The role of the protein C system in trauma induced coagulopathy and thromboinflammation: mechanisms and targeted therapy.

PROJECT SUMMARY: Trauma remains the leading cause of death for individuals aged 1 to 54, with a significant proportion of these fatalities attributed to trauma-induced coagulopathy (TIC) and a dysregulated inflammatory response, termed thromboinflammation. Advancements in resuscitation have lacked a mechanistic focus, instead, focusing on mitigating the adverse effects of crystalloid fluids, optimizing the use of blood products, and non-selectively addressing clot formation and fibrinolysis. Consequently, improvements in outcomes among trauma patients have plateaued. Further, efforts have failed to address trauma-associated thromboinflammation, which is the primary driver of late-stage morbidity and mortality. To date, there are no therapeutics to target post- trauma thromboinflammation to our inadequate understanding of the mechanistic underpinnings. The protein C system is a key mechanistic driver of TIC and its associated morbidity and mortality following injury and due to its distinct dual anticoagulant and cytoprotective activities, APC both drives TIC development and mitigates thromboinflammation. Thus, therapeutics targeting the protein C (PC) pathway could be ideal for trauma patient management. Supported by our preliminary data, we propose that activation of PC after trauma is an acute protective evolutionary response to preserve cellular function following severe injury, with the unfortunate sequalae of this otherwise beneficial response being TIC. This evolutionary protective response to severe injury is considered maladaptive, providing an early `too much of a good thing' response (cytoprotective AND coagulopathic), which is followed by a late (`too little of a good thing') exhaustion of this response with resultant dysregulated thromboinflammation and organ failure. We propose a dual APC -targeted approach, such that pharmacologic APC-based cytoprotection will help to restore endothelial function and mitigate thromboinflammation of trauma and inhibition of anticoagulant effects will help to curb bleeding and TIC. We are now positioned to explore innovative pathways for mechanistic studies aimed at developing targeted therapies to selectively modulate the protein C system, thereby preventing bleeding and treating thromboinflammation. Here, new activity-selective nanobodies to APC and an engineered factor (F) V variant that bypasses APC anticoagulant activity will be studied to counter the coagulopathy of TIC. Further, engineered 3K3A-APC with minimal anticoagulant activity and full cytoprotective activity, and novel APC-mimetic cytoprotective PAR1 and PAR3 derived agonist peptides will address thromboinflammation. Mechanistic and therapeutic exploration of these novel compounds will address the clinical challenges of TIC and thromboinflammation thereby improving both short and long-term survival among critically injured patients.