The Coagulopathy-Inflammation Interface: Integration of Coagulopathy and Complement Activation as a Mechanism for Neutrophil Priming and Tissue Damage

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

Project Summary Traumatic injury is the leading cause of death from ages 1-44 in the United States, responsible for over 180,000 deaths, 2.3 million hospital admissions, and $406 billion in healthcare costs per year. While roughly half of deaths due to trauma occur either immediately or very early after injury, the remaining mortality occurs after presentation and administration of hospital-based care, primarily from trauma-induced coagulopathy (TIC), the associated overwhelming systemic inflammatory responses that lead to end-organ failure, and sepsis due to secondary immunosuppression. While new therapies such as tranexamic acid have been introduced with limited efficacy in controlling early major bleeding, no specific therapies or early interventions exist that alter the natural history of delayed mortality following major trauma. A major risk factor for mortality is the presence of TIC, which is present in 1 of every 4 patients suffering major trauma (ISS > 15), carries a 30 day mortality of nearly 50%, and is clinically observed to have a significant inflammatory component. Based on the well-established role of neutrophils (PMN) in many systemic inflammatory and end-organ diseases such as sepsis and ARDS, we recently set out to investigate a role for PMNs in TIC and its inflammatory sequelae. Our early experiments suggest that products of clotted whole blood and clotted plasma prime PMNs for excessive reactive oxygen species (ROS) production, likely through generation of the complement fragment C5a, and can lead to breakdown of endothelial barriers, end-organ damage, and further coagulopathy. To fully investigate this promising observation, we now propose in Aim 1 to fully characterize the role of complement fragments generated during coagulation in PMN NADPH oxidase priming for ROS production, the complement pathway(s) involved, and the functional consequences of the released soluble PMN products on endothelial barrier integrity. We will then establish ex-vivo the ability of human poly-trauma patient plasma to prime the PMN NADPH oxidase complex for ROS generation, define the contribution of the complement system and pathway(s) involved, and correlate these findings with the corresponding clinical outcomes including development of TIC, end-organ injury, and mortality in Aim 2. Finally, in Aim 3 we will use murine models to demonstrate in-vivo the importance of PMN ROS production, complement, and endothelial cytokine production in the development of TIC and inflammatory organ injury following trauma and hemorrhage. Taken together, this will allow a comprehensive evaluation of the contribution of PMNs and PMN-derived ROS to the development of TIC and its associated inflammatory end-organ damage.