Abstract

After the administration of GPIIb-IIIa antagonists, 1 – 3% of patients become thrombocytopenic, and 0.5 – 1% of patients develop profound thrombocytopenia. This GPIIb-IIIa antagonist-induced thrombocytopenia may be antibody mediated. In this study we demonstrated that GPIIb-specific monoclonal antibody 5B12 augmented platelet activation, as determined by platelet surface P-selectin and leukocyte-platelet aggregation) in the presence of therapeutic concentrations of abciximab, but not epitifibatide or tirofiban. Furthermore, the GPIIIa-specific monoclonal antibody Y2/51 augmented platelet activation in the presence of therapeutic concentrations of eptifibatide or tirofiban, but not abciximab. This activation was abolished by an FcγRII receptor (CD32)-specific antibody and was absent when Fab fragments 5B12 or Y2/51 were used. These results suggest that (i) GPIIb-IIIa antagonists cause conformational changes in GPIIb-IIIa; resulting in (ii) antibody binding to GPIIb-IIIa; and, consequently (iii) platelet activation via the FcγRII receptor. To determine whether this mechanism is operative in vivo, plasma from patients who developed abciximab-induced thrombocytopenia (n=2), eptifibatide-induced thrombocytopenia (n=5) and normal donors (n=7) was incubated with ABO Rh matched donor whole blood with and without therapeutic concentrations of GPIIb-IIIa antagonists. Platelet activation was assessed by flow cytometric measurement of platelet surface P-selectin. Abciximab, but not eptifibatide or tirofiban, increased platelet surface P-selectin in patients who developed abciximab-induced thrombocytopenia. Eptifibatide, but not abciximab or tirofiban, increased platelet surface P-selectin in patients who developed eptifibatide-induced thrombocytopenia. Platelet surface P-selectin in normal donors was not changed by abciximab, tirofiban or eptifibatide. These data (i) provide novel insight into the mechanisms of GPIIb-IIIa antagonist induced thrombocytopenia; and (ii) suggest a possible assay for the clinical diagnosis and prediction of this phenomenon.

Platelet surface P-selectin after addition of a GPIIb-IIIa antagonist (% baseline fluorescence). *p<0.05

 Abciximab Eptifibatide Tirofiban 
Normal donors 103 105 99 
Eptifibatide-induced thrombocytopenia 103 170 * 104 
Abciximab-induced thrombocytopenia 1571 * 108 105 
 Abciximab Eptifibatide Tirofiban 
Normal donors 103 105 99 
Eptifibatide-induced thrombocytopenia 103 170 * 104 
Abciximab-induced thrombocytopenia 1571 * 108 105 

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