A Novel Peptide Hemostat for Enhanced Platelet Adhesion

Abstract

Uncontrolled hemorrhage is the leading cause of preventable death in trauma, particularly among individuals under 45 years of age. While significant progress has been made in managing external bleeding through pressure-based interventions and topical hemostats, internal, noncompressible hemorrhage at anatomically inaccessible sites continues to present a major clinical challenge. Current treatment strategies—such as transfusion of blood components and surgical intervention—are limited by logistical constraints, donor dependence, and inherent risks including pathogen transmission and immunogenicity. Critically, there are no systemically administered agents approved for point-of-care treatment of internal, non-compressible bleeding that could stabilize patients prior to definitive medical intervention. To address this urgent unmet need, my PhD research focused on the design and evaluation of Covodutide (Collagen and von Willebrand Factor dual binding peptide), a novel, bivalent peptide designed to enhance hemostasis through targeted platelet adhesion. Covodutide consists of two defined functional domains: a collagen-binding motif and a von Willebrand factor (vWF)- binding motif, enabling it to localize selectively to sites of vascular injury and reinforce the formation of the primary platelet plug. In contrast to conventional synthetic platforms that suffer from molecular heterogeneity and inconsistent functionalization, Covodutide is synthesized using solid-phase peptide chemistry, resulting in a molecule with fully defined architecture, fixed molecular weight, and exact stoichiometry between its functional units. This structural uniformity supports both predictable biological activity and clinically scalable manufacturing. The research presented in this thesis is structured around three central aims: (1) to design Covodutide as a uniform agent targeting physiologically relevant surfaces at the injury site; (2) to investigate its mechanism of action in enhancing platelet adhesion and plug formation in vitro; and (3) to evaluate its systemic safety and hemostatic efficacy across multiple preclinical bleeding models. Covodutide’s selective binding to collagen and vWF, by virtue of its carefully designed binding domains was confirmed via microfluidic and flow cytometry assays, while its functional capacity to augment hemostasis was demonstrated in platelet aggregation studies. In vivo, Covodutide showed robust hemostatic activity across four bleeding models including tail transection and femoral artery injury—both as a pre-treatment and as a post-injury rescue agent. Notably, Covodutide administration did not result in off-target effects, as validated by biodistribution, toxicity, and histopathological analyses. Formulated as a lyophilized powder that is easily reconstituted in saline, Covodutide is stable, rapidly deployable, and amenable to intravenous administration at precise doses in both military and civilian settings. In summary, Covodutide represents a first-in-class, dual-targeting peptide hemostat that merges molecular precision with rapid-acting hemostatic function.