Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa

Abstract

Acute thrombocytopenia is a recognized complication of treatment with GPIIb/IIIa inhibitors whose cause is not yet known. We studied 9 patients who developed severe thrombocytopenia (platelets less than 25 × 109/L) within several hours of treatment with the GPIIb/IIIa inhibitors tirofiban (4 patients) and eptifibatide (5 patients). In each patient, acute-phase serum contained a high titer (range, 1:80-1:20 000) IgG antibody that reacted with the glycoprotein IIb/IIIa complex only in the presence of the drug used in treatment. Four patients had been previously treated with the same drug, but 5 had no known prior exposure. Pretreatment serum samples from 2 of the latter patients contained drug-dependent antibodies similar to those identified after treatment. No tirofiban- or eptifibatide-dependent antibodies were found in any of 100 randomly selected healthy blood donors, and only 2 of 23 patients receiving tirofiban or eptifibatide who did not experience significant thrombocytopenia had extremely weak (titer, 1:2) tirofiban-dependent antibodies. In preliminary studies, evidence was obtained that the 9 antibodies recognize multiple target epitopes on GPIIb/IIIa complexed with the inhibitor to which the patient was sensitive, indicating that they cannot all be specific for the drug-binding site. The findings indicate that acute thrombocytopenia after the administration of tirofiban or eptifibatide can be caused by drug-dependent antibodies that are “naturally occurring” or are induced by prior exposure to drug. These antibodies may be human analogs of mouse monoclonal antibodies that recognize ligand-induced binding sites (LIBS) induced in the GPIIb/IIIa heterodimer when it reacts with a ligand-mimetic drug.

Abciximab‐Associated Thrombocytopenia After Previous Tirofiban‐Related Thrombocytopenia

“…7 Ligand-Mimetic Agents A case series of nine patients treated with ligand-mimetic agents (four received tirofiban, five received eptifibatide) demonstrated that the thrombocytopenia was the result of antibodymediated platelet destruction. 8 The serum of each patient contained a high titer of immunoglobulin G antibody that reacted with the glycoprotein IIb-IIIa complex in the presence of the study drug. Antibodies cross-reacted with other glycoprotein IIb-IIIa inhibitors in only one of the nine patients; no antibodies cross-reacted with abciximab.…”

“…In fact, abciximab in vitro has inhibited the antibody reaction that causes thrombocytopenia associated with the ligandmimetic agents. 8 The proposed mechanism for this lack of cross-reactivity is the steric hindrance the molecule provides after binding to the glycoprotein IIb-IIIa receptor.…”

“…Reported medical management methods are platelet transfusion, and administration of corticosteroids and intravenous immunoglobulin (IGIV). 7,8,[13][14][15][16] Platelet transfusion is the most common treatment for thrombocytopenia associated with glycoprotein IIb-IIIa inhibitors. 7-9, 13, 15 However, this treatment is controversial.…”

Integrin αIIbβ3 specific synthetic human monoclonal antibodies and HCDR3 peptides that potently inhibit platelet aggregation

“…Because circulating antiidiotypic antibodies would compete with platelet integrin α ΙΙb β 3 for RAD antibody binding rather than bind to the platelet surface through the RAD antibodies, it is a reasonable assumption that they would not cause severe thrombocytopenia. An interesting recent finding was that human antibodies that selectively recognized integrin α ΙΙb β 3 when complexed with tirofiban and eptifibatide were found in the very limited number of patients who developed severe thrombocytopenia after being treated with the small molecule drugs (41). In this context, the possibility remains that RAD antibodies could cause thrombocytopenia by inducing the display of immunogenic epitopes on integrin α ΙΙb β 3 as their binding mode mimics the small molecule drugs.…”

Practical approach to the diagnosis and management of thrombocytopenia associated with tirofiban treatment

“…The only trial that directly compared abciximab to tirofiban showed a statistically significant increased risk of thrombocytopenia in the abciximab arm compared with the tirofiban arm [5]. Several reports of acute (within 24 hr after the bolus) and severe thrombocytopenia have been published for abciximab [6,7]; there are very few for eptifibatide [8][9][10][11], and only four cases of thrombocytopenia associated with tirofiban treatment have been reported with scarce clinical details [8]. We report on three cases of acute thrombocytopenia most likely attributable to tirofiban (Aggrastat TM ) treatment and comment on the practical management of the persistent thrombotic risk with particular emphasis on the importance of ruling out heparininduced thrombocytopenia.…”