Peptide-mediated inhibition of surface-initiated thrombogenesis

Surface-induced fibrinogen misfolding drives thrombogenesis at hydrophobic material interfaces, as demonstrated in our prior mechanistic model. Extending this concept to pathophysiological settings, viral infection creates a clinically relevant prothrombotic environment by promoting lipid droplet release and elevating circulating fibrinogen levels, generating vascular interfaces that favor aberrant fibrin assembly. Targeted peptide inhibitors may provide a selective strategy to interrupt this surface-mediated process. P12, a fibronectin-derived peptide previously shown to attenuate burn progression, is a promising candidate for modulating surface-driven thrombogenesis.

To evaluate whether P12 disrupts surface-initiated thrombogenesis on biomaterial surfaces and prothrombotic endothelium and to define its mechanism of action.

P12-fibrin(ogen) interactions were assessed by immunofluorescence and supported by molecular dynamics simulations. Effects on fibrin(ogen) assembly, from molecular interactions to macroscopic clot formation, were analyzed using complementary multiscale microscopy techniques.

P12 selectively bound fibrin(ogen) within the αC-domain, specifically the N-terminal subdomain (Aα392-503), with preferential interaction spanning residues Aα476-496. Binding inhibited intermolecular interactions among surface-bound fibrin(ogen) and disrupted protofibril formation, thereby limiting fibrin assembly. P12 also bound soluble fibrin, reducing both its surface adsorption and ability to aggregate into fibers. Consistent with these effects, platelet accumulation was markedly reduced and thrombogenesis suppressed. Importantly, these inhibitory effects were preserved in a pathological context involving viral infection.

A targeted peptide can effectively inhibit surface-initiated thrombogenesis without directly impairing physiological clotting mechanisms. These findings support the translational potential of P12 for treating pathological thrombosis and inform the rational design of antithrombotic surfaces and therapeutics.