Tirofiban-induced thrombocytopenia is a well-known although uncommon complication of therapy . Delayed thrombocytopenia has been reported in association with abciximab, but not with tirofiban . We describe two cases of delayed tirofiban-induced thrombocytopenia in which tirofiban-dependent platelet antibodies were identified.
Patient 1, an 80-year-old man, was admitted to a peripheral hospital with a non-ST elevation myocardial infarction and was transferred to our institution for coronary angiography. The platelet count on admission was 240 × 109 L−1. Angiography showed severe triple vessel disease. An apical left ventricular thrombus was noted on a transthoracic echocardiogram. Intravenous heparin was commenced. He had significant ongoing chest pain, requiring the addition of tirofiban. He proceeded to coronary artery bypass grafting 4 days after admission. The platelet count on day 4 after initial tirofiban exposure was 122 × 109 L−1. This fell progressively, and reached a nadir of 1 × 109 L−1 on day 9. The patient was commenced on danaparoid and intravenous immunoglobulin, and received a platelet transfusion.
Patient 2, a 67-year-old man, was admitted with a non-ST elevation myocardial infarction and commenced on intravenous heparin and tirofiban. The initial platelet count was 212 × 109 L−1. Percutaneous coronary angioplasty and stent placement to the left anterior descending artery were performed. Both tirofiban and heparin were discontinued 24 h after the procedure. Clopidogrel and aspirin were continued. On day 5 after initial tirofiban exposure, the platelet count was 199 × 109 L−1. By day 7, the platelet count was 13 × 109 L−1. Clopidogrel was withheld and the patient was commenced on corticosteroids temporarily pending investigations.
In both cases, heparin-induced thrombocytopenia was excluded by both ELISA and serotonin release assay. Tirofiban-dependent antiplatelet antibodies were demonstrable in both cases by two separate methods. Drug-dependent antibodies to platelets were demonstrated in the presence of tirofiban, using flow cytometry techniques (Fig. 1a). A monoclonal antibody immobilization of platelet antigen assay confirmed the presence of antibodies to glycoprotein (GP) IIb/IIIa, detected only with the addition of tirofiban. Both these methods have been described in detail previously .
The platelet count of patient 1 on day 13 after tirofiban exposure was >50 × 109 L−1 and subsequently returned to normal. The platelet count of patient 2 recovered to >50 ×109 L−1 by day 11. We concluded that both these patients had a delayed tirofiban-induced thrombocytopenia, in which the nadir of the platelet counts occurred more than 6 days after first exposure to tirofiban (Fig. 1b).
These patients represent the first reported cases of delayed thrombocytopenia associated with tirofiban. GP IIb/IIIa inhibitor-induced thrombocytopenia is mediated by pre-existing autoantibodies (either naturally occurring or secondary to prior drug exposure) that bind after drug-induced conformational changes in the GP IIb/IIIa receptor, causing acute and severe thrombocytopenia several hours after drug administration [1,3]. A delayed thrombocytopenia is unexpected, as tirofiban is cleared early from the circulation, with a half-life of 2 h. We postulate that the nature of delayed GP IIb/IIIa inhibitor-induced thrombocytopenia is consistent with a primary immune response where antibodies develop after several days of drug exposure. Such a mechanism was shown for the recently described cases of delayed thrombocytopenia associated with abciximab in which drug-dependent antibodies were demonstrable . However, whilst antibody formation with drug exposure is easily understood, the mechanism of ongoing antibody binding to GP IIb/IIIa is less clear, as it appears to be drug-dependent in vitro. With regards to abciximab, there is evidence of platelet internalization of drug with binding to non-surface expressed GP IIb/IIIa , with persisting platelet inhibition well beyond the drug half-life . Whether such a phenomenon occurs with tirofiban is speculative. There is evidence of an increased rate of tirofiban-induced thrombocytopenia in association with other stimuli of platelet activation, presumably due to conformational changes in the GP IIb/IIIa receptor and exposure of neoepitopes . Perhaps platelet activation in vivo allows persistent antibody binding in the absence of drug.
In our institution, a protocol has been developed to identify cases of acute thrombocytopenia by performing a platelet count at 6 and 24 h following tirofiban administration with coronary angioplasty. However, the possibility of delayed thrombocytopenia may justify monitoring platelet counts up to a week following administration of tirofiban. Furthermore, measurement of drug-dependent antibodies is possible days after drug discontinuation and may be useful in confirming the cause of thrombocytopenia.