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 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 triggers (eg, cold), and withdrawal of drugs.
(See also Overview of Hemolytic Anemia.)
Etiology of Autoimmune Hemolytic Anemia
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 react at temperatures ≥ 37° C. Autoimmune hemolytic anemia may be classified as
Primary (idiopathic)
Secondary (occurring in association with an underlying disorder such as systemic lupus erythematosus (SLE), lymphoma, or chronic lymphocytic leukemia or after use of certain drugs)
Drugs That Cause Warm Antibody Hemolytic Anemia
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 [mycoplasma] or i [Epstein Barr virus] antigens)
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.
Symptoms and Signs of Autoimmune Hemolytic Anemia
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. AIHA is rarely complicated by hepatic failure due to extensive red cell agglutination.
Cold agglutinin disease manifests as an acute or chronic hemolytic anemia. Other symptoms or signs include 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 of Autoimmune Hemolytic Anemia
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 (see photo Spherocytes) 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 (see figure Direct Antiglobulin 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. 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 (see figure Indirect Antiglobulin 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 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 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 with unwarmed blood, 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 results 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.
By permission of the publisher. From Tefferi A, Li C. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
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 of Autoimmune Hemolytic Anemia
Blood transfusion for severe, life-threatening anemia (usually with reticulocytopenia).
For drug-induced warm antibody hemolytic anemia, drug withdrawal and sometimes IV immune globulin
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, their hemolysis will be slower than the patient's own cells, so blood transfusion can be life-saving until more definitive therapy can be done.
More specific treatment depends on the mechanism of the hemolysis.
Warm antibody hemolytic anemias
In drug-induced warm antibody hemolytic anemias,> 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,
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.
1). It is a treatment option in patients with severe anemia.
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.
Treatment reference
1. Roth A, Barcellini W, D'Sa S, et al: Sutimlimab in cold agglutinin disease. N Engl J Med 384(14):1323–1334, 2021. doi: 10.1056/NEJMoa2027760
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 if reticulocytopenia is also present.
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.
