Immune hemolysis can be triggered by:
This chapter will deal with autoimmune hemolytic anemia. Alloimmune hemolysis will be covered in Chapter 25 (Transfusion Medicine).
Autoimmune hemolytic anemia is conveniently divided into two categories based on the temperature dependence of autoantibody binding to red cells, summarized in Table 11-2.
TABLE 11-2Hemolytic Autoantibodies ||Download (.pdf) TABLE 11-2 Hemolytic Autoantibodies
| ||Warm ||Cold |
|Autoantibody ||IgG ||IgM |
|Specificity ||Rh complex ||I antigen |
|I0 site of clearance ||Spleen ||Liver |
|Mode of recognition ||Common IgG H chain ||C3 |
|Blood film ||Spherocytes ||Agglutination |
Warm autoantibodies bind avidly to the patient's red cells at body temperature. They are immunoglobulin G (IgG) antibodies with specificity for Rh group antigens found on red cells of nearly all individuals. IgG-coated red cells are cleared primarily in the spleen, where they are engulfed by resident macrophages that have receptors for the constant region (Fc) of the heavy (H) chain of IgG. Figure 11-1A shows a macrophage from a patient with warm antibody hemolytic anemia that has just ingested two red cells and is about to destroy them. Alternatively, the patient's IgG-coated red cells may bind to the surface of the macrophage but escape total engulfment. Under these circumstances, the macrophage nibbles at the red cell membrane and removes a small portion of it. As shown in Figure 11-1B, this depletion of the red cell surface area results in the formation of a spherocyte. Spherocytes are the predominant morphologic feature in two disorders: warm antibody autoimmune hemolytic anemia (Fig. 11-2A) and hereditary spherocytosis (Chapter 10). Even though these two types of anemia have very different pathogenic mechanisms, they produce identical morphologic alterations in red cells.
Patients with warm antibody immune hemolysis usually present with fatigue, shortness of breath, and general symptoms of anemia. Physical examination often reveals slight icterus and splenomegaly.
Conditioning of antibody-coated red cells by macrophages. A) Erythrophagocytosis of two red cells by a macrophage in a patient with immune hemolytic anemia. (Used with permission from Lichtman MA, Lichtman's Atlas of Hematology. www.accessmedicine.com. McGraw-Hill, New York.) B) Conversion of a normal, disk-shaped red cell into a spherocyte by macrophage conditioning.
Blood films from patients with autoimmune hemolytic anemia due to a warm antibody. A) Idiopathic. B) Secondary to chronic lymphocytic leukemia. Note the presence of many spherocytes in both. (Used with permission from Lichtman MA, Lichtman's Atlas of Hematology. www.accessmedicine.com. McGraw-Hill, New York, New York.)
Cold autoantibodies bind to the patient's red cells with much higher affinity at low temperature than at body temperature. As a result, binding of cold autoantibodies to red cells is restricted to cool areas of the body, such as the extremities and the ear lobes. In the vast majority of cases, they are IgM macroglobulins that have specificity for the I antigen, which (like the Rh complex) is found on nearly all adult red cells. The large pentameric IgM binds the C3 component of complement much more efficiently than does IgG. As red cells return from the periphery and the blood warms, the IgM falls off the surface, but complement remains attached. C3-coated red cells are prey to two modes of destruction. If complement components are fully assembled, the cell will lyse and release its cytosolic contents into the plasma. More often, however, full fixation of complement does not occur, but sufficient C3b is deposited on the red cell surface for it to be recognized by C3 receptors on macrophages in the liver and elsewhere, which clear the cells from the circulation.
The clinical presentation of patients with cold-type autoantibodies is fully in accord with the pathogenic events described earlier. Most patients have extravascular hemolysis and a clinical presentation similar to that of patients with warm autoantibody hemolysis. Others, however, have a more dramatic clinical picture, in which vascular sludging in parts of the body exposed to low temperature (toes, fingers, ear lobes) results in pain, cyanosis, and even gangrene. In another subset of patients with cold-type autoantibody, the full fixation of complement, particularly following cold exposure, results in acute intravascular hemolysis with hemoglobinuria and a sudden drop in hemoglobin level.
Table 11-3 classifies autoimmune hemolytic anemias according to etiology. In about half of cases, the cause is unknown (idiopathic). In a small fraction of patients the autoimmune process is incited by drugs, some of which act as haptens. More often, drugs, particularly the cephalosporins, trigger autoantibody formation by an unknown mechanism. Patients with idiopathic or drug-induced disease usually have warm IgG autoantibodies. In the remainder of patients, an underlying disease is responsible for the development of autoimmune hemolysis. Lymphoproliferative disorders, particularly chronic lymphocytic leukemia and non-Hodgkin lymphoma (Chapter 22), account for most of these cases. Figure 11-2B shows a blood film of a patient with chronic lymphocytic leukemia who has developed autoimmune hemolysis. Patients with systemic lupus erythematosus are also at risk of developing immune hemolysis. In both lymphomas and systemic lupus erythematosus, the hemolysis is often due to a combination of warm and cold autoantibodies. Patients with either lymphoma or systemic lupus erythematosus are also at high risk of developing autoimmune thrombocytopenia (Chapter 14). Those with mycoplasma pneumonia and infectious mononucleosis occasionally develop transient acute hemolysis secondary to cold autoantibodies.
TABLE 11-3Causes of Autoimmune Hemolysis ||Download (.pdf) TABLE 11-3 Causes of Autoimmune Hemolysis
Secondary to underlying disease
Lymphoproliferative: CLL, NHL
Connective tissue: SLE, etc.
Infections: Mycoplasma, etc.
Patients with autoimmune hemolytic anemia generally have straightforward hemolysis with elevation of the reticulocyte count as well as of unconjugated bilirubin and lactate dehydrogenase in the serum. Serum haptoglobin is usually undetectable. As mentioned earlier, the peripheral blood film often reveals spherocytes.
The diagnosis is definitively established by the direct antiglobulin or Coombs test, which is depicted in Figure 11-3A. Following the addition of an animal anti-human IgG antibody, red cells will form visible clumps if they are coated with IgG immunoglobulin. The direct antiglobulin test can also utilize anti-C3 to detect complement on the surface of red cells of patients with a cold autoantibody. If cold autoantibodies are present, clumps of red cells may be seen in the blood film (agglutination) due to the fall in temperature between the time the blood is drawn and when the film is prepared. Usually, cold agglutinins are of no clinical significance, but some are associated with the cold-induced symptoms and signs described earlier.
The antiglobulin (Coombs) test. A) Direct antiglobulin test: antiserum against IgG or C3 is added to the patient's red cells (RBC). If they are coated with antibody or complement, agglutination occurs. B) Indirect antiglobulin test: the patient's serum is added to a sample of red cells expressing a known set of blood group antigens, followed by addition of anti-human immunoglobulin (Ig). Agglutination signifies that the patient's serum contains antibodies that recognize antigenic determinants on the test sample. (Courtesy of Dr. Peter Marks.)
The indirect antiglobulin test, shown in Figure 11-3B, detects antibody that can bind to a cognate red cell antigen. Patients with warm-type hemolysis usually have a high titer of autoantibody in the serum, which, as mentioned earlier, has specificity for the Rh group of red cell antigens. However, as explained in Chapter 25, the primary application of the indirect antiglobulin test is in blood banking, where it is used to identify and characterize the specificity of alloantibodies in serum of patients who are about to receive transfused red cells.
Similar to that of other autoimmune disorders, the mainstay of therapy is immunosuppression. Initial treatment usually entails the administration of high-dose corticosteroids, with gradual tapering once the hemolysis abates. Patients with warm autoantibodies who fail to respond or require a high dose of steroids to remain in remission are treated either with splenectomy or with rituximab, a monoclonal antibody directed against CD20 on B lymphocytes. This treatment is virtually identical to that used for the treatment of immune thrombocytopenia (Chapter 14). Patients with cold-type immune hemolysis are usually more difficult to treat. A simple but critically important measure is avoidance of exposure to cold, including the warming of blood prior to transfusion. Occasionally, a patient needs to move to a warmer climate before the hemolysis is controlled. Steroids and splenectomy are much less effective in cold antibody disease. However, some impressive remissions have been achieved with rituximab therapy.