PB0990 - Efficacy of a Platelet-derived Hemostatic Agent in Reversing P2Y12 Antagonist Therapy in Vivo

Background: Management of life-threatening bleeding in patients receiving antiplatelet agents (APA) remains a clinical dilemma. Although platelet transfusion is the principal therapeutic option, APA can also blunt the hemostatic effect of donor platelets placing patients at continued risk for significant hemorrhage

Aims: Here, we explored the preclinical efficacy and mechanism by which a freeze-dried, platelet-derived hemostat (FPH) agent modulates the activity of platelets from patients on APA.

Methods: Thirty APA-treated patients undergoing a percutaneous intervention (PCI) were enrolled and blood drawn after obtaining informed consent. Light transmission aggregometry and point-of-care (POC) assay were used to confirm inhibition of platelet function. Flow cytometry and VerifyNow PRUTest were employed to assess expression and activity of the P2Y12 receptor on FPH. The ability of FPH to reverse the blunted hemostatic and thrombotic activity of platelets from PCI patients was analyzed in a tail bleeding assay and intravital vascular injury model in mice that express the human A1 domain of von Willebrand factor (VWF HA1). A mechanism by which FPH exerts a pro-hemostatic activity was established using an FDA approved antithrombotic agent bivalirudin in identical in vivo assays.

Results: The POC device confirmed patient platelet hypo-responsiveness similar to LTA and correlated to the reduction in thrombus formation in vivo. FPH potently corrected the hemostatic defect in VWF HA1 mice in a dose dependent manner and reversed the effects of APA by augmenting the accrual of patient platelets at sites of vascular injury. This restoration in platelet function and hemostasis was largely attributable to adherent FPH-induced thrombin production at the site of injury, overcoming P2Y12 receptor blockage, which was obviated by the administration of the direct-thrombin inhibitor bivalirudin.

Conclusion(s): This study demonstrated the potential effectiveness of FPH in ameliorating the bleeding risk of patients on APAs, offering a titratable strategy for the management of bleeding complications induced by antiplatelet therapy