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Drug-Induced Immune Thrombocytopenia

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Drug-Induced Immune Thrombocytopenia T h e new england journal o f medicine review article current concepts Drug-Induced Immune Thrombocytopenia Richard H. Aster, M.D., and Daniel W. Bougie, Ph.D. From the Department of Medicine, Medi- rug-induced thrombocytopenia can be caused by dozens, per- cal College of Wisconsin (R.H.A.), and the haps hundreds, of medications. Because thrombocytopenia can have many Blood Research Institute, BloodCenter of Wisconsin (R.H.A., D.W.B.) — both in Dother causes, the diagnosis of drug-induced thrombocytopenia can easily Milwaukee. Address reprint requests to be overlooked. On occasion, outpatients with drug-induced thrombocytopenia are Dr. Aster at the Blood Research Institute, treated for autoimmune thrombocytopenia and can have two or three recurrences BloodCenter of Wisconsin, 8727 Water- 1 town Plank Rd., Milwaukee, WI 53226-3548, before the drug causing the disorder is identified. In acutely ill, hospitalized pa- or at [email protected]. tients, drug-induced thrombocytopenia can be overlooked because thrombocytope- nia is attributed to sepsis, the effect of coronary-artery bypass surgery, or some other N Engl J Med 2007;357:580-7. Copyright © 2007 Massachusetts Medical Society. underlying condition. Although drug-induced thrombocytopenia is uncommon, it can have devastating, even fatal consequences that can usually be prevented simply by discontinuing the causative drug. It is therefore important that clinicians have a general understanding of this condition and the drugs that can cause it. In this review, we focus on conditions in which exposure to a drug leads to the destruction of circulating platelets, often accompanied by bleeding symptoms. We do not consider thrombocytopenia resulting from dose-dependent hematosuppres- sion, which often occurs after treatment with chemotherapeutic and immunosup- pressive agents such as cisplatin and cyclophosphamide.2 Although heparin-induced thrombocytopenia is the most common drug-related cause of a drop in the platelet count, we do not discuss this condition because of its complexity and because thrombosis, rather than thrombocytopenia, is the major threat to an affected pa- tient. Because heparin is often given together with certain drugs that are likely to cause drug-induced thrombocytopenia (platelet inhibitors and vancomycin), it is important to distinguish between heparin-induced thrombocytopenia and drug- induced thrombocytopenia. Heparin-induced thrombocytopenia was recently re- viewed in the Journal.3 Drug-induced platelet destruction is usually caused by drug-induced antibodies, but this can be difficult to prove. In this review, we include many conditions for which an immune cause has not yet been fully documented. Although platelets are the preferred targets of drug-induced antibodies, drugs can also cause immune hemolytic anemia4 and neutropenia5 through similar mechanisms. Presentation Acute thrombocytopenia after exposure to quinine was recognized as a clinical entity about 140 years ago.6 Subsequently, many other medications were implicated in the development of this condition. Quinine, which is rarely used now as an anti- malarial drug but is often prescribed for nocturnal muscle cramps, may still be the most common trigger. People of any age and either sex can be affected. The course of drug-induced thrombocytopenia in a representative patient is shown in Figure 1. Typically, a patient will have taken the sensitizing drug for about 1 week or intermittently over a longer period before presenting with petechial 580 n engl j med 357;6 www.nejm.org august 9, 2007 Downloaded from www.nejm.org at NORTHSHORE UNIVERSITY HEALTH SYSTEM on April 22, 2009 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. current concepts hemorrhages and ecchymoses that are indicative of thrombocytopenia. Occasionally, symptoms de- 3.0 velop within 1 or 2 days after what is apparently the first exposure to a drug, particularly in pa- 2.5 ) tients given platelet inhibitors such as abciximab 3 2.0 who may have preexisting, perhaps naturally oc- Platelet /mm transfusion 7 −5 curring, antibodies. Systemic symptoms such as 0 1.5 lightheadedness, chills, fever, nausea, and vom- ×1 iting often precede bleeding symptoms. Severely Petechiae and 1.0 oral and urinary affected patients have florid purpura and bleed- bleeding Platelets ( ing from the nose, gums, and gastrointestinal 0.5 or urinary tract (“wet purpura”). In such cases, thrombocytopenia is invariably severe (<20,000 0.0 platelets per cubic millimeter). 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 If the causative medication is stopped, symp- Days toms usually resolve within 1 or 2 days, and the platelet count returns to normal in less than a Figure 1. Course of Immune Thrombocytopenia in a Patient Treated with Sulfamethoxazole. week. For reasons that are poorly understood, Trimethoprim–sulfamethoxazole was prescribed for treatment of a urinary patients with drug-induced thrombocytopenia oc- tract infection in a 29-year-old woman. On day 7 of treatment,RETAKE 1stpetechiae ICM AUTHOR: Aster casionally present with disseminated intravascu- and ecchymoses, buccal hemorrhage, and gross urinary bleeding2nd developed, REG F FIGURE: 1 of 2 lar coagulation8 or renal failure and other find- and the antibiotic treatment was stopped. Her platelet count was3rd 4000 per cubic millimeter.CASE A platelet transfusion given on day 9 Revisedhad little effect on ings indicative of the hemolytic–uremic syndrome EMail Line 4-C SIZE 9 the platelet count. SustainedARTIST: recoveryts occurred during the next few days. or thrombotic thrombocytopenic purpura. H/T H/T 22p3 A strong sulfamethoxazole-dependent,Enon Combo platelet-reactive antibody was detect- ed in a blood sample obtainedAUTHOR, on day PLEASE 9 and was NOTE: still present after 3 months Incidence and after 5 years. FigureNo trimethoprim-dependent has been redrawn and type hasantibodies been reset. were detected. Please check carefully. The incidence of drug-induced thrombocytope- JOB: 356xx ISSUE: 08-02-07 nia is not well defined, in part because reporting is voluntary and is not critically reviewed. On have been implicated.2,12,13 Many of the drugs that the basis of several epidemiologic studies in the are common triggers for this disorder also cause United States and Europe, the estimated minimum sensitivity reactions involving the skin and other incidence is about 10 cases per million population organs.14 per year but the number could be higher in select- George and colleagues critically analyzed re- ed groups, such as hospitalized patients and ports of drug-induced thrombocytopenia pub- elderly people.10 A case–control study of patients lished through 200513,15 and identified 85 medi- in Massachusetts, Rhode Island, and Philadelphia cations for which a cause-and-effect relationship showed that during each week of exposure, tri- was considered to be “definite” (58 agents) or methoprim–sulfamethoxazole and quinine–quin- “probable” (27 agents) on the basis of clinical idine caused thrombocytopenia in 38 and 26 of criteria (Table 2).13 (A compendium of implicated every 1 million users, respectively.11 Since these drugs and case reports updated through August drugs carry relatively high risks of drug-induced 2004 is available at http://moon.ouhsc.edu/jgeorge/ thrombocytopenia, the rate at which most drugs DITP.html.) In the analysis by George et al., no cause the condition is probably lower. However, weight was given to laboratory demonstration of a few drugs (including abciximab and gold salts) drug-dependent antibodies. As improved tech- cause immune thrombocytopenia in about 1% of niques are developed, serologic testing may be- patients. come increasingly useful for identifying the spe- cific cause of thrombocytopenia in individual Causative Agents cases — albeit after the fact. Rare but convincing examples of drug-induced Many of the drugs shown in multiple studies to thrombocytopenia induced by herbal remedies16,17 be capable of causing drug-induced thrombocy- and foods18 have been described, and there are topenia are listed in Table 1, but at least 100 others numerous reports of acute, severe thrombocyto- n engl j med 357;6 www.nejm.org august 9, 2007 581 Downloaded from www.nejm.org at NORTHSHORE UNIVERSITY HEALTH SYSTEM on April 22, 2009 . Copyright © 2007 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine Table 1. Drugs Commonly Implicated as Triggers of Drug-Induced Thrombocytopenia.* Drug Category Drugs Implicated in Five or More Reports Other Drugs Heparins Unfractionated heparin, low-molecular-weight heparin Cinchona alkaloids Quinine, quinidine Platelet inhibitors Abciximab, eptifibatide, tirofiban Antirheumatic agents Gold salts D-penicillamine Antimicrobial agents Linezolid, rifampin, sulfonamides, vancomycin Sedatives and anticonvulsant agents Carbamazepine, phenytoin, valproic acid Diazepam Histamine-receptor antagonists Cimetidine Ranitidine Analgesic agents Acetaminophen, diclofenac, naproxen Ibuprofen Diuretic agents Chlorothiazide Hydrochlorothiazide Chemotherapeutic and immuno- Fludarabine, oxaliplatin Cyclosporine, rituximab suppressant agents * For a more extensive list, see Aster,2 Warkentin,12 and George et al.13 and the University of Oklahoma Web site (http:// moon.ouhsc.edu/jgeorge/DITP.html). Table 2. Criteria and Level of Evidence for Establishing a Causative Relationship in Drug-Induced Thrombocytopenic Purpura.* Criterion and Level of Evidence Description Criterion 1 Therapy with the candidate drug preceded thrombocytopenia,
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