This is an application for a K23 award for Dr. Lucy Kornblith, a trauma and surgical critical care fellow at the University of California, San Francisco and Zuckerberg San Francisco General Hospital. Dr. Kornblith is establishing herself as a young investigator in patient-oriented research with a translational focus on trauma- induced coagulopathy and its pathogenesis to improve the care of injured patients. This K23 award will provide her with the support necessary to accomplish the following goals: (1) to become an expert translational researcher in post-injury platelet biology as it relates to trauma-induced coagulopathy; (2) to study the drivers, mechanisms, and outcomes of alterations in post-injury platelet biology; and (3) to develop all the tools necessary to have an independent translational research career. Dr. Kornblith is supported by a scientific advisory committee comprised of a multidisciplinary mentoring team of experts: her primary mentor, Dr. Michael Matthay has extensive expertise in prospective observational studies, basic science methodology critical to this proposal, and he is an expert in the career development of early stage investigators; co-mentors are Dr. Mitchell Cohen, a translational researcher who is an expert in the field of trauma-induced coagulopathy, and Dr. Guy Zimmerman, an expert platelet biologist. Her advisory committee includes Dr. Shibani Pati, an expert vascular biologist, and Dr. Alan Hubbard, a biostatistician consultant specializing in causal inference in trauma. Trauma-induced coagulopathy is a central cause of preventable deaths from hemorrhage after injury. The contribution and impact of altered post-injury platelet biology on trauma-induced coagulopathy is not well understood despite the pivotal contribution of platelets to normal coagulation and endothelial integrity. The central hypothesis for this proposal is that severe injury and shock drive altered platelet activation, platelet aggregation, and platelet-endothelial interactions that are associated with increased rates of transfusion, organ failure, and mortality. Dr. Kornblith will investigate these causal pathways, mechanisms, and associated outcomes in a prospective observational trauma cohort through collection of biospecimens and detailed clinical data. This proposal represents an innovative approach to studying post-injury platelet biology because it incorporates methods that have not previously been applied together in trauma populations. Dr. Kornblith will determine the phenotypes of endothelial injury and platelet biology driven by severe injury and shock following trauma (AIM 1), the effect of post-injury platelets on in vitro endothelial permeability (AIM 2), and the morbidity and mortality associated with phenotypes of platelet activation, platelet aggregation, and platelet-endothelial interactions following trauma (AIM 3). The proposal addresses a major gap in our understanding of the role of platelets in trauma-induced coagulopathy, and the training plan it requires will form the basis for a compelling R01 proposal to identify associated molecular mechanisms and the role of platelet transfusions and platelet-based treatments in reduction of morbidity and mortality for hemorrhaging trauma patients.
The proposed research is relevant globally to public health because each year trauma is a leading cause of five million deaths. The majority of early preventable deaths are due to uncontrolled hemorrhage and therefore understanding trauma-induced coagulopathy, a multi-factorial disorder of inflammation and coagulation characterized by impaired clot formation, is critical to effective treatment and the rescue of a large proportion of injured patients. Since the role of platelets in trauma-induced coagulopathy is not well understood despite their central role in normal coagulation and endothelial integrity, determining the drivers, mechanisms, and outcomes associated with altered post-injury platelet biology is a critical step in a continuum of research that is paving the way to targeted treatments and goal-directed resuscitation of hemorrhaging trauma patients.