Comparative efficacy of fibrinogen and platelet supplementation on the in vitro reversibility of competitive glycoprotein IIb/IIIa (αIIb/β3
) receptor-directed platelet inhibition
Background: Platelet surface glycoprotein (GP) IIb/IIIa (αIIb/β3) receptor inhibition, by preventing fibrinogen binding and platelet aggregation, concomitantly attenuates arterial thrombotic capacity and impairs protective hemostasis, 2 divergent platelet-dependent processes. Because the currently available Food and Drug Administration-approved small molecule GP IIb/IIIa receptor antagonists are considered "competitive" inhibitors and because there is limited information on the reversibility of platelet inhibition by fibrinogen or platelet supplementation, the following series of in vitro experiments were performed. Methods and Results: Washed platelets from 24 healthy volunteers were suspended in Tyrodes buffer and incubated with achievable (in vivo) steady-state concentrations of either tirofiban or eptifibatide before activation with TRAP (thrombin receptor agonist peptide) (15 μmol/L). Platelet aggregation was inhibited by 40% to 50%, but reversal was achieved by fibrinogen supplementation in a concentration-dependent manner. In a separate series of in vitro experiments, platelet inhibition exceeding 90% was established with tirofiban (average concentration 9.28 μg/L) and eptifibatide (average concentration 95.4 μg/L). Recovery of platelet aggregation to at least 50% was achieved after the addition of fibrinogen (0.76-0.80 g/L), platelets (2.4 × 1011/L), or their combination. There was an inverse relationship between plasma baseline fibrinogen and the amount of supplemental fibrinogen required to restore platelet aggregability (r = -0.60, P < .01). Conclusions: The reversibility of GP IIb/IIIa-directed platelet inhibition is influenced by cell surface receptor availability and the intrinsic pharmacodynamic mechanism of action. Fibrinogen supplementation with fresh frozen plasma or cryoprecipitate either alone or in combination with platelet transfusion, represents an important and readily available treatment consideration for restoring hemostatic potential and managing major hemorrhagic complications associated with the administration of small molecule competitive GP IIb/IIIa receptor antagonists.
Li, YF; Spencer, FA; Becker, RC
Volume / Issue
Start / End Page
Digital Object Identifier (DOI)