The Interaction of Estradiol and Platelet Biology: A Mechanistic Exploration of Sex Dimorphisms in Coagulation - PROJECT SUMMARY/ABSTRACT Dr. Julia Coleman is establishing herself as an early-career, translational surgeon-scientist with expertise in trauma-induced coagulopathy (TIC), sex dimorphisms in platelet function, and their mechanistic underpinnings to improve the care of injured patients. This K08 award will provide her with the support necessary to accomplish the following goals: (1) become an expert surgeon-scientist in sex dimorphisms in platelet function as it relates to TIC; (2) study the mechanisms underlying estradiol’s pro-platelet effect in vitro in donor platelets intended for transfusion in bleeding trauma patients; and (3) develop the tools necessary to have an independent translational research career. Dr. Coleman is supported by a multidisciplinary scientific advisory committee: primary mentor Dr. Richard Gumina (Professor in Internal Medicine with expertise in purinergic biology and functional platelet assays critical to this proposal); content co-mentors Dr. Thomas Hund (biochemist with expertise in calcium signaling) and Dr. Bryce Kerlin (hematologist with expertise in thrombosis and hemostasis); scientific advisors Dr. Kristy Townsend (neuroscientist with expertise in the effect of sex and estrogen on disease processes) and Drs. Mitchell Cohen and Matthew Neal (translational surgeon-scientists with expertise in TIC and platelet dysfunction). Trauma-induced coagulopathy, characterized by platelet dysfunction, is a leading cause of preventable death despite decades of resuscitation practice optimization. An opportunity for advancement in TIC treatment stems from an awareness that coagulation demonstrates a strong sex-dependent effect. Compared to males, females have increased platelet reactivity, and in the setting of TIC, this results in decreased morbidity and mortality. Platelets demonstrate sex-specific reactivity to P2Y receptor stimulation, which signals through Src kinase. In addition to P2Y receptors, platelets also express estradiol-β receptors, and 17β-estradiol is known to exert nongenomic effects on intracellular signaling pathways including Src kinase. As such, the objective of this proposal is to test the central hypothesis that estrogen receptor-β stimulation on platelets primes Src kinase signaling pathways to potentiate aggregation through nongenomic effects on P2Y receptors (Aim 1) and the platelet proteome (Aim 2). To address these aims, we will perform a variety of platelet function assays in native and estrogen-treated platelets in human apheresis platelets. Understanding these mechanisms at a basic level is critical to advance translational studies to improve TIC-related morbidity and mortality for both sexes, as it may impact donor sex-specific transfusion and support the use of estrogen-treated platelets in the resuscitation of bleeding trauma patients. This proposal addresses a major gap in our understanding of the effect of biological sex and estrogen on donor platelet biology. This will also generate data for an R01 application that translates concepts from this platelet donor-focused project to platelet dysfunction in TIC to examine the role of recipient sex and estrogen treatment in the blood of trauma patients.
