Connecting Sex to Platelet Function after Mechanical Activation

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Cardiovascular disease is the most common cause of death worldwide. Differences in cardiovascular disease in males and females have been well established, but despite the importance of thrombosis in ischemic stroke, ischemic heart disease, and venous thromboembolism, sex differences in platelet function are often absent from the conversation. None the less, males and females have differences in bleeding risk, response to anti-platelet therapy, thrombosis-related disease incidence and outcomes, and mortality post-trauma. In combination with hormonal and genetic factors, differences may be due to variability in platelet biology such as well-established differences in platelet count, alleged differences in expression of key surface receptors, and variability of surface receptor activation. While previous work has used clinical tests to examine differences in thrombotic function between males and females and found modest significant differences or no significant differences, these tests use classic biochemical agonists to activate platelets, rather than biophysical activation of the mechanoreceptors platelet glycoprotein Ibα (GPIbα) and integrin αIIbβ3. In this work, I seek to investigate how sex affects mechanically-activated platelet function, which is critical in arterial thrombosis. The goal of this grant is to determine whether hemostatic function varies by sex under arterial, high-shear activated environments without exogenous biochemical agonists. I will also address whether sex differences exist in aspects of platelet biology related to arterial thrombosis, including mechanical activatability of platelet mechanoreceptors GPIbα and integrin αIIbβ3, platelet adhesion in flow, and platelet contractile forces. This investigation is important because understanding variability in thrombosis between males and females will affect characterization of healthy platelet function, design of future research studies, application of anti- platelet treatments, and development of future preventative and curative therapeutics.