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Autoimmune hemolytic anemia is caused by autoantibodies that react with RBCs at temperatures ≥37° C (warm antibody hemolytic anemia) or < 37° C (cold agglutinin disease). Hemolysis is usually extravascular. The direct antiglobulin (Coombs') test establishes the diagnosis and may suggest the cause. Treatment depends on the cause and may include corticosteroids, splenectomy, IV immune globulin, immunosuppressants, avoidance of blood transfusions, and withdrawal of drugs.

Etiology

Warm antibody hemolytic anemia: 

Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia (AIHA); it is more common among women. Autoantibodies in warm antibody hemolytic anemia generally react at temperatures ≥ 37° C. They may occur spontaneously or in association with certain disorders (SLE, lymphoma, chronic lymphocytic leukemia). Some drugs (eg, α-methyldopa, levodopa—see Table 3: Anemias Caused by Hemolysis: Drugs That Cause Warm Antibody Hemolytic Anemia) stimulate production of autoantibodies against Rh antigens (α-methyldopa-type of AIHA). Other drugs stimulate production of autoantibodies against the antibiotic–RBC-membrane complex as part of a transient hapten mechanism; the hapten may be stable (eg, high-dose penicillin, cephalosporins) or unstable (eg, quinidine, sulfonamides).

In warm antibody hemolytic anemia, hemolysis occurs primarily in the spleen. It is often severe and can be fatal. Most of the autoantibodies in warm antibody hemolytic anemia are IgG. Most are panagglutinins and have limited specificity.

Symptoms and Signs

Symptoms of warm antibody hemolytic anemia tend to be due to the anemia. If the disorder is severe, fever, chest pain, syncope, or heart failure may occur. Mild splenomegaly is typical.

Diagnosis

·        Assays for hemolytic anemia (eg, peripheral smear, reticulocyte count; sometimes urinary hemosiderin, serum haptoglobin)

·        Direct antiglobulin test

AIHA is suspected in patients with hemolytic anemia, particularly if symptoms are severe or other suggestive symptoms are present. Routine laboratory tests generally suggest extravascular hemolysis (eg, hemosiderinuria is absent; haptoglobin levels are near normal) unless anemia is sudden and severe or PCH is the cause. Spherocytosis and a high MCHC are typical.

AIHA is diagnosed by detection of autoantibodies with the direct antiglobulin (direct Coombs') test. Antiglobulin serum is added to washed RBCs from the patient; agglutination indicates the presence of immunoglobulin or complement (C) bound to the RBCs. Generally IgG is present in warm antibody hemolytic anemia, and C3 (C3b and C3d) in cold antibody disease. The test is ≤ 98% sensitive for AIHA; false-negative results can occur if antibody density is very low or if the autoantibodies are IgA or IgM. In general, the intensity of the direct antiglobulin test correlates with the number of molecules of IgG or C3 bound to the RBC and, roughly, with the rate of hemolysis. A complementary test consists of mixing the patient's plasma with normal RBCs to determine whether such antibodies are free in the plasma (the indirect antiglobulin [indirect Coombs'] test). A positive indirect antiglobulin test and a negative direct test generally indicate an alloantibody caused by pregnancy, prior transfusions, or lectin cross-reactivity rather than immune hemolysis. Even identification of a warm antibody does not define hemolysis, because 1/10,000 healthy blood donors has a positive test result.

Once AIHA has been identified by the Coombs' test, testing should differentiate between warm antibody hemolytic anemia and cold agglutinin disease as well as the mechanism responsible for warm antibody hemolytic anemia. This determination can often be made by observing the pattern of the direct antiglobulin reaction. Three patterns are possible:

·        The reaction is positive with anti-IgG and negative with anti-C3. This pattern is common in idiopathic AIHA and in the drug-associated or α-methyldopa-type of AIHA, usually warm antibody hemolytic anemia.

·        The reaction is positive with anti-IgG and anti-C3. This pattern is common in patients with SLE and idiopathic AIHA, usually warm antibody hemolytic anemia, and is rare in drug-associated cases.

·        The reaction is positive with anti-C3 but negative with anti-IgG. This pattern occurs in cold agglutinin disease. It is uncommon in idiopathic AIHA, warm antibody hemolytic anemia, when the IgG antibody is of low affinity, in some drug-associated cases, and in PCH.

Treatment

·        For drug-induced warm antibody hemolytic anemia, drug withdrawal, sometimes IV immune globulin

·        For idiopathic warm antibody hemolytic anemia, corticosteroids

·        For cold agglutinin disease, avoidance of cold

Treatment depends on the specific mechanism of the hemolysis.

Warm antibody hemolytic anemias: 

In drug-induced warm antibody hemolytic anemias, drug withdrawal decreases the rate of hemolysis. With α-methyldopa-type AIHA, hemolysis usually ceases within 3 wk; however, a positive Coombs' test may persist for > 1 yr. With hapten-mediated AIHA, hemolysis ceases when the drug is cleared from the plasma. Corticosteroids have only little effect in drug-induced hemolysis; infusions of immune globulin may be more effective.Corticosteroids (eg, prednisone1 mg/kg po once/day or higher doses) are the treatment of choice in idiopathic warm antibody AIHA. In very severe hemolysis, an initial loading dose of 100 to 200 mg is recommended. Most patients have an excellent response, which in about ¹/₃ is sustained after 12 to 20 wk of therapy. When stable RBC values are achieved, corticosteroids are tapered slowly. In patients who relapse after corticosteroid cessation or who are not helped by corticosteroids, splenectomy is done. About ¹/₃ to ¹/₂ of patients have a sustained response after splenectomy. In cases of fulminant hemolysis, plasma exchange has been used. For less severe but uncontrolled hemolysis, immune globulin infusions have provided temporary control. Long-term management with immunosuppressants (including cyclosporine) has been effective in patients in whom corticosteroids and splenectomy have been ineffective.

The presence of panagglutinating antibodies in warm antibody hemolytic anemia makes cross-matching of donor blood difficult. In addition, transfusions often superimpose an alloantibody on the autoantibody, accelerating hemolysis. Thus, transfusions should be avoided whenever possible. When necessary, they should be given only in small aliquots (100 to 200 mL over 1 to 2 h, with monitoring for hemolysis).

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