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Autoimmune Hemolytic Anemia

By

Evan M. Braunstein

, MD, PhD, Johns Hopkins School of Medicine

Last full review/revision Sep 2020| Content last modified Sep 2020
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Autoimmune hemolytic anemia is caused by autoantibodies that react with red blood cells at temperatures 37° C (warm antibody hemolytic anemia) or < 37° C (cold agglutinin disease). Hemolysis is usually extravascular. The direct antiglobulin (direct 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 (except in cases of life-threatening anemia), avoidance of triggers (eg, cold), and withdrawal of drugs.

Etiology

Autoimmune hemolytic anemia is caused by abnormalities extrinsic to the red blood cell (RBC).

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. Autoimmune hemolytic anemia may be classified as

Some drugs (eg, alpha-methyldopa, levodopa—see table Drugs That Cause Warm Antibody Hemolytic Anemia) stimulate production of autoantibodies against Rh antigens (alpha-methyldopa-type of autoimmune hemolytic anemia). 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 and is not due to direct lysis of RBCs. 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. Causes include

  • Idiopathic (usually associated with a clonal B-cell population)

  • Infections, especially mycoplasmal pneumonias or infectious mononucleosis (antibodies are directed against the I or I antigen)

  • Lymphoproliferative disorders (antibodies are usually directed against the I antigen)

Infections tend to cause acute disease, whereas idiopathic disease (the common form in older adults) tends to be chronic. The hemolysis occurs largely in the extravascular mononuclear phagocyte system of the liver and spleen. The anemia is usually mild (hemoglobin > 7.5 g/dL [70.5 g/L]). Autoantibodies in cold agglutinin disease are usually IgM. Antibody thermal amplitude is more important than its titer; 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. PCH is more common in children. Hemolysis results from exposure to cold, which may even be localized (eg, from drinking cold water, from washing hands in cold water). An IgG antibody binds to the P antigen on RBCs at low temperatures and causes intravascular hemolysis and hemoglobinuria 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. In children, this disease is often self-resolving.

Table
icon

Drugs That Can Cause Warm Antibody Hemolytic Anemia

Mechanism

Drugs

Autoantibody to Rh antigens

Cephalosporins

Diclofenac

Ibuprofen

Interferon alfa

Levodopa

Mefenamic acid

Alpha-methyldopa

Procainamide

Teniposide

Thioridazine

Tolmetin

Stable hapten

Cephalosporins

Fluorescein sodium

Penicillins

Tetracycline

Tolbutamide

Unstable hapten or unknown mechanism

p-Aminosalicylic acid

Amphotericin B

Antazoline

Cephalosporins

Chlorpropamide

Diclofenac

Diethylstilbestrol

Doxepin

Hydrochlorothiazide

Isoniazid

Probenecid

Quinidine

Quinine

Rifampin

Sulfonamides

Thiopental

Tolmetin

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 liver 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 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.

Diagnosis

  • Peripheral smear, reticulocyte count, lactic dehydrogenase (LDH)

  • Direct antiglobulin test

Autoimmune hemolytic anemia should be suspected in any patient with a hemolytic anemia (as suggested by the presence of anemia and reticulocytosis). The peripheral smear usually shows microspherocytes and a high reticulocyte count with few or no schistocytes, indicating extravascular hemolysis. Laboratory tests typically indicate hemolysis (eg, elevated LDH and indirect bilirubin). A high mean corpuscular volume (MCV) may occur due to extreme reticulocytosis. Hemolytic anemia in the setting of a low reticulocyte count is rare but can occur and is suggestive of severe disease.

Autoimmune hemolytic anemia 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. In warm antibody hemolytic anemia, IgG is nearly always present, and C3 (C3b and C3d) may be present as well. In cold antibody disease, C3 is present while IgG is usually absent. The test is ≥ 98% sensitive for autoimmune hemolytic anemia; false-negative results can occur if antibody density is very low or, rarely, if the autoantibodies are IgA or IgM. In most cases of warm antibody hemolytic anemia, the antibody is an IgG identified only as a panagglutinin, meaning the antigen specificity of the antibody can not be determined. In cold antibody disease, the antibody is usually an IgM directed against the I/i carbohydrate on the RBC surface. Antibody titers can usually be determined but do not always correlate with disease activity. The direct antiglobulin (direct Coombs) test may be positive in the absence of autoimmune hemolytic anemia, and thus should be ordered only in the proper clinical setting. A false-positive direct antiglobulin test may result from the presence of clinically insignificant antibodies.

The indirect antiglobulin (indirect Coombs) test is a complementary test that consists of mixing the patient’s plasma with normal RBCs to determine whether such antibodies are free in the plasma. 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.

Direct Antiglobulin (Direct Coombs) Test

The direct antiglobulin (direct Coombs) test is used to determine whether red blood cell (RBC)-binding antibody (IgG) or complement (C3) is present on RBC membranes. The patient's RBCs are incubated with antibodies to human IgG and C3. If IgG or C3 is bound to RBC membranes, agglutination occurs—a positive result. A positive result suggests the presence of autoantibodies to RBCs. A false-positive can occur and does not always equate with hemolysis. False-negative results occur when the antibody titer on the RBCs is low. Thus, results should always be correlated with the clinical signs and symptoms.

Direct Antiglobulin (Direct Coombs) Test

Indirect Antiglobulin (Indirect Coombs) Test

The indirect antiglobulin (indirect Coombs) test is used to detect IgG antibodies against red blood cells (RBCs) in a patient's plasma. The patient's plasma is incubated with reagent RBCs; then Coombs serum (antibodies to human IgG, or human anti-IgG) is added. If agglutination occurs, IgG antibodies (autoantibodies or alloantibodies) against RBCs are present. This test is also used to determine the specificity of an alloantibody.

Indirect Antiglobulin (Indirect Coombs) Test

Once autoimmune hemolytic anemia has been identified by the antiglobulin 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 alpha-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 systemic lupus erythematosus (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 (where the antibody is most commonly an IgM). It can also occur in warm antibody hemolytic anemia when the IgG antibody is of low affinity, in some drug-associated cases, and in PCH.

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 mean corpuscular volume and spuriously low hemoglobin 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 paroxysmal cold hemoglobinuria (PCH) is suspected, the Donath-Landsteiner test, which is specific for PCH, should be done. In this test, the patient's serum is incubated with normal RBCs at 4° C for 30 minutes to allow for fixation of complement and then warmed to body temperature. Hemolysis of the RBCs during this test is indicative of PCH. Because the PCH antibody fixes complement at low temperatures, the direct antiglobulin (direct Coombs) test is positive for C3 and negative for IgG. However, the antibody in PCH is an IgG against the P antigen.

Treatment

  • Blood transfusion for severe, life-threatening anemia

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

  • For idiopathic warm antibody hemolytic anemia, corticosteroids and, in refractory cases, rituximab, IV immune globulin, or splenectomy

  • For cold agglutinin disease, avoidance of cold and treatment of underlying disorder

  • For PCH, avoidance of cold, immunosuppressants, and treatment of syphilis if present. In children, this disease is often self-resolving.

Blood transfusion is the most important treatment for symptomatic patients who rapidly develop severe, life-threatening anemia. In this situation, transfusion should never be withheld due to lack of "compatible" units. In general, patients who have not had a previous blood transfusion or been pregnant are at low risk for hemolysis of ABO-compatible blood. Even if transfused cells are hemolyzed, blood transfusion can be life-saving until more definitive therapy can be done.

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 alpha-methyldopa-type AIHA, hemolysis usually ceases within 3 weeks; however, a positive antiglobulin test may persist for > 1 year. With hapten-mediated AIHA, hemolysis ceases when the drug is cleared from the plasma. Corticosteroids and/or infusions of immune globulin may be used as second-line therapies.

In idiopathic warm antibody AIHA, corticosteroids (eg, prednisone 1 mg/kg orally once a day) are the standard first-line treatment. When stable RBC values are achieved, corticosteroids are tapered slowly with laboratory monitoring of hemolysis (eg, by hemoglobin and reticulocyte counts). The goal is to wean the patient completely from corticosteroids or to maintain remission with the lowest possible corticosteroid dose. About two thirds of patients respond to corticosteroid treatment. In patients who relapse after corticosteroid cessation or who are refractory to corticosteroids, rituximab is usually used as a second-line drug.

Other treatments include use of additional immunosuppressive drugs and/or splenectomy. About one third to one half of patients have a sustained response after splenectomy.

In cases of fulminant hemolysis, immunosuppression with high-dose pulse corticosteroids or cyclophosphamide can be 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 could superimpose an alloantibody on the autoantibody, accelerating hemolysis. Thus, transfusions should be avoided when anemia is not life-threatening but should not be withheld in patients with severe autoimmune hemolytic anemia, particularly when the reticulocyte count is low.

Cold agglutinin disease

In many cases, avoidance of cold environments and other triggers of hemolysis may be all that is needed to prevent symptomatic anemia.

In cases associated with a lymphoproliferative disease, treatment is directed at the underlying disorder. Rituximab is commonly used, and chemotherapy regimens used to treat lymphoproliferative disorders can be effective.

In severe cases, plasmapheresis is an effective temporary treatment. Transfusions should be given sparingly, with the blood warmed through an on-line warmer.

Splenectomy is usually of no value, and immunosuppressants have only modest effectiveness.

Paroxysmal cold hemoglobinuria

In paroxysmal cold hemoglobinuria (PCH), therapy consists of strict avoidance of exposure to cold. Immunosuppressants have been effective, but use should be restricted to patients with progressive or idiopathic cases.

Splenectomy is of no value.

Treatment of concomitant syphilis may cure PCH.

Key Points

  • Autoimmune hemolytic anemia is divided into warm antibody hemolytic anemia and cold agglutinin disease based on the temperature at which the autoantibodies react with red blood cells (RBCs).

  • Hemolysis tends to be more severe in warm antibody hemolytic anemia and can be fatal.

  • Immunoglobulin and/or complement bound to the patient's RBCs is demonstrated by the occurrence of agglutination after antiglobulin serum is added to washed RBCs (positive direct antiglobulin test).

  • The pattern of the direct antiglobulin reaction can help distinguish warm antibody hemolytic anemia from cold agglutinin disease and can sometimes identify the mechanism responsible for warm antibody hemolytic anemia.

  • Treatment is directed at the cause (including stopping drugs, avoiding cold, treating underlying disorder).

  • Corticosteroids remain the first-line treatment for idiopathic warm antibody hemolytic disease.

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