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.
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.
Cold agglutinin disease:
Cold agglutinin disease (cold antibody disease) is caused by autoantibodies that react at temperatures < 37° C. It sometimes occurs with infections (especially mycoplasmal pneumonias or infectious mononucleosis) and lymphoproliferative states; about ½ of cases are idiopathic, which is the common form in older adults. Infections tend to cause acute disease, whereas idiopathic disease tends to be chronic. The hemolysis occurs largely in the extravascular mononuclear phagocyte system of the liver. The anemia is usually mild (Hb > 7.5 g/dL). Autoantibodies in cold agglutinin disease are usually IgM. The higher the temperature (ie, the closer to normal body temperature) at which these antibodies react with the RBC, the greater the hemolysis.
Paroxysmal cold hemoglobinuria:
Paroxysmal cold hemoglobinuria (PCH; Donath-Landsteiner syndrome) is a rare type of cold agglutinin disease. Hemolysis results from exposure to cold, which may even be localized (eg, from drinking cold water, from washing hands in cold water). An IgG autohemolysin binds to RBCs at low temperatures and causes intravascular hemolysis after warming. It occurs most often after a nonspecific viral illness or in otherwise healthy patients, although it occurs in some patients with congenital or acquired syphilis. The severity and rapidity of development of the anemia varies and may be fulminant.
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.
Cold agglutinin disease manifests as an acute or chronic hemolytic anemia. Other cryopathic symptoms or signs may be present (eg, acrocyanoses, Raynaud's syndrome, cold-associated occlusive changes). Symptoms of PCH may include severe pain in the back and legs, headache, vomiting, diarrhea, and passage of dark brown urine; hepatosplenomegaly may be present.
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:
Other studies can suggest the cause of AIHA but are not definitive. In cold agglutinin disease, RBCs clump on the peripheral smear, and automated cell counts often reveal an increased MCV and spuriously low Hb due to such clumping; hand warming of the tube and recounting result in values significantly closer to normal. Warm antibody hemolytic anemia can often be differentiated from cold agglutinin disease by the temperature at which the direct antiglobulin test is positive; a test that is positive at temperatures ≥ 37° C indicates warm antibody hemolytic anemia, whereas a test that is positive at lower temperatures indicates cold agglutinin disease.
If PCH is suspected, the Donath-Landsteiner test, which is specific for PCH, should be done. Testing for syphilis is recommended.
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, prednisone 1 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).
Cold agglutinin disease:
Treatment is largely supportive in acute cases, because the anemia may be self-limited. In chronic cases, treatment of the underlying disorder often controls the anemia. However, in idiopathic chronic cases, mild anemia (Hb, 9 to 10 g/dL) may persist for life. Avoidance of cold exposure is often helpful. Splenectomy is of no value. Immunosuppressants have only modest effectiveness. Transfusions should be given sparingly, with the blood warmed through an on-line warmer. Because the autologous RBCs have already survived the autoantibodies, autologous cell survival is better than that of transfused cells, limiting the efficacy of transfusion.
In PCH, therapy consists of strict avoidance of exposure to cold. Splenectomy is of no value. Immunosuppressants have been effective but should be restricted to patients with progressive or idiopathic cases. Treatment of concomitant syphilis may cure PCH.
Last full review/revision February 2009 by Alan E. Lichtin, MD
Content last modified February 2012