Background: Hemorrhage, in particular noncompressible hemorrhage, is the leading cause of casualties in combat trauma and civilian trauma. Although systemic agents can stop bleeding at both inaccessible and accessible injury sites, the application of systemic hemostats in clinics is strictly limited by the nontargeting ability of hemostats and their subsequent potential for thromboembolic complications.
Objectives: To engineer an anticoagulant/procoagulant self-converting and bleeding site-targeting systemic nanohemostat to rapidly control noncompressible bleeding without thrombosis risk.
Methods: A multiscale computer simulation was taken to guide the self-assembly of sulindac (SUL, a prodrug of the antiplatelets agent) and poly-L-lysine (a cation polymer with platelets activation ability) for forming poly-L-lysine/SUL nanoparticles (PSNs). In vitro platelet-adhering ability, platelet activation effect, and hemostasis activity of PSNs were evaluated. Then, the biosafety, level of thrombosis, targeting ability, and hemostasis effect of systemic applied PSNs were carefully evaluated in various hemorrhage models.
Results: PSNs were successfully prepared and showed good platelet adhesion and activation in vitro. The bleeding site-targeting ability and hemostatic efficiency in different bleeding models were leveled up by PSNs markedly compared with vitamin K and etamsylate in vivo. SUL in PSNs could be metabolized into sulindac sulfide at clot sites in 4 hours for antiplatelet aggregation, thus reducing thrombotic risk compared with other hemostatic agents, via the ingenious utilization of prodrug metabolism in terms of time intervals and the adhesion on platelets.
Conclusion: PSNs are expected to be a low-cost, safe, efficient, clinically translatable first-aid hemostat for first-aid scenarios.
Keywords: hemostasis; poly-L-lysine; sulindac; thrombosis; trauma.
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