis, while Ig infusions are more effective.

Glucocorticoids (eg, prednisolone 1 mg/kg orally twice daily) are the treatment of choice for idiopathic autoimmune warm antibody hemolytic anemia. When hemolysis is severe, the recommended initial dose is 100 to 200 mg. Most patients have a good response to therapy, which is maintained after 12 to 20 weeks of therapy in one-third of cases. When stabilization of the red blood cell count is achieved, the glucocorticoid dose should be tapered slowly. Patients with recurrent hemolysis after discontinuation of glucocorticoids or with initial failure of this treatment should undergo splenectomy. After splenectomy, a good response is observed in one-third to one-half of patients. In case of fulminant hemolysis, plasmapheresis is effective. In less severe but uncontrolled hemolysis, immunoglobulin infusions provide temporary control. Long-term immunosuppressant therapy (including cyclosporine) may be effective in recurrence of the disease after glucocorticoid therapy and splenectomy.

The presence of panagglutinating antibodies in warm antibody hemolytic anemia makes cross-matching of donor blood difficult. In addition, transfusions often result in the summation of alloantibody and autoantibody activity, stimulating hemolysis. Therefore, blood transfusions should be avoided whenever possible. If necessary, blood transfusions should be performed in small quantities (100-200 ml in 1-2 hours) under hemolysis control.

In acute cases of Cold Agglutinin Disease, only supportive therapy is given, since the anemia is self-limiting. In chronic cases, treatment of the underlying disease often controls the anemia. However, in chronic idiopathic variants, moderate anemia (hemoglobin from 90 to 100 g / l) can persist throughout life. Cooling should be avoided. Splenectomy does not give a positive effect. The effectiveness of immunosuppressants is limited. The use of blood transfusions requires caution; if blood transfusions are necessary, the blood should be heated in thermostatic heaters. The effectiveness of transfusions is low, since the lifespan of allogeneic red blood cells is significantly shorter than that of autologous ones.

In case of PCH, treatment consists of strictly limiting exposure to cold. Splenectomy is not effective. Immunosuppressants have been shown to be effective, but their use should be limited to cases of progression of the process or idiopathic variants. Therapy of existing syphilis can cure PCH.