Modulating the adhesive strength of blood clots by coagulation factor XIIIa-based technologies

Trauma is the number one killer of people under the age of 45 worldwide. Hemorrhage is the second-leading cause of death after injuries to the central nervous system and constitutes more than 90% of potentially survivable injuries as reported in a military trauma study. Understanding the components and functions of the blood coagulation system has led to advances in the development of hemostatic materials. Blood clots form plugs over leaking vessels to stop bleeding. They need to be cohesive to resist fracture from the pressures of blood flow, and adhesive to stay localized to the wound site. While the adhesive properties of individual clot components have been well-characterized, the adhesive properties of the bulk clot are still poorly understood. It is unclear how clot components interact with themselves and substrates on the wound surface to mediate attachment of the clot to the wound site. In this study, we evaluated the adhesive strength of bulk blood clots. We determined which clot components were important in increasing clot adhesive strength to collagen, a common substrate found in wound tissues. We found that fibrin and FXIIIa increased clot adhesive strength in a concentration-dependent manner. Using this knowledge, we designed a formulation containing Q-PEG, a FXIIIa-crosslinkable synthetic macromer. The gelation of Q-PEG was coupled to the coagulation network through FXIIIa, allowing it to copolymerize with blood when clotting was activated. Copolymerizing Q-PEG with blood led to increased clot adhesion, particularly during fibrin-depleted or fibrinolytic conditions. This shows that clot adhesive strength is a property that can be modulated. Similar strategies, of coupling synthetic polymer formation to the coagulation cascade, may be useful for the design of novel hemostatic materials that improve the mechanical properties of blood clots to help them resist high pressure arterial hemorrhage. A broader application would be in the design of smart, stimuli-responsive materials, using natural biochemical networks as highly sensitive and specific sensors and signal amplifiers to control polymer formation. Science, Faculty ofGraduat