Williams Hematology



Definitions and History
Etiology and Pathogenesis

Hapten or Drug Adsorption Mechanism

Ternary Complex Mechanism: Drug-Antibody–Target Cell Complex

Autoantibody Mechanism

Nonimmunologic Protein Adsorption
Clinical Features
Laboratory Features
Differential Diagnosis
Therapy, Course, and Prognosis


Course and Prognosis
Chapter References

Drugs may cause immune injury of RBC by three mechanisms. These types of injury are classified by the effector mechanisms of hemolysis, since the induction mechanisms of antibody formation are poorly understood. (1) The hapten/drug adsorption mechanism involves covalent binding of drug to RBC membrane and attachment of anti-drug antibody to the membrane-bound drug, which opsonizes the cells for destruction by splenic macrophages. (2) The ternary complex mechanism is characterized by formation of a trimolecular immune complex consisting of drug, RBC membrane antigen, and an antibody that recognizes the compound neoantigen formed by drug and membrane antigen. RBC destruction occurs intravascularly, by activation of the whole complement sequence. The antibodies involved in hapten/drug adsorption- and ternary complex-mediated hemolysis are said to be drug-dependent, since the drug must be present with RBC and antibody in vivo or in vitro for the antibody to cause RBC injury. (3) In sharp contrast, some drugs induce formation of true autoantibodies indistinguishable from the autoantibodies seen in autoimmune hemolytic anemia, perhaps by T-lymphocyte immuno-modulation. In these cases, presence of the drug is not necessary for RBC injury to occur.
Hemolysis with drug-related immune mechanisms is generally mild, but severe and sometimes fatal hemolysis may be seen in cases mediated by the ternary complex mechanism and in patients with chronic lymphocytic leukemia with autoantibodies induced by purine analogs. These latter cases often respond to prednisone therapy, whereas in most other cases, withdrawal of the offending drug is usually the only treatment required.

Acronyms and abbreviations that appear in this chapter include: CLL, chronic lymphocytic leukemia; RBC, red blood cell.

The first example of drug-related immune blood cell destruction was Ackroyd’s description of Sedormid purpura in 1949.1 In 1953, Snapper and coworkers described a case of immune hemolysis and pancytopenia in a patient treated with mephenytoin (Mesantoin).2 The hemolysis ceased upon withdrawal of the drug. In 1956, Harris reported what are now classical studies of a patient who developed immune hemolytic anemia during a second course of stibophen for schistosomiasis.3 Since then, many drugs have been implicated in the production of positive direct antiglobulin tests and accelerated red cell destruction. Table 57-1 lists important drugs or classes of drugs implicated in immune red cell injury.


Three general mechanisms of drug-mediated immunologic injury to red cells are recognized (Table 57-2 and Fig. 57-1). This classification is based on the effector mechanism of red cell injury, since the induction mechanism for formation of drug-related red cell antibodies is unknown. Two of these mechanisms, hapten/drug adsorption and ternary complex formation, involve drug-dependent antibodies, while in the third mechanism the drugs in question appear to induce formation of true autoantibodies capable of reacting with human red cells in the absence of the inciting drug. Distinguishing among these mechanisms is not always possible, and some cases involve a combination of mechanisms. In addition, drug-related nonimmunologic protein adsorption by red cells may result in a positive direct antiglobulin test without actual red cell injury. This phenomenon should be distinguished from the other three forms of drug-induced immune red cell injury.


FIGURE 57-1 These figures show the effector mechanisms by which drugs mediate a positive direct antiglobulin test, demonstrating the relationships of drug, antibody-combining site, and red cell membrane protein. Only a single immunoglobulin Fab region (bearing one combining site) is shown in panels A, B, and C. (A) Drug adsorption/hapten mechanism. The drug (
) binds avidly to an unknown red cell membrane protein in vivo. Antidrug antibody (usually IgG) binds to the protein-bound drug. So far as is known, the membrane protein is not part of the epitope recognized by the antidrug antibody. The direct antiglobulin test (with anti-IgG) detects IgG antidrug antibody on the patient’s circulating (drug-coated) red cells. The indirect antiglobulin test detects antibody in the patent’s serum only when the test red cells have been precoated with the drug by incubation in vitro. (B) Ternary complex mechanism. Drug binds loosely or in undetectable amounts to red cell membrane. However, in the presence of appropriate antidrug antibody, a stable trimolecular (ternary) complex is formed among drug, red cell membrane protein, and antibody. In general, the antibody-combining site (Fab) recognizes both drug and membrane protein components but binds only weakly to either drug or protein unless both are present in the reaction mixture. In this mechanism, the direct antiglobulin test typically detects only red cell–bound complement components (e.g., C3 fragments) that are bound covalently and in large number to the patient’s red cells in vivo. The antibody itself escapes detection, possibly due to its low concentration but also because washing of the red cells (in the antiglobulin test procedure) apparently dissociates antibody and drug from the cells, leaving only the covalently bound C3 fragments. The indirect antiglobulin test also detects complement proteins on the test red cells when both antibody (patient serum) and a complement source (fresh patient serum or fresh normal serum) are present in the reaction mixture together with the drug. (C) Autoantibody induction. Some drug-induced antibodies can bind avidly to red cell membrane proteins (usually Rh proteins) in the absence of the inducing drug and are indistinguishable from the anti–red cell autoantibodies of patients with autoimmune hemolytic anemia (see Chap. 55). The direct antiglobulin test detects the IgG antibody on the patient’s red cells. The indirect antiglobulin test usually detects antibody in the serum of patients with active hemolysis. (D) Drug-induced nonimmunologic protein adsorption. Certain drugs cause plasma proteins to attach to the red cell membrane nonspecifically. The direct antiglobulin test detects nonspecifically bound IgG and complement components. If special antiglobulin reagents are used, other plasma proteins, such as transferrin, albumin, and fibrinogen, may be detected as well. In contrast to the other mechanisms of drug-induced red cell injury, this mechanism does not shorten red cell survival in vivo.

This mechanism applies to drugs that can bind firmly to proteins, including red cell membrane proteins. The classic setting is very high dose penicillin therapy,4,5,6,7,8,9 and 10 which is encountered less commonly today than in previous decades.
Most individuals who receive penicillin develop IgM antibodies directed against the benzylpenicilloyl determinant of penicillin, but this antibody plays no role in penicillin-related immune injury to red cells. The antibody responsible for hemolytic anemia is of the IgG class, occurs less frequently than the IgM antibody, and may be directed against the benzylpenicilloyl7 or, more commonly, nonbenzylpenicilloyl determinants.4,5 and 6,8 Other manifestations of penicillin sensitivity usually are not present.
Patients receiving high doses of penicillin develop substantial coating of their red cells with penicillin. This penicillin coating itself is not injurious. If the dose of penicillin is very high (10 × 106 to 30× 106 units per day, or less in the setting of renal failure) and if the patient has an IgG antipenicillin antibody, the antibody binds to the red cell–bound penicillin molecules, and the direct antiglobulin test with anti-IgG becomes positive5,7,8,23,78 (see Fig. 57-1a). Antibodies eluted from such patients’ red cells, or present in their sera, react (in indirect antiglobulin tests) only against penicillin-coated red cells. This is a critical step in distinguishing these drug-dependent antibodies from true autoantibodies.
Significantly, not all patients receiving high-dose penicillin develop a positive direct antiglobulin reaction or hemolytic anemia, since only a small proportion of such individuals produce the requisite antibody. Destruction of red cells coated with penicillin and IgG antipenicillin antibody occurs mainly through sequestration by splenic macrophages.6,79 In some patients with penicillin-induced immune hemolytic anemia, blood monocytes, and presumably splenic macrophages, may lyse the IgG-coated red cells without phagocytosis.80 Hemolytic anemia due to penicillin typically occurs only after the patient has received the drug for 7 to 10 days and ceases a few days to 2 weeks after discontinuing the drug.
Low-molecular-weight substances, such as drugs, generally are not immunogenic in their own right. Induction of antidrug antibody is thought to require firm chemical coupling of the drug (as a hapten) to a protein carrier. In the case of penicillin, the carrier protein involved in antibody induction need not be the same as the erythrocyte membrane protein to which penicillin is coupled in the effector phase, i.e., when the IgG antipenicillin antibodies bind to penicillin-coated red cells. In contrast to growing evidence concerning the ternary complex mechanism (see below), there is no present evidence that the drug-dependent antibodies responsible for red cell injury in this hapten/drug adsorption mechanism also recognize native erythrocyte membrane structures.
Cephalosporins have antigenic cross-reactivity with penicillin81,82 and 83 and also bind firmly to red cell membranes, as do semisynthetic penicillins.9,10 Hemolytic anemia similar to that seen with penicillin has been ascribed to cephalosporins11,12,13,14 and 15 and some semisynthetic penicillins.9,10 Tetracycline16,17 and tolbutamide19,20 also may cause hemolysis by this mechanism. Carbromal causes positive IgG antiglobulin reactions by a similar mechanism,18 but hemolytic anemia has not been described.
Many drugs can induce immune injury not only of red cells but also of platelets or granulocytes by a process that differs in several ways from the mechanism of hapten/drug adsorption. First, drugs in this group (see Table 57-1) exhibit only weak direct binding to blood cell membranes. Second, a relatively small dose of drug is capable of triggering destruction of blood cells. Third, cellular injury appears to be mediated chiefly by complement activation at the cell surface. The cytopathic process induced by such drugs previously has been termed the immune complex mechanism. This reflected the prevailing notion that, in vivo, drug-antidrug complexes formed first and then became secondarily bound to target blood cells as “innocent bystanders,” either nonspecifically or possibly via membrane receptors (e.g., Fcg receptors on platelets or C3b receptors on red cells), with the potential for subsequent activation of complement by bound complexes.
The “immune complex” and “innocent bystander” terminology now seems less appropriate because of models developed from research on analogous drug-dependent platelet injury84,85 and 86 (see Chap. 117), together with a series of relevant serologic observations on drug-mediated immune hemolytic anemia. These studies suggest that blood cell injury actually is mediated by a cooperative interaction among three reactants to generate a ternary complex (see Fig. 57-1b) involving (1) the drug (or drug metabolite in some cases), (2) a drug-binding membrane site on the target cell, and (3) antibody. For example, several patients were found to possess drug-dependent antibodies that exhibited specificity for red cells bearing defined alloantigens such as those of the Rh, Kell, or Kidd blood groups. That is, those antibodies were selectively nonreactive with human red cells lacking the alloantigen in question even in the presence of drug.30,52,87,88 and 89 In each of these cases, high-affinity drug binding to cell membrane could not be demonstrated. The drug-dependent antibody may bind, through its Fab domain, to a compound neoantigen consisting of loosely bound drug and a blood group antigen intrinsic to the red cell membrane. Elegant studies on quinidine- or quinine-induced immune thrombocytopenia have demonstrated that the IgG antibodies implicated in this disorder bind through their Fab domains, not by their Fc domains to platelet Fcg receptors.90,91
These data elucidate how one patient with quinidine sensitivity may have selective destruction of platelets and another may have selective destruction of red cells. This is because the pathogenic antibody recognizes the drug only in combination with a particular membrane structure of the red cell (e.g., a known alloantigen) or of the platelet [e.g., a domain of the glycoprotein Ib (GPIb) complex]. Therefore, at least in these cases, the target cell does not appear to be purely an innocent bystander. Binding of the drug itself to the target cell membrane is weak until stabilized by the attachment of the antibody to both drug and cell membrane. Yet the binding of the antibody is drug-dependent. Such a three-reactant interdependent “troika” is unique to this mechanism of immune cytopenia.
The foregoing discussion depicting drugs as creating a “self+ nonself” neoantigen on the target cell applies to the effector phase of the process. The same drug-binding membrane protein appears to be involved in some way in forming the immunogen that induces the antibody, as evidenced by those drug-dependent antibodies exhibiting selective reactivity with defined red cell alloantigens (carrier specificity).30,52,87,88 and 89 How this is accomplished in the absence of evidence for strong, covalent binding of the drugs in this group to a host membrane protein remains to be elucidated.
Red cell destruction by this mechanism may occur intravascularly after completion of the whole complement sequence, resulting in hemoglobinemia and hemoglobinuria. Some destruction of intact C3b-coated red cells may be mediated by splenic and liver sequestration via the C3b/C3bi receptors on macrophages. The direct antiglobulin test is positive usually only with anticomplement reagents, but exceptions occur. Sometimes, however, the drug-dependent antibody itself can be detected on the red cell if the offending drug (or its metabolites) is included in all steps of the antiglobulin test, including red cell washing.92
A variety of drugs have been reported to induce the formation of autoantibodies reactive with autologous (or homologous) red cells in the absence of the instigating drug (see Table 57-1). The most important drug in this category has been amethyldopa.41,42,43 and 44 Levodopa and several unrelated drugs also have been incriminated.15,21,31,33,40,45,46,47,48,49,50,51,52,53 and 54 Patients with chronic lymphocytic leukemia (CLL) treated with pentostatin,55 fludarabine,56 or chlorodeoxyadenosine57 are particularly predisposed to autoimmune hemolysis which is usually severe and sometimes fatal.
Positive direct antiglobulin reactions (with anti-IgG reagents) in patients taking a-methyldopa vary in frequency from 8 to 36 percent. Patients taking higher doses of the drug develop positive reactions with greater frequency.41,43,44 There is a lag period of 3 to 6 months between the start of therapy and development of a positive antiglobulin test. The delay is not shortened when the drug is administered to patients who previously had positive antiglobulin tests while taking a-methyldopa.43
In contrast to the frequent observation of positive antiglobulin reactions, less than 1 percent of patients taking a-methyldopa exhibit hemolytic anemia.42 Development of hemolytic anemia does not depend on drug dosage. The hemolysis is usually mild to moderate and occurs chiefly by splenic sequestration of IgG-coated red cells. It has been proposed that amethyldopa suppresses splenic macrophage function in some patients, and that normal survival of antibody-coated red cells in such patients may be related, in part, to this effect of the drug.93
The direct antiglobulin reaction is usually positive only for IgG.94,95 Occasionally, weak anticomplement reactions are encountered as well.95 Patients with immune hemolytic anemia due to a-methyldopa therapy typically have strongly positive direct antiglobulin reactions as well as serum antibody, evidenced by the indirect antiglobulin reaction.95 (See Chap. 137 for explanation of direct and indirect antiglobulin tests.) Antibodies in the serum or eluted from red cell membranes react optimally at 37°C (98.6°F) with unaltered autologous or homologous red cells in the absence of drug42,44,96 (see Fig. 57-1c). The antibodies frequently are reactive with determinants of the Rh complex.42,44,96 The autoantibodies of some patients with hemolytic anemia associated with a-methyldopa therapy appear to target the same 34-kDa Rh-related polypeptide that is targeted by the autoantibodies in many cases of “spontaneously arising” autoimmune hemolytic anemia.97 Thus, it is not presently possible to distinguish these antibodies from similar warm-reacting autoantibodies in idiopathic autoimmune hemolytic anemia.
The mechanism by which a drug can induce formation of an autoantibody is unknown. Radiolabeled a-methyldopa does not react directly with the membranes of intact human red cells.44,98 However, both a-methyldopa and levodopa have been reported to bind to isolated red cell membranes. Binding of the drug to membranes of intact red cells is inhibited by red cell superoxide dismutase and probably by hemoglobin.98,99 Although not formally demonstrated, these drugs probably bind to membrane antigens of cells that are relatively hemoglobin-free, for example, cells at the early proerythroblast stage or red cell stroma. In any case, the resulting altered membrane antigens then may induce autoantibodies. The concept that a drug-membrane compound neoantigen could lead to production of an autoantibody is supported by studies of patients receiving drugs unrelated to a-methyldopa. These patients simultaneously developed a drug-dependent antibody and an autoantibody, both of which showed specificity for the same red cell alloantigen.52 It also has been hypothesized that a-methyldopa may interact with human T-lymphocytes, resulting in loss of suppressor cell function.100 However, subsequent studies have failed to demonstrate any evidence for such a mechanism.101
Uncommonly, patients with CLL treated with the purine analogs fludarabine or chlorodeoxyadenosine develop autoimmune hemolysis.56,57 Risk factors for autoimmune hemolysis include prior therapy with a purine analog, a positive direct antiglobulin test prior to therapy, and hypogammaglobulinemia. Purine analogs are potent suppressors of T-lymphocytes. These drugs may accelerate the pre-existing T-cell immune suppression that normally occurs during progression of CLL, exacerbating the underlying tendency to autoimmunity in CLL. However the degree of depletion of T-cell subsets is similar in those patients who develop hemolysis and in those who do not.
Fewer than 5 percent of patients receiving cephalosporin antibiotics develop positive antiglobulin reactions95 due to nonspecific adsorption of plasma proteins to their red cell membranes.58,59,102 This may occur within a day or two after the drug is instituted. Multiple plasma proteins, including immunoglobulins, complement, albumin, fibrinogen, and others, may be detected on red cell membranes in such cases.102,103 Hemolytic anemia due to this mechanism has not been reported. The clinical importance of this phenomenon is its potential to complicate cross-match procedures unless the drug history is taken into account. As noted above, cephalosporin antibiotics also may induce red cell injury by the hapten mechanism or by the ternary complex mechanism. These latter reactions are more serious but apparently occur less frequently than the nonimmunologic reaction.
A careful history of drug exposure should be obtained in all patients with hemolytic anemia and/or a positive direct antiglobulin test. As in idiopathic autoimmune hemolytic anemia (see Chap. 55 and Chap. 56), the clinical picture in drug-related immune hemolytic anemia is quite variable. The severity of symptoms is largely dependent upon the rate of hemolysis. In general, patients with hapten/drug adsorption (e.g., penicillin) and autoimmune (e.g., a-methyldopa) types of drug-induced hemolytic anemia exhibit mild to moderate red cell destruction, with insidious onset of symptoms developing over a period of days to weeks. In contrast, many patients with hemolysis mediated by the ternary complex mechanism (e.g., cephalosporins or quinidine) may have sudden onset of severe hemolysis with hemoglobinuria. In the latter setting, hemolysis can occur after only one dose of the drug if the patient has been previously exposed to the drug. Acute renal failure may accompany severe hemolysis by the ternary complex mechanism.15,28,30,34,35,54,94 Several reports indicate that second- and third-generation cephalosporins may cause severe, even fatal, hemolysis by the ternary complex mechanism.13,14 and 15,36
The hematologic findings are similar to those described for spontaneously occurring autoimmune hemolytic anemia (see Chap. 55 and Chap. 56). Most patients exhibit anemia and reticulocytosis. Leukopenia and thrombocytopenia may be noted in cases of ternary complex–mediated hemolysis. The appearance of hemoglobinemia or hemoglobinuria suggests the ternary complex mechanism. The serologic features are summarized in Table 57-2.
Immune hemolysis due to drugs should be distinguished from (1) the warm- or cold-antibody types of idiopathic autoimmune hemolytic anemia, (2) congenital hemolytic anemias such as hereditary spherocytosis, and (3) drug-mediated hemolysis due to disorders of red cell metabolism, such as glucose-6-phosphate dehydrogenase deficiency. Patients with drug-related immune hemolytic anemia have a positive direct antiglobulin test. This feature generally makes it easy to distinguish this group from those with inherited red cell defects.
In the hapten/drug adsorption mechanism of immune injury associated with cephalosporins or penicillin, the patient’s drug-coated red cells bind drug-specific IgG antibody and exhibit positive direct antiglobulin reactions with anti-IgG. Rarely, both anti-IgG and anti-C3d antisera produce positive antiglobulin reactions. Such cases could have superficial resemblance to warm-antibody autoimmune hemolytic anemia. The key serologic difference is that in this form of drug-induced immune hemolytic anemia the antibodies in the patient’s serum or eluted from the patient’s red cells react only with drug-coated red cells. In contrast, the IgG antibodies in warm-type autoimmune hemolytic anemia react with unmodified human red cells and may show preference for certain known blood groups (e.g., within the Rh complex). Such serologic distinction plus the history of exposure to high blood levels of penicillin or a cephalosporin should be decisive.
In hemolysis mediated by the ternary complex mechanism, the direct antiglobulin test is positive with anticomplement serum. Immunoglobulins are only rarely detectable on the patient’s red cells. This pattern is similar to that encountered in autoimmune hemolytic anemia mediated by cold agglutinins. Moreover, the brisk type of hemolysis in the ternary complex mechanism also is seen in certain cases of cold-antibody autoimmune hemolytic anemia (see Chap. 56). In the drug-induced cases, however, the cold agglutinin titer and the Donath-Landsteiner test are normal, and the demonstration of serum antibody acting on human red cells is dependent upon the presence of the drug in the test system. For example, the indirect antiglobulin reaction with anticomplement serum may be positive if the incubation mixture permits the interaction of (1) normal red cells; (2) antidrug antibody from the patient’s serum; (3) the relevant drug, either still in the patient’s serum or added in vitro in appropriate concentration; and (4) a source of complement, that is, fresh normal serum or the patient’s own serum if freshly obtained. A negative result does not necessarily absolve the suspected drug because the critical determinant may be a metabolite of the drug in question. In some cases, the use of urine or serum (of the patient or a volunteer taking the drug) as a source of drug metabolite has permitted successful demonstration of a drug-dependent mechanism.33,88,92,104
In patients with autoimmune hemolytic anemia due to a-methyldopa, the direct antiglobulin reaction is strongly positive for IgG, but only rarely is complement detected on the patient’s red cells. Anti–red cell autoantibody is regularly present in the serum of those patients and mediates a positive indirect antiglobulin reaction with unmodified human red cells, often showing specificity related to the Rh complex. There is, however, no presently available specific serologic test to separate idiopathic warm-reacting IgG autoantibodies with Rh-related specificities from those induced by a-methyldopa administration. The evidence must be circumstantial, with the helpful knowledge that discontinuation of amethyldopa, without any form of immunosuppressive therapy, has consistently permitted a slow recovery from anemia and a gradual disappearance of anti–red cell antibodies.
In recently transfused patients, a positive “direct” antiglobulin test may reflect the binding of newly formed alloantibodies to transfused donor red cells. Neither the drugs the patient is receiving nor autoantibodies may be involved.
Drugs not now known to cause immune red cell injury will be implicated in the future. In any patient with a clinical picture compatible with drug-related immune hemolysis it is reasonable to stop any drug that is suspect while serologic studies are being obtained. The patient should be monitored for improvement in hematocrit level, decrease in reticulocytosis, and gradual disappearance of the positive antiglobulin reaction. Repeat challenge with the suspected drug may confirm the diagnosis, but this measure is seldom necessary in patient management and may be unsafe. Therefore, rechallenge to exclude the possibility that a suspected drug-caused hemolytic anemia in a patient should be undertaken only for compelling reasons, such as the need to use that drug in particular for the patient’s illness.
Discontinuation of the offending drug is often the only treatment needed. This measure is essential and may be life-saving in patients with severe hemolysis mediated by the ternary complex mechanism.
If high-dose penicillin is the treatment of choice in a life-threatening infection and alternative antibiotic regimens are clearly inferior to penicillin, the drug need not be discontinued because of a positive direct antiglobulin reaction alone. A change in therapy is indicated only in the presence of overt hemolytic anemia. Lowering the penicillin dose, for example, by coadministering other antibiotics, may allow continuation of drug in some cases, particularly if hemolysis is not severe.
In patients taking a-methyldopa in the absence of hemolysis, a positive direct antiglobulin test is not necessarily an indication for stopping the drug, although it may be prudent to consider alternative antihypertensive therapy.
Glucocorticoids are generally unnecessary, and their efficacy is questionable. However prednisone is effective in patients with CLL and autoimmune hemolysis caused by purine analogs.56,57 Transfusions should be given in the unusual circumstance of severe, life-threatening anemia. Problems with cross-matching, similar to those encountered in warm-antibody autoimmune hemolytic anemia, may occur in patients with a strongly positive indirect antiglobulin test, for example, in a-methyldopa-related cases. Patients with hemolytic anemia due to the hapten/drug adsorption mechanism should have a compatible cross-match, because the serum antibody reacts only with the drug-coated cells. However, if therapy with the offending drug is still in progress, transfused cells may be destroyed at an increased rate as they become coated with drug in vivo.
Several cases of transfusion-associated graft-versus-host disease have been reported in CLL patients transfused for hemolysis due to purine analogs.57,105,106 Such patients should receive irradiated blood products.
Immune hemolysis due to drugs is usually mild, and the prognosis good. Occasional episodes of exceptionally severe hemolysis with renal failure or death have been reported, usually due to drugs operating through the ternary complex mechanism or due to purine analogs in patients with CLL.15,28,30,34,35,36 and 37,39,54,73,74,94 In hemolysis due to ternary complex or hapten/drug adsorption mechanisms, the direct antiglobulin test becomes negative within a short time after the drug is discontinued, that is, soon after the drug is cleared from the circulation. In addition, the hemolysis associated with a-methyldopa-induced autoantibodies ceases promptly after cessation of the drug. However, a positive direct antiglobulin test of gradually diminishing intensity may remain for weeks or months.

Ackroyd JF: The pathogenesis of thrombocytopenic purpura due to hypersensitivity to Sedormid (allylisopropyl-acetylcarbamide). Clin Sci 7:249, 1949.

Snapper I, Marks D, Schwartz L, Hollander L: Hemolytic anemia secondary to Mesantoin. Ann Intern Med 39:619, 1953.

Harris JW: Studies on the mechanism of drug-induced hemolytic anemia. J Lab Clin Med 47:760, 1956.

VanArsdel PP Jr, Gilliland BC: Anemia secondary to penicillin treatment: Studies on two patients with non-allergic serum hemagglutinins. J Lab Clin Med 65:277, 1965.

Petz LD, Fudenberg HH: Coombs-positive hemolytic anemia caused by penicillin administration. N Engl J Med 274:171, 1966.

Swanson MA, Chanmougan D, Schwartz RS: Immuno-hemolytic anemia due to antipenicillin antibodies. N Engl J Med 274:178, 1966.

Levine B, Redmond A: Immunochemical mechanisms of penicillin-induced Coombs positivity and hemolytic anemia in man. Int Arch Allergy Appl Immunol 1:594, 1967.

White JM, Brown DL, Hepner GW, Worlledge SM: Penicillin-induced hemolytic anaemia. Br Med J 3:26, 1968.

Seldon MR, Bain B, Johnson CA, Lennox CS: Ticarcillin-induced immune haemolytic anaemia. Scand J Haematol 28:459, 1982.

Tuffs L, Manoharan A: Flucloxacillin-induced haemolytic anaemia. Med J Aust 144:559, 1986.

Gralnick HR, McGinnis MH, Elton W, McCurdy P: Hemolytic anemia associated with cephalothin. JAMA 217:1193, 1971.

Branch DR, Berkowitz LR, Becker RL, et al: Extravascular hemolysis following the administration of cefamandole. Am J Hematol 18:213, 1985.

Chambers LA, Donovan BA, Kruskall MS: Ceftazidime-induced hemolysis patient with drug-dependent antibodies reactive by immune complex and drug adsorption mechanisms. Am J Clin Pathol 95:393, 1991.

Gallagher NI, Schergen AK, Sokol-Anderson ML, et al: Severe immune-mediated hemolytic anemia secondary to treatment with cefotetan. Transfusion 32:266, 1992.

Garratty G, Nance S, Lloyd M, Domen R: Fatal immune hemolytic anemia due to cefotetan. Transfusion 32:269, 1992.

Wenz B, Klein RL, Lalezari P: Tetracycline-induced immune hemolytic anemia. Transfusion 14:265, 1974.

Simpson MB, Pryzbylik J, Innis B, Denham MA: Hemolytic anemia after tetracycline therapy. N Engl J Med 312:840, 1985.

Steanini M, Johnson NL: Positive antihuman globulin test in patients receiving carbromal. Am J Med Sci 259:49, 1970.

Bird GWG, Ecles GH, Litchfield JA, et al: Haemolytic anaemia associated with antibodies to tolbutamide and phenacetin. Br Med J 1:728, 1972.

Malacarne P, Castaldi G, Bertusi M, Zavagli G: Tolbutamide-induced hemolytic anemia. Diabetes 26:156, 1977.

Salama A, Mueller-Eckhardt C: Cianidanol and its metabolites bind tightly to red cells and are responsible for the production of auto- and/or drug-dependent antibodies against these cells. Br J Haematol 66:263, 1987.

Muirhead EE, Halden ER, Granes M: Drug-dependent Coombs (antiglobulin) test and anemia: observations on quinine and acetophenetidine (phenacetin). Arch Intern Med 101:827, 1958.

Croft JD Jr, Swisher SN, Gilliland BC, et al: Coombs test positivity induced by drugs: mechanisms of immunologic reactions and red cell destruction. Ann Intern Med 68:176, 1968.

Freedman AL, Barr PS, Brody E: Hemolytic anemia due to quinidine: observations on its mechanism. Am J Med 20:806, 1956.

Logue GL, Boyd AE, Rosse WF: Chlorpropamide-induced immune hemolytic anemia. N Engl J Med 283:900, 1970.

Kopicky JA, Packman CH: The mechanisms of sulfonylurea-induced immune hemolysis. Case report and review of the literature. Am J Hematol 23:283, 1986.

Lakshminarayan S, Sahn SA, Hudson LD: Massive hemolysis caused by rifampicin. Br Med J 2:282, 1973.

Pereira A, Sanz C, Cervantes F, Castillo R: Immune hemolytic anemia and renal failure associated with rifampicin-dependent antibodies with anti-I specificity. Ann Hematol 63:56, 1991.

Bengtsson U, Staffan A, Aurell M, Kaijser B: Antazoline-induced immune hemolytic anemia, hemoglobinuria and acute renal failure. Acta Med Scand 198:223, 1975.

Habibi B, Basty R, Chodez S, Prunat A: Thiopental-related immune hemolytic anemia and renal failure. N Engl J Med 312:353, 1985.

Squires JE, Mintz PD, Clark S: Tolmetin-induced hemolysis. Transfusion 25:410, 1985.

Sosler SD, Behzad V, Garratty G, et al: Immune hemolytic anemia associated with probenecid. Am J Clin Pathol 84:391, 1985.

Salama A, Mueller-Eckhardt C: Two types of nomifensine-induced immune haemolytic anaemias: drug-dependent sensitization and/or autoimmunization. Br J Haematol 64:613, 1986.

Habibi B, Cartron JP, Bretagne M, et al: Anti-nomifensine antibody causing immune hemolytic anemia and renal failure. Vox Sang 40:79, 1981.

Fulton JD, Briggs JD, Dominiczak AF, et al: Intravascular haemolysis and acute renal failure induced by nomifensine. Scott Med J 31:242, 1986.

Garratty G, Postoway N, Schwellenbach J, McMahill PC: A fatal case of ceftriaxone (Rocephin)-induced hemolytic anemia associated with intravascular immune hemolysis. Transfusion 31:176, 1991.

Rosenfeld CS, Winters SJ, Tedrow HE: Diethylstilbestrol-associated hemolytic anemia with a positive direct antiglobulin test result. Am J Med 86:617, 1989.

Salama A, Burger M, Mueller-Eckhardt C: Acute immune hemolysis induced by a degradation product of amphotericin B. Blut 58:59, 1989.

Wolf B, Conradty M, Grohmann R, et al: A case of immune complex hemolytic anemia, thrombocytopenia, and acute renal failure associated with doxepin use. J Clin Psychiatry 50:99, 1989.

Salama A, Kroll H, Wittmann G, Mueller-Eckhardt C: Diclofenac-induced immune haemolytic anaemia: simultaneous occurrence of red blood cell autoantibodies and drug-dependent antibodies. Br J Haematol 95:640, 1996.

Carstairs KC, Breckenridge A, Dollery CT, Worlledge SM: Incidence of a positive direct Coombs test in patients on alpha-methyldopa. Lancet 2:133, 1966.

Worlledge SM, Carstairs KC, Dacie JV: Autoimmune haemolytic anaemia associated with amethyldopa therapy. Lancet 2:135, 1966.

Breckenridge A, Dollery CT, Worlledge SM, et al: Positive direct Coombs tests and antinuclear factors in patients treated with methyldopa. Lancet 2:1265, 1967.

Lo Buglio AF, Jandl JH: The nature of alpha-methyldopa red cell antibody. N Engl J Med 276:658, 1967.

Cotzias GC, Papavasiliou PS: Autoimmunity in patients treated with levodopa. JAMA 207:1353, 1969.

Henry RE, Goldberg LS, Sturgeon P, Ansel RD: Serologic abnormalities associated with l-dopa therapy. Vox Sang 20:306, 1971.

Joseph C: Occurrence of positive Coombs test in patients treated with levodopa. N Engl J Med 286:1400, 1972.

Gabor EP, Goldberg LS: Levodopa-induced Coombs positive haemolytic anaemia. Scand J Haematol 11:201, 1973.

Territo MC, Peters RW, Tanaka KR: Autoimmune hemolytic anemia due to levodopa therapy. JAMA 226:1347, 1973.

Scott GL, Myles AB, Bacon PA: Autoimmune haemolytic anaemia and mefenamic acid therapy. Br Med J 3:543, 1968.

Robertson JH, Kennedy CC, Hill CM: Haemolytic anaemia associated with mefenamic acid. Irish J Med Sci 140:226, 1971.

Habibi B: Drug-induced red blood cell autoantibodies co-developed with drug-specific antibodies causing a hemolytic anaemia. Br J Haematol 61:139, 1985.

Kleinman S, Nelson R, Smith L, Goldfinger D: Positive direct antiglobulin tests and immune hemolytic anemia in patients receiving procainamide. N Engl J Med 311:809, 1984.

Kramer MR, Levene C, Hershko C: Severe reversible autoimmune haemolytic anaemia and thrombocytopenia associated with diclofenac therapy. Scand J Haematol 36:118, 1986.

Byrd JC, Hertler AA, Weiss RB, et al: Fatal recurrence of autoimmune hemolytic anemia following pentostatin therapy in a patient with a history of fludarabine-associated hemolytic anemia. Ann Oncol 6:300, 1995.

Gonzalez H, Leblond V, Azar N, et al: Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther 40:113, 1998.

Chasty RC, Myint H, Oscier DG, et al: Autoimmune haemolysis in patients with B-CLL treated with chlorodeoxyadenosine (CDA). Leuk Lymphoma 29:391, 1998.

Gralnick HR, Wright LD, McGinnis MH: Coombs’ positive reactions associated with sodium cephalothin therapy. JAMA 199:725, 1967.

Molthan L, Reidenberg MM, Eichman MF: Positive direct Coombs’ tests due to cephalothin. N Engl J Med 277:123, 1967.

Zeger G, Smith L, McQuiston D, Goldfinger D: Cisplatin-induced nonimmunologic adsorption of immunoglobulin by red cells. Transfusion 28:493, 1988.

Muirhead EE, Groves M, Guy R, et al: Acquired hemolytic anemia, exposures to insecticides and positive Coombs’ test dependent on insecticide preparations. Vox Sang 4:277, 1959.

Lindberg LG, Norden A: Severe hemolytic reaction to chlorpromazine. Acta Med Scand 170:195, 1961.

Eyster ME: Melphalan (Alkeran) erythrocyte agglutinin and hemolytic anemia. Ann Intern Med 66:573, 1967.

Robinson MG, Foadi M: Hemolytic anemia with positive Coomb’s test. Association with isoniazid therapy. JAMA 208:656, 1969.

Mueller-Eckhardt C, Kretschmer V, Coburg KH: Allergic, immunohemolytic anemia due to para-aminosalicylic acid (PAS). Immunohematologic studies of three cases. Dtsch Med Wochenschr 97:234, 1972.

Manor E, Marmor A, Kaufman S, Leiba H: Massive hemolysis caused by acetaminophen. JAMA 236:2777, 1976.

Vilal JM, Blum L, Dosik H: Thiazide-induced immune hemolytic anemia. JAMA 236:1723, 1976.

Letona JM-L, Barbolla L, Frieyro E, et al: Immune haemolytic anaemia and renal failure induced by streptomycin. Br J Haematol 35:561, 1977.

Korsager S, Sorensen H, Jensen OH, Falk JV: Antiglobulin tests for determination of autoimmunohaemolytic anaemia during long-term treatment with ibuprofen. Scand J Rheumatology 10:174, 1981.

Takahashi H, Tsukada T: Triamterine-induced immune hemolytic anemia with acute intravascular hemolysis and acute renal failure. Scand J Haematol 23:169, 1979.

Wong KY, Boose GM, Issitt CH: Erythromycin-induced hemolytic anemia. J Pediatr 98:647, 1981.

Sandvei P, Nordhagen R, Michaelsen TE, Wolthuis K: Fluorouracil (5-FU) induced acute immune haemolytic anaemia. Br J Haematol 65:357, 1987.

Tafani O, Mazzoli M, Landini G, Alterini B: Fatal acute immune haemolytic anaemia caused by nalidixic acid. Br Med J 285:936, 1982.

Angeles ML, Reid ME, Yacob UA, Cash KL, Fetten JV: Sulindac-induced immune hemolytic anemia. Transfusion 34:255, 1994.

Marks DR, Joy JV, Bonheim NA: Hemolytic anemia associated with the use of omeprozole. Am J Gastroenterol 86:217, 1991.

Blum MD, Graham DJ, McCloskey CA: Temafloxacin syndrome: review of 95 cases. Clin Infect Dis 18:946, 1994.

Marani TM, Trich MB, Armstrong KS, et al: Carboplatin-induced immune hemolytic anemia. Transfusion 36:1016, 1996.

Kerr RO, Cardamone J, Dalmasso AP, Kaplan ME: Two mechanisms of erythrocyte destruction in penicillin-induced hemolytic anemia. N Engl J Med 287:1322, 1972.

Nesmith LW, Davis JW: Hemolytic anemia caused by penicillin. JAMA 203:27, 1968.

Yust I, Frisch B, Goldsher N: Simultaneous detection of two mechanisms of immune destruction of penicillin-treated human red blood cells. Am J Hematol 13:53, 1982.

Brandriss MW, Smith JW, Steinman HG: Common antigenic determinants of penicillin G, cephalothin and 6-aminopenicillanic acid in rabbits. J Immunol 94:696, 1965.

Abraham GN, Petz LD, Fudenberg HH: Immuno-hematological cross-allergenicity between penicillin and cephalothin in humans. Clin Exp Immunol 3:343, 1968.

Petz LD: Immunologic cross reactivity between penicillins and cephalosporins: a review. J Infect Dis 137:S74, 1978.

Kunicki TJ, Russell N, Nurten AT, et al: Further studies of the human platelet receptor for quinine- and quinidine-dependent antibodies. J Immunol 126:398, 1981.

Christie DJ, Aster RH: Drug-antibody-platelet interaction in quinine- and quinidine-induced thrombocytopenia. J Clin Invest 70:989, 1982.

Berndt MC, Chong BH, Bull HA, et al: Molecular characterization of quinine/quinidine drug-dependent antibody platelet interaction using monoclonal antisera. Blood 66:1292, 1985.

Sosler SD, Behzad O, Garratty G, et al: Acute hemolytic anemia associated with a chlorpropamide-induced apparent auto-anti-Jka. Transfusion 24:206, 1984.

Salama A, Mueller-Eckhardt C: Rh blood group-specific antibodies in immune hemolytic anemia induced by nomifensine. Blood 68:1285, 1986.

Salama A, Mueller-Eckhardt C: On the mechanisms of sensitization and attachment of antibodies to RBC in drug-induced immune hemolytic anemia. Blood 69:1006, 1987.

Christie DJ, Mullen PC, Aster RH: Fab-mediated binding of drug-dependent antibodies to platelets in quinidine- and quinine-induced thrombocytopenia. J Clin Invest 75:310, 1985.

Smith ME, Reid DM, Jones CE, et al: Binding of quinine- and quinidine-dependent drug antibodies to platelets is mediated by the Fab domain of immunoglobulin G and is not Fc dependent. J Clin Invest 29:912, 1987.

Salama A, Mueller-Eckhardt C: The role of metabolite-specific antibodies in nomifensine-dependent immune hemolytic anemia. N Engl J Med 313:469, 1985.

Kelton JG: Impaired reticuloendothelial function in patients treated with methyldopa. N Engl J Med 313:596, 1985.

Worlledge SM: Immune drug-induced hemolytic anemias. Semin Haematol 10:327, 1973.

Petz LD, Garratty G (eds): Acquired Immune Hemolytic Anemia. Churchill Livingstone, New York, 1980.

Bakemeier RF, Leddy JP: Erythrocyte autoantibody associated with alpha-methyldopa: heterogeneity of structure and specificilty. Blood 32:1, 1968.

Leddy JP, Falany JL, Kissel GE, et al: Erythrocyte membrane proteins reactive with human (warm-reacting) anti-red cell autoantibodies. J Clin Invest 91:1672, 1993.

Green FA, Jung CY, Rampal A, Lorusso DJ: Alpha-methyldopa and the erythrocyte membrane. Clin Exp Immunol 40:554, 1980.

Green Fa, Jung CY, Hui H: Modulation of alpha-methyldopa binding to the erythrocyte membrane by superoxide dismutase. Biochem Biophys Res Commun 95:1037, 1980.

Kirtland HH III, Mohler DN, Horwitz DA: Methyldopa inhibition of suppressor-lymphocyte function. A proposed cause of autoimmune hemolytic anemia. N Engl J Med 302:825, 1980.

Garratty G, Arndt P, Prince HE, Schulman IA: The effect of methyldopa and procainamide on suppressor cell activity in relation to red cell autoantibody production. Br J Haematol 84:310, 1993.

Spath P, Garratty G, Petz LD: Studies on the immune response to penicillin and cephalothin in humans. II. Immunohematologic reactions to cephalothin administration. J Immunol 107:860, 1971.

Garratty G, Petz L: Drug-induced hemolytic anemia. Am J Med 58:398, 1975.

Salama A, Santoso S, Mueller-Eckhardt C: Antigenic determinants responsible for the reactions of drug-dependent antibodies with blood cells. Br J Haematol 78:535, 1991.

Zulian GB, Roux E, Tiercy J-M, et al: Transfusion-associated graft-versus-host disease in a patient treated with cladribine (2-chlorodeoxyadenosine): demonstration of exogenous DNA in various tissue extracts by PCR analysis. Br J Haematol 89:83, 1995.

Briz M, Cabrera R, Sanjuan I: Diagnosis of transfusion-associated graft-versus-host disease by polymerase chain reaction fludarabine-treated B-chronic lymphocytic leukaemia. Br J Haematol 91:409, 1995.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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