Immune Hemolytic Anemia And/Or Positive Direct Antiglobulin Tests Caused by Drugs

Review: immune hemolytic anemia and/or positive direct antiglobulin tests caused by drugs G. GARRATTY In 19851and 19892I reviewed, in this journal, the cur- The Immune Response to Drugs rent viewpoints on drug-induced immune hemolytic ane- To explain the mechanisms involved in positive DATs, mia w)and/or positive direct antiglobulin tests (DATs). and possibly IHA, one has to know what epitopes the At the end of my 1989 review I wrote, "It seems to me drug-induced antibody is directed against. Although that in 1989 we still have more questions than answers. very little new data have emerged since my last review Perhaps we will have more answers when I rereview the in this journal in 1989,2wider reading of the pertinent subject in 1994." Although more drugs causing immune literature convinces me even more that putative anti- aberrations have been added to the list (Table 1),not bodies can be formed only if the drug binds, however much data have emerged since the 1989 review to prove loosely, to the cell (e.g., red blood cell [RBC], granulo- or disprove the theories postulated to explain the in vitro cyte, or platelet) surface. Table 2 lists drugs that have and in vivo findings.Nevertheless, sufficientnew data been shown to bind well to RBCs, that is, the drug bind- have emerged to warrant an update at this time. ing withstands multiple washes in vitro. Thus, it is easy Table 1. Drugs and other products that have caused immune hemolytic to explain formation of drug-RBC membrane protein anemia (IHA) and/or positive direct antiglobulin tests (DATs). conjugates that would provide the basis for antibody for- Acetaminophen Diethylstilbestrol Nafcillin mation through the classic haptenic mechanism. Most Amphotericin B Diglycoaldehyde Nomifensine Ampicillin Dipyrone p-aminosalicylicacid drugs causing positive DATs and IHA do not bind to Antazoline Erythromycin Penicillin G RBCs efficiently, but it is possible, and I believe proba- Aspirin Fenoprofen Phenacetin ble, that they do bind loosely (i.e., noncovalently) to Butizide Fluorescein Podophyllotoxin Carbenicillin Fluorouracil(5-FU) Probenecid RBCs in vivo. Although the classic concept of an Carbimazole Fluorsemide Procainamide immune response to low-molecular-weight substances Carbromal Glafenine Pyramidon Cefamandole Hydralazine Quinidine (e.g., drugs) involves covalent binding, exceptions have cefazolin Hydrochlorothiazide Quinine been described. The Forssman hapten, for example, Cefotaxime 9-Hydroxy-methyl- Ranitidine Cefotetan ellipticinium Rifampicin becomes immunogenic upon binding to a carrier Cefoxitin Ibuprofen Sodium pentothal through noncovalent binding.3 Nucleic acids and Ceftazidime Indene derivatives streptomycin Ceftriaxone (e.g., sulindac) Sulfonamides oligonucleotides, which are acidic polymers, can also Cephalexin Insulin Suprofen become immunogenic, when complexed to basic pro- Cephaloridine Isoniazid Teniposide Cephalothin Latamoxef Tetracycline tein carriers through multiple salt linkages.3 Chlorinated Levodopa Thiopental Thus, if drugs bind to RBCs, however loosely, it is hydrocarbons Mefenamic acid Tolbutamide (insecticides) Melphalan Tolmetin Chlorpropamide Methadone Triamterene Table 2. Drugs that have been shown to combine with the red blood cell Chlorpromazine Methicillin Trimellitic anhydride membrane in vitro efficiently enough lo withstand multiple washes Cianidanol Methotrexate Unasyn† Penicillins (most) Cisplatin Methyldopa Zomepirac Cephalosporins (some) Cyclofenil Methysergide Cisplatin *Drugs were included only when reasonable evidence was presented in the Carbimazole literature to support the conclusion that they caused the immune reaction Carbromal There are many more reported, but the evidence that they caused a positive Cianidanol DAT or drug-induced IHA is often minimal or is totally lacking. Erythromycin Streptomycin †This is B product name for ampicillin sodium + sulbactam sodium. All Tolbutamide other drugs on the list are listed by their chemical, not trade. name. IMMUNOHEMATOLOGY, VOLUME 10, NUMBER 2, 1994 41 G. GARRATTY possible that a haptenic response may occur. When the ly, activating complement and leading to thrombocy- hapten (e.g., the drug) combines with a macromolecule topenia. This “immunecomplex” theory was extended (e.g., RBC membrane components), several epitopes to RBCs to explain drug-induced IHA due to drugs other may be created.4,5 Some epitopes would be only on the than the penicillins and methyldopa.15-17 drug (or a metabolite of the drug). Some epitopes may In 1958, penicillin antibodies were discovered. Ley et be so-called “neoantigens”or ‘new antigenic determi- found that a patient’s serum reacted with RBCs nants” (NADs) and would be composed of part drug, from a pilot bottle of a unit of blood, but not with RBCs part membrane components. It is also possible that the from the unit itself. The reaction was due to the then- drug may change the normal membrane components, common practice of adding penicillin to the pilot bottle creating further diversity in the spectrum of neoantigens to reduce bacterial growth resulting from contamination formed. The possibility of this haptenic response for all during frequent sampling for crossmatching purposes. drugs bas been used to explain the mechanisms involved This showed that penicillin-coatedRBCs were easy to in the serologic and clinical findings associated with prepare in vitro and could be used to detect IgM and drug-induced immune cytopenias. It has led to a unifying IgG penicillin antibodies. Soon after, several cases of hypothesis to replace the three suggested mechanisms penicillin-induced IHA were described, and some years (i.e., drug adsorption, immune complex, and autoanti- later cases of penicillin-induced immune thrombocy- body) that have been used for some years.6,7 topenia and granulocytopenia were described.l9 This finding added another possible mechanism for drug- Proposed Mechanisms to Explain Positive induced cytopenia to those mechanisms already DATs and IHA Caused by Drugs described.8-14 This second mechanism, called the Ackroyd8 suggested that a drug (allylisopropylacety- “drug-adsorption”mechanism by Garratty and Petz,I6 lurea [Sedormid/Apronal]), acting as a hapten, con- suggested that RBCs became coated with penicillin in ferred new antigenic properties on platelets, leading to vivo, and that if IgG penicillin antibodies were present antibodies that reacted with drug only when it was they would react with the RBC-bound penicillin, lead- bound to the cell membrane. In 1952, Miescher and ing to IgG sensitized RBCs. This situation would lead to Meischer9 suggested an alternative theory: drug anti- a positive DAT and possible destruction of the IgG-coat- bodies might initially be formed against the drug, and ed RBCs by macrophages. then these antibodies might then react with the drug, In 1966, it was shown that drugs (e.g., methyldopa) forming drug-anti-drug immune complexes. These could cause the production of true RBC autoantibod- complexes could attach nonspecifically to platelets, ies.20 This added a third possible mechanism for drug- leading to their destruction by macrophages. In later induced positive DATs and IHA. A fourth mechanism, publications, Miescher et al. presented some experi- called the “membrane modification” mechanism by mental work in animals to support this Garratty and Petz,16 was suggested when it was shown Shulman12-14 also criticized Ackroyd’s hypothesis. He in 1967 that cephalothin,21,22and later some other proved that drugs such as quinine and quinidine did not drugs (e.g., diglycoaldehyde [INOX] and cisplatin),23-25 bind firmly to platelet membranes because quinidine can affect the RBC membrane so that proteins become could be removed by a single washing of the platelets. bound to the RBCs nonimmunologically. This mecha- He reported that concentrations of drug on the order of nism may lead to a positive DAT, but so far has not been 1 million times the concentration of membrane sites for proven to cause hemolytic anemia. antibody fixation did not interfere with antibody reac- tions. Using equilibrium dialysis, Shulmanalso showed Criticisms of the immune complex theory that the association between cells and drugs was much The so-called immune complex mechanism has come too weak to account for the large amount of antibody under ever-increasing attack in the last few years. Some that the same cells adsorbed; however, drug antibodies of the reasons for the search for an alternative theory are were shown to combine efficiently with drug in the that- absence of cells. Thus, he suggested that patients make 1. No one has clearly demonstrated drug immune an antibody against a stable complex of the drug with complexes on platelets, granulocytes, or RBCs or in some soluble noncellular macromolecule; when the the serum of patients who have drug-dependent drug is received again, drug-anti-drug immune com- antibodies. plexes form and these attach to platelets nonspecifical- 2. Drugs, such as quinine and quinidine, that were 42 IMMUNOHEMATOLOGY, VOLUME 10, NUMBER 2, 1994 Drug-induced red cell problems thought to react by this mechanism cause throm- binding of quinidine-dependentantibody is consis- bocytopenia in some patients and hemolytic anemia tent with this possibility. in others. It is unusual for both conditions to occur Increasing numbers of drug-dependent anti- together, and it is difficult to explain why the drug bodies reacting with RBCs are being reported to immune complexes would be so selective in indi- have blood group specificity6,28,35-45

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