Defining the mechanistic causes of clot failure arising from trauma-induced coagulopathy

Traumatic injury is a leading cause of death worldwide, accounting for nearly 5 million deaths annually. Hemorrhage leads to 40% of these deaths and remains the leading cause of potentially preventable death, underscoring the need for improved treatments. Trauma-Induced Coagulopathy (TIC), a multifactorial disruption of coagulation, impairs stable blood formation and can exacerbate bleeding and thrombotic complications. Present in up to 25% of severely injured trauma patients, TIC increases mortality 4-6-fold. Diverse coagulopathic phenotypes exist, ranging from hyper- to hypocoagulant, and can be paired with fibrinolytic activity, each presenting a unique challenge for clinical management. Significant contributors to coagulopathy include hypothermia, metabolic acidosis, dilution of blood from resuscitation fluids, and release of enzymes and proteins from severe tissue trauma influencing hemostatic processes. These pathways govern the progression of TIC on a patient-specific basis. However, the impact of these pathways on clot stability, and hemorrhage mortality have not been fully defined. This dissertation addresses these knowledge gaps by evaluating how TIC-related factors, novel biomarkers and patient vital signs, influence clot formation, mechanical stability and clinical outcome. Utilizing viscoelastic testing of whole blood, plasma rheology and turbidity, and confocal imaging, we defined how severe injury and patient characteristics shape fibrin network formation, fibrinolysis, fibrin network structure. In collaboration with critical care physicians, we characterized post-injury pathophysiology and their relation to coagulation within a cohort of severely injured trauma patients at the Robert Wood Johnson University Hospital. By recreating these changes in-vitro, we identified that fibrinogen depletion, hyperfibrinolysis and hypothermia are key drivers of impaired clot formation and weakened clot stiffness. Additional analysis identified a key role that injury mechanism produces unique coagulopathic phenotypes, underscoring the need for personalized treatment. This work has identified measurable coagulation parameters and biomarkers predictive of mortality, establishing targetable mechanistic links between dysregulated clot formation and patient mortality.