A systematic evaluation of laboratory testing for drug‐induced immune thrombocytopenia

Abstract

To cite this article: Arnold DM, Kukaswadia S, Nazi I, Esmail A, Dewar L, Smith JW, Warkentin TE, Kelton JG. A systematic evaluation of laboratory testing for drug-induced immune thrombocytopenia. J Thromb Haemost 2013; 11: 169-76.Summary. Background: Drug-induced immune thrombocytopenia (DITP) can be confirmed by the demonstration of drugdependent platelet antibodies in vitro; however, laboratory testing is not readily accessible and test methods are not standardized. Objective: To identify drugs with the strongest evidence for causing DITP based on clinical and laboratory criteria. Patients/Methods: We developed a grading system to evaluate the quality of DITP laboratory testing. The ÔDITP criteriaÕ were: (i) Drug (or metabolite) was required for the reaction in vitro; (ii) Immunoglobulin binding was demonstrated; (iii) Two or more laboratories obtained positive results; and (iv) Platelets were the target of immunoglobulin binding. Laboratory diagnosis of DITP was considered definite when all criteria were met and probable when positive results were reported by only one laboratory. Two authors applied the DITP criteria to published reports of each drug identified by systematic review. Discrepancies were independently adjudicated. Results: Of 153 drugs that were clinically implicated in thrombocytopenic reactions, 72 (47%) were associated with positive laboratory testing. Of those, 16 drugs met criteria for a definite laboratory diagnosis of DITP and thus had the highest probability of causing DITP. Definite drugs were: quinine, quinidine, trimethoprim/sulfamethoxazole, vancomycin, penicillin, rifampin, carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxaliplatin and suramin; the glycoprotein IIbIIIa inhibitors abciximab, tirofiban and eptifibatide; and heparin. Conclusions: We identified drugs with the strongest evidence for an association with immune thrombocytopenia. This list may be helpful for ranking potential causes of thrombocytopenia in a given patient.

Approach to the Diagnosis and Management of Drug-Induced Immune Thrombocytopenia

“…Review of the serial platelet counts revealed that the platelet count began to fall on postoperative day 6 (from 220 × 10 9 /L on day 5 to 190 × 10 9 /L on day 6). This was compatible with DITP that could be explained by any of the following six drugs: carbamazepine, phenytoin, gentamicin, vancomycin, ranitidine, digoxin, with 2 of them (carbamazepine, vancomycin) meeting criteria for drugs that were known to have been implicated in DITP reactions by clinical and laboratory features (drug-dependent antibodies) [5]. In contrast, heparin-induced thrombocytopenia (HIT) was not a plausible diagnosis, for several reasons: (a) the onset of thrombocytopenia began only 3 days after starting UFH (eg, too soon to be explained by heparin-induced immunization), and (b) HIT is not characterized by such severe thrombocytopenia and mucocutaneous bleeding (rather, HIT is a prothrombotic syndrome).…”

“…Thus, by consensus among a group of experts, Arnold et al proposed the following criteria for the assessment of the quality of DITP laboratory test methods and results from published reports, called the "DITP criteria": (1) Drug (or drug metabolite) was required for the reaction in vitro; (2) Immunoglobulin binding was demonstrated; (3) Two or more laboratories obtained positive results on separate occasions; and (4) Platelets were the target of immunoglobulin binding. The laboratory diagnosis of DITP was considered definite when all criteria were met; and probable when positive results were reported by only one laboratory instead of two [5].…”

“…Author manuscript; available in PMC 2013 July 30. Test methods used to evaluate drugs suspected of causing DITP that met all validity criteria [5] Method Description…”

Difficulties in establishing the diagnosis of immune thrombocytopenia: An agreement study

“…Our proposed clinical criteria are similar to the framework previously used to classify patients with druginduced immune thrombocytopenia [7]. Limitations were the small sample size, lack of a gold standard for the diagnosis of many thrombocytopenic disorders and referral bias from our tertiary-care hematology clinic.…”

Metronidazole caused profound drug‐induced immune thrombocytopenia

“…The patient should be flagged as allergic to the drug, to prevent future exposures. The clinical role of DDab testing has not been firmly established, and DITP remains a clinical diagnosis, because there are few centers that offer DDab testing and laboratory protocols for DDab testing are not standardized between these centers 6.…”