In Focus
Drug-Induced Immune Thrombocytopenia
Challenges in both diagnosis and treatment
Drug-induced immune thrombocytopenia (DITP) stands as a considerable diagnostic and therapeutic hurdle in clinical practice, warranting a detailed understanding of its mechanisms, identification, and management. DITP is characterized by an acute drop in platelet counts triggered by pharmacotherapy. The condition is not rare, but is most likely underdiagnosed. up to 6.3% of hospitalized patients may experience DITP1.
Pathophysiology
Certain medications trigger an immune response, resulting in the production of antibodies, primarily of the IgG subtype. These antibodies bind to platelets and activate two main pathways leading to platelet destruction: the complement cascade, or phagocytosis2. Drug-dependent antibodies bind to glycoproteins on the platelet surface exclusively in the presence of the drug; once the drug is absent from the patient’s circulation, no further platelet destruction is observed. Typical drugs with the ability to induce DITP include antibiotics and painkillers. A comprehensive list can be found in the recent article by Nusrat et al3.
Clinical Presentation
Patients typically develop DITP within 5-10 days following the initial dose of the implicated drug. The hallmark of DITP is a dramatic drop in platelet counts, often below 20.000/uL. Such depletion predisposes patients to bleeding. Bleeding can range from mild to severe, with a 9% incidence of severe bleeding and a 0.8% chance of fatal outcomes in older case series4. In case of drug re-exposure, DITP can occur within the first 1-2 days.
Diagnosis
DITP should be suspected in patients who present with thrombocytopenia 5-10 days after starting a new medication. A set of clinical criteria, including recovery of platelet counts after discontinuation of the suspected drug, has been described to help clinicians diagnose DITP (Table 1)4. The diagnosis of DITP should only be made if the presence of drug-dependent antibodies is confirmed in a specific assay that demonstrated the binding of antibodies to platelets in the presence, but not in the absence of the drug5. Fluorescence-activated cell sorting (FACS) is particularly useful, as it uses fluorescently labeled anti-human IgG and IgM antibodies to identify drug-dependent antibodies bound to platelets. Platelets isolated from healthy donors are incubated with the patient's serum, both in the presence and absence of the suspected drug, to determine the drug-dependency of the antibodies (Figure 1.) A positive result in the test is highly specific for the presence of drug-dependent platelet antibodies, making it advisable for patients with such a result to avoid future exposures to the implicated drug. Conversely, a negative test outcome does not necessarily exclude the possibility of the syndrome, especially considering the test's low sensitivity concerning certain medications5. It should be kept in mind that not only drug itself, but also its water-soluble metabolites may cause DITP. Many laboratories are thus also using patient urine in the diagnostic set-up. Although this approach is conceivable and may increase diagnostic sensitivity, it is very difficult to control.
Figure 1. Fluorescence histograms showing IgG drug dependent antibody detection by flow cytometry assay.
Treatment Modalities
Immediate discontinuation of the suspected drug is the cornerstone of DITP treatment. Following drug withdrawal, platelet counts usually begin to recover after 4-5 half-lives of the drug or its metabolites. In complex cases involving multiple medications, it may be necessary to stop all medication if a laboratory test is not available in an appropriate amount of time. Intravenous immunoglobulin (IVIG) in addition to stopping the drug is a treatment modality that shows efficacy, usually leading to an increase in platelet counts within 48 hours of administration6. It may be considered in DITP patients with severe thrombocytopenia and life-threatening bleeding.
Conclusions
DITP is a relevant clinical entity that requires rapid diagnosis and management to prevent severe complications It is very important to consider DITP as a differential diagnosis especially in patients with sudden-onset, severe thrombocytopenia.
Table 1. Criteria and level of evidence for drug induced immune thrombocytopenia (adapted from George et al. 19984) Note: Criterion no. 4 should not be sought, especially not prospectively.
References
- Fountain EM, Arepally GM. Etiology and complications of thrombocytopenia in hospitalized medical patients. J Thromb Thrombolysis. 2017 May;43(4):429-436. doi: 10.1007/s11239-016-1467-8. PMID: 28054307.
- Curtis BR. Drug-induced immune thrombocytopenia: incidence, clinical features, laboratory testing, and pathogenic mechanisms. Immunohematology. 2014;30(2):55-65. PMID: 25247620.
- Nusrat S, Borogovac A, George JN, Curtis BR, Reese JA. Drug (vaccine)-induced thrombocytopenia 2021: Diversity of pathogenesis and clinical features. Am J Hematol. 2022 Apr;97(4):E162-E165. doi: 10.1002/ajh.26482. Epub 2022 Feb 15. PMID: 35092624; PMCID: PMC9011425.
- George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S, Vondracek T. Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med. 1998 Dec 1;129(11):886-90. doi: 10.7326/0003-4819-129-11_part_1-199812010-00009. PMID: 9867731.
- Arnold DM, Curtis BR, Bakchoul T; Platelet Immunology Scientific Subcommittee of the International Society on Thrombosis and Hemostasis. Recommendations for standardization of laboratory testing for drug-induced immune thrombocytopenia: communication from the SSC of the ISTH. J Thromb Haemost. 2015 Apr;13(4):676-8. doi: 10.1111/jth.12852. Epub 2015 Feb 17. PMID: 25604471; PMCID: PMC4854622.
- Marini I, Uzun G, Jamal K, Bakchoul T. Treatment of drug-induced immune thrombocytopenias. Haematologica. 2022 Jun 1;107(6):1264-1277. doi: 10.3324/haematol.2021.279484. PMID: 35642486; PMCID: PMC9152960.
