Comparative efficacy of fibrinogen and platelet supplementation on the in vitro reversibility of competitive glycoprotein IIb/IIIa (alpha IIb/beta(3)) receptor-directed platelet inhibition

Background Platelet surface glycoprotein (GP) IIb/IIIa (alpha IIb/beta (3)) receptor inhibition, by preventing fibrinogen binding and platelet aggrega tion, concomitantly attenuates arterial thrombotic capacity and impairs pro tective hemostasis, 2 divergent platelet-dependent processes. Because the c urrently available Food and Drug Administration-approved small molecule GP IIb/IIIa receptor antagonists are considered "competitive" inhibitors and b ecause there is limited information on the reversibility of platelet inhibi tion by fibrinogen or platelet supplementation, the following series of in vitro experiments were performed. Methods and Results Washed platelets from 24 healthy volunteers were suspen ded in Tyrodes buffer and incubated with achievable (in vivo) steady-state concentrations of either tirofiban or eptifibatide before activation with T RAP (thrombin receptor agonist peptide) (15 mu mol/L). Platelet aggregation was inhibited by 40% to 50%, but reversal was achieved by fibrinogen suppl ementation in a concentration-dependent manner. In a separate series of in vitro experiments, platelet inhibition exceeding 90% was established with t irofiban (average concentration 9.28 mug/L) and eptifibatide (average conce ntration 95.4 mug/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 x 10(11)/L), or their combination. There was an inverse relationship between plasma baseline fibrinogen and the amount of supplemental fibrinogen requi red to restore platelet aggregability (r = -0.60, P <.01). Conclusions The reversibility of GP IIb/IIIa-directed platelet inhibition i s influenced by cell surface receptor availability and the intrinsic pharma codynamic mechanism of action. Fibrinogen supplementation with fresh frozen plasma or cryoprecipitate either alone or in combination with platelet tra nsfusion, represents an important and readily available treatment considera tion For restoring hemostatic potential and managing major hemorrhagic comp lications associated with the administration of small molecule competitive GP IIb/IIIa receptor antagonists.