Fibrin Structure and Function: New Insights in Coagulopathy and Cardiovascular Therapies

Fibrinogen polymerizes into fibrin in the final steps of the coagulation cascade producing the structural backbone for blood clots. After fulfilling its initial function as a wound sealant, fibrin provides scaffolding and chemotactic gradients for recellularization. As such, fibrin is essential to the success of short-term wound closure and long-term tissue remodeling. The overall goal of the studies described in this dissertation was to investigate the relationship between fibrinogen structure and function in order to develop novel approaches to cardiovascular disease, with emphasis on three different clinical applications. Aim 1 used fibrinogen as a lens for building a deeper understanding of COVID-induced coagulopathy. These studies demonstrated that COVID-19 patient fibrinogen had more sialic acid residues and formed denser and stiffer clots with altered polymerization kinetics. Desialylation partially resolved these differences, indicating a potential molecular cause. In neonates, acquired hypofibrinogenemia is a common outcome of cardiopulmonary bypass, which can lead to life-threatening bleeding, but current treatments are not as effective when applied to the altered neonatal hemostatic balance. Aim 2 explored the use of fibrinogen concentrate in neonates after cardiopulmonary bypass. These studies showed that clot structure was successfully recovered through the use of fibrinogen concentrate. In surgery, vessel (re)connection requires significant time, but high-density fibrin glues used to prevent bleeding and hasten procedures worsen long-term healing. Aim 3 focused on the development of colloidal-fibrillar composite fibrin gels for use as a surgical sealant and wound healing material through the integration of colloidal fibrin-based nanoparticles (FBNs) into fibrillar fibrin. FBNs loaded with the retinoid agonist tazarotene were used to make a drug-loaded composite gel. Testing in a leporine model of vascular healing demonstrated that both forms of colloidal-fibrillar sealant resulted in superior tissue remodeling than gold standard control or high-density fibrin glue. Fibrinogen structure and function continue to hold promise for further discoveries in the fields of wound healing and biomaterials development. The varied studies completed in pursuit of this dissertation represent a contribution to both bulk and colloidal fibrin materials for intraoperative applications, as well as deepening understanding of the role of fibrin structure in varied coagulopathies.