Drug‐induced thrombocytopenia: 2019 Update of clinical and laboratory data
Authors: Alekhya Mitta, Brian R. Curtis, Jessica A. Reese, James N. George
Journal: American Journal of Hematology (2018)

Thrombocytopenia caused by drug-dependent antibodies occurs suddenly, is typically severe, is often misdiagnosed and therefore commonly recurs. To document drugs (and also beverages, foods and food supplements) that have definite clinical evidence for causing immune-mediated thrombocytopenia, we have systematically reviewed all published reports of drug-induced thrombocytopenia (DITP) since 1998.1 We established a web site that lists all reports of thrombocytopenia attributed to drugs, beverages, foods and food supplements with their level of evidence for a causal association (www.ouhsc.edu/platelets/ditp). Our web site also includes the experience of the BloodCenter of Wisconsin with identification of drug-dependent, platelet-reactive antibodies in patients with suspected DITP.2 We have defined definite evidence for a causal association of a drug with thrombocytopenia as recurrent acute thrombocytopenia with recurrent drug exposure and/or documentation of drug-dependent, platelet-reactive antibodies. This combination methodology provides strong support for clinicians who are considering the diagnosis of DITP. This report describes our current search of 8 databases for articles published January, 2015-November, 2018 (Supporting Information Table S1) to identify reports describing definite evidence for a causal association of the drug with thrombocytopenia. Fifty-two articles reported evaluable data for 61 individual patients with thrombocytopenia attributed to 46 drugs and 1 food supplement. Definite clinical evidence for a causal association was described for 18 drugs and the food supplement; 10 drugs and the food supplement had not been previously described with definite evidence. Nine articles reported evaluable group data; only one report of quinine treatment described definite evidence for a causal association and quinine has been previously reported with definite evidence.1 Supporting Information Table S2 summarizes the data for the 61 evaluable reported patients and the 9 articles reporting evaluable group data. These new data from our systematic literature review together with the new data from the BloodCenter of Wisconsin are merged with the previously reported data on our updated web site. Table 1A lists the 10 drugs plus 1 food supplement that have not been previously reported with definite evidence for a causal association with thrombocytopenia. Three of the 10 drugs (dexamethasone, leukovorin, ondansetron) were simultaneously identified in two patients receiving combination cancer chemotherapy.3 Both patients had platelet-reactive antibodies dependent on each of these three drugs. Both patients also had oxaliplatin-dependent and irinotecan-dependent, platelet-reactive antibodies; these two drugs had been previously reported to cause DITP (www.ouhsc.edu/platelets/ditp). The authors postulated that the primary immunologic reaction was the formation of oxaliplatin-dependent antibodies, which then created increased risk for development of platelet-reactive antibodies dependent on the other drugs.3 The report of thrombocytopenia caused by a food supplement containing citrus flavonoids described a patient who had recurrent episodes of severe thrombocytopenia before recognition of the food supplement as the etiology.4 Presence of citrus flavonoid-dependent, antibodies was not reported. Testing for food or food supplement-dependent antibodies may be more complex than testing for drug-dependent antibodies, since foods and food supplements may contain many distinct molecules. However, the previous documentation of platelet-reactive antibodies dependent on English walnuts in a patient with recurrent severe English walnut-induced thrombocytopenia provides a clear example for laboratory confirmation of food-induced acute, severe, recurrent thrombocytopenia.5 Trivalent inactivated influenza vaccination was reported to precede the sudden occurrence of severe thrombocytopenia by 6-7 days in 2010, 2012 and 2013 in a 4 year-old boy.6 The authors' interpretation was that the influenza vaccine induced primary immune thrombocytopenia (ITP), rather than DITP, because ITP has been previously associated with measles-mumps-rubella (MMR) vaccinations. This child recovered from his third episode within 10 days, with IVIg treatment; previous episodes persisted longer. We believe that DITP is the appropriate diagnosis because the 3 acute episodes of severe thrombocytopenia all occurred within a week following influenza vaccinations and his recovery was complete. Recovery of DITP typically occurs in less than 1 week after the drug is discontinued, but the duration of thrombocytopenia may be longer when the sensitizing molecule (in this patient, inactivated influenza viruses) remains in the plasma for longer than 1 day. During this period, 2015-2018, the BloodCenter of Wisconsin identified drug-dependent antibodies associated with 8 drugs for which drug-dependent antibodies had not been previously identified (Table 1B). The relative frequency of individual drugs as the cause of thrombocytopenia can be estimated by the frequency of identification of drug-dependent antibodies among all requests for testing for drug-dependent antibodies in patients with suspected DITP. Table 1C lists the drugs for which drug-dependent, anti-platelet antibodies were most commonly identified. Vancomycin was the most commonly suspected etiology for DITP, based on the number of requests for testing for drug-dependent antibodies. Vancomycin was also the drug for which drug-dependent, platelet-reactive antibodies were most often identified. Sulfamethoxazole was the second most common drug for which drug-dependent, platelet-reactive antibodies were identified. Sulfamethoxazole is combined with trimethoprim in Bactrim; trimethoprim-dependent antibodies have also been identified in patients taking Bactrim. Piperacillin was the third most common drug for which drug-dependent, platelet-reactive antibodies were identified. Piperacillin is commonly given in combination with tazobactam (Zosyn). Tazobactam-dependent, platelet-reactive antibodies have not been identified. Rifampin and oxaliplatin were also common causes of DITP, based on the frequency of drug-dependent, platelet-reactive antibodies identified by the BloodCenter of Wisconsin. Acute, severe and recurrent episodes of thrombocytopenia caused by drugs (and also beverages, foods, and food supplements) are not rare. Our data describing drugs that have been documented to cause immune-mediated DITP by both clinical and laboratory evidence can help clinicians accurately diagnose DITP. This study involved no human or animal subjects and required no Institutional Review Board approval. All authors have no conflicts of interest or financial conflicts with this study. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.