Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + ETIOLOGY AND PATHOGENESIS Download Section PDF Listen +++ ++ Table 26–1 lists the drugs implicated in the production of a positive direct antiglobulin test and accelerated red cell destruction. Three mechanisms of drug-related immunologic injury to red cells are defined: — Hapten/drug adsorption involving drug-dependent antibodies. — Ternary complex formation involving drug-dependent antibodies. — Induction of autoantibodies that react with red cells in the absence of the inciting drug. Drug-related nonimmunologic protein adsorption may also result in a positive direct antiglobulin test without red cell injury. ++Table Graphic Jump LocationTABLE 26–1ASSOCIATION BETWEEN DRUGS AND POSITIVE DIRECT ANTIGLOBULIN TESTS*View Table||Download (.pdf) TABLE 26–1 ASSOCIATION BETWEEN DRUGS AND POSITIVE DIRECT ANTIGLOBULIN TESTS* Drugs Hapten or Drug Adsorption Mechanism Penicillins Carbromal Cephalosporins Tolbutamide Tetracycline Cianidanol 6-Mercaptopurine Hydrocortisone Oxaliplatin Ternary Complex Mechanism Stibophen Probenecid Quinine Nomifensine Quinidine Cephalosporins Chlorpropamide Diethylstilbestrol Rifampicin Amphotericin B Antazoline Doxepin Thiopental Diclofenac Tolmetin Etodolac Metformin Hydrocortisone Oxaliplatin Pemetrexed Autoantibody Mechanism Cephalosporins Cianidanol Tolmetin Latamoxef Nomifensine Glafenine α-Methyldopa Procainamide l-Dopa Diclofenac Mefenamic acid Pentostatin Teniposide Fludarabine Oxaliplatin Cladribine Efalizumab Lenalidomide Nonimmunologic Protein Adsorption Cephalosporins Cisplatin Oxaliplatin Carboplatin Uncertain Mechanism of Immune Injury Mesantoin Streptomycin Phenacetin Ibuprofen Insecticides Triamterene Chlorpromazine Erythromycin Melphalan 5-Fluorouracil Isoniazid Nalidixic acid p-Aminosalicylic acid Sulindac Acetaminophen Omeprazol Thiazides Temafloxacin Efavirenz Carboplatin *It is not always possible to infer the mechanism of immune injury induced by a drug. Moreover, some drugs can act by more than one mechanism. In cases of uncertain mechanism, the cited drug use is coincident with the hemolytic anemia, and causality is inferred, not established experimentally. These cases are included so that the reader may be aware of these potential associations.Source: Williams Hematology, 8th ed, Chap. 53, Table 53–2, p. 780. + HAPTEN OR DRUG ADSORPTION MECHANISM Download Section PDF Listen +++ ++ Occurs with drugs that bind firmly to red cell membrane proteins. Penicillin is the classic example. In patients receiving high-dose penicillin, red cells have a substantial coating of the drug. In a small proportion of patients, an antipenicillin antibody (usually IgG) develops and binds to the penicillin on the red cell. The direct antiglobulin test then becomes positive and hemolytic anemia may ensue. Hemolytic anemia caused by penicillin typically occurs after 7 to 10 days of treatment and ceases a few days to 2 weeks once the drug is stopped. Other manifestations of penicillin allergy are usually not present. Antibody-coated ("opsonized") red cells are destroyed mainly in the spleen. Antibodies eluted from red cells, or present in sera, react only against penicillin-coated red cells. This specificity distinguishes drug-dependent antibodies from true autoantibodies. Hemolytic anemia similar to that seen with penicillin has also been ascribed to other drugs (see Table 26–1). + TERNARY COMPLEX MECHANISM: DRUG-ANTIBODY TARGET-CELL COMPLEX Download Section PDF Listen +++ ++ The mechanism of red cell injury is not clearly defined, but it appears to be mediated by a cooperative interaction to generate a ternary complex involving the drug or drug-metabolite, a drug-binding membrane site on the target cell, and antibody, with consequent activation of complement (see Fig. 26–1B). The antibody attaches to a neoantigen consisting of loosely bound drug and red cell antigen; binding of drug to the target cell is weak until stabilized by the attachment of the antibody to both drug and cell membrane. Some of these antibodies have specificity for blood group antigens, such as Rh, Kell, or Kidd, and are nonreactive with red cells lacking the alloantigen even in the presence of drug. The direct antiglobulin test is usually positive with anticomplement reagents. Intravascular hemolysis may occur after activation of complement, with hemoglobinemia and hemoglobinuria, and C3b-coated red cells may be destroyed by the spleen and liver. ++ FIGURE 26–1 Effector mechanisms by which drugs mediate a positive direct antiglobulin test. Relationships of drug, antibody-combining site, and red blood cell membrane protein are shown. Panels A, B, and C show only a single immunoglobulin Fab region (bearing one combining site). A. Drug adsorption/hapten mechanism. The drug (▼) binds avidly to an unknown red blood cell membrane protein in vivo. Antidrug antibody (usually IgG) binds to the protein-bound drug. The direct antiglobulin test (with anti-IgG) detects IgG antidrug antibody on the patient's circulating (drug-coated) red blood cells. B. Ternary complex mechanism. Drug binds loosely or in undetectable amounts to red blood cell membrane. However, in the presence of appropriate antidrug antibody, a stable trimolecular (ternary) complex is formed by drug, red blood cell membrane protein, and antibody. In this mechanism, the direct antiglobulin test typically detects only red blood cell–bound complement components (e.g., C3 fragments) that are bound covalently and in large number to the patient's red blood cells in vivo. The antibody itself escapes detection. C. Autoantibody induction. Some drug-induced antibodies can bind avidly to red blood cell membrane proteins (usually Rh proteins) in the absence of the inducing drug and are indistinguishable from the autoantibodies of patients with autoimmune hemolytic anemia. The direct antiglobulin test detects the IgG antibody on the patient's red blood cells. D. Drug-induced non-immunologic protein adsorption. Certain drugs cause plasma proteins to attach nonspecifically to the red blood cell membrane. The direct antiglobulin test detects nonspecifically bound IgG and complement components. In contrast to the other mechanisms of drug-induced red blood cell injury, this mechanism does not shorten red blood cell survival in vivo. (Source: Williams Hematology, 8th ed, Chapter 53, Fig. 53–1, p. 779.) Graphic Jump LocationView Full Size||Download Slide (.ppt) + AUTOANTIBODY MECHANISM Download Section PDF Listen +++ ++ Many drugs induce the formation of autoantibodies to autologous (or homologous) red cells, most importantly α-methyldopa (see Table 26–1). The mechanism by which a drug can induce formation of an autoantibody is unknown. Positive direct antiglobulin tests are seen in 8 to 36 percent of those taking α-methyldopa. The positive test develops 3 to 6 months after the start of therapy. In contrast, less than 1 percent of those taking α-methyldopa develop hemolytic anemia. Infrequently, patients with chronic lymphocytic leukemia treated with purine analogues (e.g., fludarabine) develop autoimmune hemolytic anemia. Antibodies in the serum or eluted from red cells react optimally at 37°C with autologous or homologous red cells in the absence of drug. As in autoimmune hemolytic anemia, these antibodies frequently react with the Rh complex. Destruction of red cells occurs chiefly by splenic sequestration of IgG-coated red cells. + NONIMMUNOLOGIC PROTEIN ADSORPTION Download Section PDF Listen +++ ++ Patients receiving cephalosporins occasionally develop positive direct antiglobulin tests as a consequence of nonspecific adsorption of immunoglobulins, complement, albumin, fibrinogen, and other plasma proteins to red cell membranes (see Fig. 26–1D). Hemolytic anemia has not been reported. The clinical importance is the potential to complicate cross-matching. + CLINICAL FEATURES Download Section PDF Listen +++ ++ A careful drug history should be obtained in all patients with hemolytic anemia and/or positive direct antiglobulin test. The severity of symptoms depends on the rate of hemolysis, and the clinical picture is quite variable. Patients with hapten/drug adsorption (e.g., penicillin) and autoimmune (e.g., α-methyldopa) mechanisms generally exhibit mild to moderate red cell destruction with insidious onset of symptoms over days to weeks. If the ternary complex mechanism is operative (e.g., cephalosporins or quinidine), there may be sudden onset of severe hemolysis with hemoglobinuria and acute renal failure. Hemolysis can occur after only one dose of the drug if the patient has been previously exposed. + LABORATORY FEATURES Download Section PDF Listen +++ ++ Findings are similar to those of autoimmune hemolytic anemia, with anemia, reticulocytosis, and high MCV. Leukopenia, thrombocytopenia, hemoglobinemia, or hemoglobinuria may be observed in cases of ternary complex-mediated hemolysis. The serologic features are included under "Differential Diagnosis," below. + DIFFERENTIAL DIAGNOSIS Download Section PDF Listen +++ ++ Immune hemolysis caused by drugs should be distinguished from autoimmune hemolytic anemia (warm or cold antibodies), congenital hemolytic anemias (e.g., hereditary spherocytosis), and drug-mediated hemolysis caused by disorders of red cell metabolism (e.g., G-6-PD deficiency). In drug-related hemolytic anemia, the direct antiglobulin test is positive. In the hapten/drug mechanism, the key difference from autoimmune hemolytic anemia is that serum antibodies react only with drug-coated red cells. This serologic distinction plus a history of the specific drug exposure should be decisive. In the ternary complex mechanism, the direct antiglobulin test is positive with anticomplement serum, similar to cold autoimmune hemolytic anemia. However, the cold agglutinin titer and Donath-Landsteiner test are normal and the indirect antiglobulin test is positive only in the presence of drug. The direct antiglobulin test becomes negative shortly after stopping the drug. In hemolytic anemia caused by α-methyldopa, the direct antiglobulin reaction is strongly positive for IgG (rarely for complement) and the indirect antiglobulin reaction is positive with unmodified red cells, often showing Rh specificity. There is no specific serologic test to differentiate this disorder from warm-autoimmune hemolytic anemia with Rh complex specificities. The diagnosis is supported by recovery from anemia and disappearance of antibodies upon discontinuing the drug. With a clinical picture of drug-induced immune hemolysis, it is reasonable to stop any drug while serologic studies are performed and to monitor for increase in hematocrit, decrease in reticulocytosis, and disappearance of positive antiglobulin test. Rechallenge with the suspected drug may confirm the diagnosis but should be tried only for compelling reasons. + THERAPY, COURSE, AND PROGNOSIS Download Section PDF Listen +++ ++ Discontinuation of the offending drug is often the only treatment needed, and may be lifesaving in severe hemolysis mediated by the ternary complex mechanism. Transfuse only for severe, life-threatening anemia. Glucocorticoids are generally unnecessary and are of questionable efficacy. If high-dose penicillin is the treatment of choice in life-threatening infection, therapy need not be changed as a result of a positive direct antiglobulin test, unless there is overt hemolytic anemia. A positive direct antiglobulin test alone is not necessarily an indication for stopping α-methyldopa, although it may be prudent to consider alternative antihypertensive therapy. Hemolysis associated with α-methyldopa ceases promptly after stopping the drug. The positive direct antiglobulin test gradually diminishes over weeks or months. Problems with cross-matching may occur in patients with a strongly positive indirect antiglobulin test. Immune hemolysis caused by drugs is usually mild, but occasional episodes of severe hemolysis with renal failure or death have been seen, usually as a consequence of the ternary complex mechanism. ++ For a more detailed discussion, see Charles H. Packman: Hemolytic Anemia Resulting from Immune Injury. Chapter 53, p. 777 in Williams Hematology, 8th ed.