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

BACKGROUND: Platelet surface glycoprotein IIb/IIIa (alphaIIb/beta3) receptor inhibition, with prevention of fibrinogen binding and platelet aggregation, concomitantly attenuates arterial thrombotic capacity and impairs protective hemostasis, 2 divergent platelet-dependent processes. PURPOSE: Because the currently available, Food and Drug Administration-approved small molecule glycoprotein IIb/IIIa receptor antagonists are considered "competitive" inhibitors and there is limited information on the reversibility of platelet inhibition with 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) concentrations of either tirofiban or eptifibatide before activation with thrombin receptor agonist peptide (15 micromol/L). Platelet aggregation was inhibited by 40% to 50%, but reversal was achieved with 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 microg/L) and eptifibatide (average concentration 95.4 microg/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 needed to restore platelet aggregability (r = -0.60; P <.01). CONCLUSION: The reversibility of glycoprotein IIb/IIIa-directed platelet inhibition is influenced by cell surface receptor availability and 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 glycoprotein IIb/IIIa receptor antagonists.