Abstract Number: OC 26.4
Meeting: ISTH 2021 Congress
Background: Platelets render hemostasis by (i) adhering to vWF and collagen, (ii) aggregating via fibrinogen-mediated binding to GPIIb-IIIa, and (iii) exposing anionic phosphatidylserine (PS) on the surface to enable thrombin amplification which converts fibrinogen to fibrin. Therefore, platelet transfusions are approved for hemostatic management of severe bleeding. However, platelets have limited availability, high risk of bacterial contamination, and short shelf-life (~ 5 days), which severely limit their use. To address this, we have developed novel procoagulant synthetic platelets (P-SP), which (i) mimic the adhesion and aggregation capabilities of platelets and (ii) also enable procoagulant PS-exposure. Uniquely, this PS exposure was designed to be triggered by plasmin, such that injury site-localized plasmin activity, which usually causes fibrin instability, could instead be exploited to generate fibrin and offset lysis.
Aims: To evaluate P-SP in bleeding mitigation in thrombocytopenia and trauma.
Methods: P-SPs were manufactured with lipid nanoparticles surface-decorated with vWF-binding, collagen-binding and GPIIb-IIIa-binding peptides. PS was incorporated on the particle surface but was masked by a polymer brush that could only be cleaved by active plasmin. P-SP ability to restore thrombin and fibrin was measured spectrometrically in platelet-depleted plasma. P-SP ability to stabilize clots under tPA-spiked lytic environment was studied by microfluidics and ROTEM. Finally, P-SP effect was evaluated in vivo in a thrombocytopenic mouse model (tail clip) and a rat liver trauma model.
Unmasked P-SP significantly restored thrombin and fibrin generation in platelet-depleted plasma. Masked P-SP increased clot stability and delayed lysis under tPA-spiked environment, providing evidence that the plasmin produced by tPA could unmask the PS in situ for procoagulant function. In vivo, P-SP did not pose thrombotic risk but significantly reduced bleeding in thrombocytopenic mice. In rat trauma, P-SP reduced bleeding and improved survival.
Conclusions: P-SP can uniquely function as a platelet surrogate for hemostatic treatment of bleeding, when natural platelets are unavailable.
To cite this abstract in AMA style:Sen Gupta A, Didar Singh Sekhon U, Luc N, Girish A, de la Fuente M, Nieman M. Plasmin-responsive Procoagulant Synthetic Platelets for Fibrin Clot Stabilization in Hemorrhage Control [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/plasmin-responsive-procoagulant-synthetic-platelets-for-fibrin-clot-stabilization-in-hemorrhage-control/. Accessed March 4, 2024.
« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/plasmin-responsive-procoagulant-synthetic-platelets-for-fibrin-clot-stabilization-in-hemorrhage-control/