Dysregulation of Platelet-von Willebrand Factor Interaction in Trauma-Induced Coagulopathy

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PROJECT SUMMARY/ABSTRACT The overall goal of this project is to improve the outcomes of injured patients with trauma-induced coagulopa- thy (TIC), both by performing detailed investigation of the mechanisms underlying this disorder and by providing a junior clinician-scientist the training required to continue this work as an independent researcher. Trauma is the leading cause of disability-adjusted life-years (a measure of overall disease burden), both in the United States and worldwide. In trauma patients, hemorrhage is the leading cause of potentially preventable death. TIC is a common complication of serious injury that impairs normal hemostasis and contributes to the burden of death from hemorrhage. Two prominent features of TIC are impairment of platelet adhesion and aggregation function and derangement of microvascular blood flow. The causes of these abnormalities are not known, but preliminary data suggest several possible contributors. First, trauma patients have changes in their plasma von Willebrand factor (VWF) profiles that suggest high levels of endothelial cell activation and VWF secretion. Second, trauma patients have high levels of oxidative stress, which is known to make VWF hyperadhesive. Third, trauma patients have low levels of gelsolin, a protein that normally solubilizes actin polymers, which can obstruct microvascular blood flow and promote thrombus formation. Other disease states that involve similar pathways have associated microthrombus formation leading to microvascular blood flow changes similar to those seen in TIC. Finally, three key surface receptors that serve as mechanical anchors for platelets (GPIbα, αIIbβ3, and GPVI) show alterations in number and structure. Together, this suggests that the VWF-platelet adhesion axis mechanistically contrib- utes to platelet function impairment and microcirculation derangement through microvascular thrombosis and platelet receptor cleavage or occupancy. This project includes a set of experiments to elucidate the underlying causes of the platelet and microvascular changes of TIC. In Aim 1, the defects in the VWF-platelet adhesion axis will be characterized by detailed study of the changes that occur with VWF, its primary cleaving protein (ADAMTS13), and platelet adhesiveness in trauma patient blood samples. Aim 2 will characterize the alterations of platelet receptors GPIbα, αIIbβ3, and GPVI seen in TIC by testing for receptor occupancy and for receptor cleavage and loss in trauma patient samples. Aim 3 will evaluate the effects of agents that decrease VWF- platelet adhesion and actin polymerization on microvascular blood flow and clinical outcomes using contrast- enhanced ultrasound in a rat model of TIC. In addition to filling critical knowledge gaps in the pathophysiology of TIC, this project will allow the PI to develop advanced research career skills. Under a multidisciplinary team of expert mentors, the PI will gain a comprehensive conceptual and practical knowledge base in primary hemo- stasis, learn how to apply a powerful ultrasound imaging tool in an animal model, and complete career advance- ment activities to generate a unique expertise that will empower his future research. Ultimately, this project will both advance our knowledge of TIC and catalyze a junior investigator's transition to independence.