Hemorrhage and hemorrheology – the critical interaction of the erythrocyte and the endothelium after injury

University Of Cincinnati, Cincinnati OH

Investigators

Abstract

Project Summary Over the last two decades, clinical outcomes research has firmly established the presence of trauma induced coagulopathy and emphasized its critical role in the increased risk of persistent hemorrhagic shock and death. With increasing recognition of the critical nature of post-traumatic coagulability, there has also been increased interest in the role of the endothelium, with its ability to be the connection between vascular permeability, microcirculatory perfusion, hemostasis, and inflammation. While balanced blood product transfusion is known to improve both coagulopathy and survival of the injured patient, further investigation into both the mechanism of the induction and resolution of the endotheliopathy of trauma is critical to understand optimal blood product selection to induce hemostasis and restore endothelial integrity. An inherent but underappreciated element of transfusion-based resuscitation after injury is the erythrocyte, which provides crucial contributions to post- traumatic hemostasis, thrombosis, and capillary patency. The variable interaction of the erythrocyte with the intact and injured endothelium represents one of the most critical physiologic underpinnings of microcirculatory dysfunction following traumatic injury and better understanding of this relationship will help optimize resuscitation strategies based on blood product transfusion and pharmacologic adjuncts. This proposal will leverage our experience in establishing preclinical polytrauma models and evaluating our trauma patient population to uniquely synergize projects in cellular, small animal, and human studies to better understand the diversities in the endothelial response to injury and resuscitation. The first project will focus on determining the critical elements of the intracellular aggregation response in the RBC that affects the interaction with the injured endothelium. The second project will utilize organ-specific endothelial cell lines to establish the differential responses to physiologic stimuli relevant to the post-injury systemic environment and to post-injury resuscitation strategies. The third project will utilize murine polytrauma models to determine the in vivo endothelial effects of resuscitation with transfusion and pharmacologic adjuncts. The fourth project will longitudinally determine the profiles of acute endothelial injury across all admitted trauma patients to discern whether certain profiles can predict post-injury mortality, morbidity, and disposition outcomes. Successful completion of this proposal will provide critical insights across multiple platforms and species into the utilization of specific blood transfusion strategies and pharmacologic adjuncts to resolve the endotheliopathy of trauma and improve patient outcomes.