Connecting Sex to Platelet Function after Mechanical Activation

心血管疾病是全世界最常见的死亡原因。差异 男性和女性的心血管疾病已经很好地建立，但尽管 血栓形成在缺血性卒中、缺血性心脏病和静脉血栓形成中重要性 血栓栓塞，血小板功能的性别差异往往是缺席的谈话。 尽管如此，男性和女性在出血风险、抗血小板反应、 治疗、血栓形成相关疾病的发病率和结局以及创伤后死亡率。在 结合激素和遗传因素，差异可能是由于血小板的变异性 生物学，如血小板计数的明确差异， 关键表面受体和表面受体活化的可变性。虽然以前的工作 使用临床试验来检查男性和女性之间血栓形成功能的差异， 发现适度的显着差异或无显着差异，这些测试使用经典 生物化学激动剂来激活血小板，而不是生物物理激活血小板。 机械受体血小板糖蛋白Ibα（GPIbα）和整合素αIIbβ3。在这项工作中，我试图 研究性别如何影响机械活化血小板功能，这在动脉粥样硬化中至关重要。 血栓形成这项补助金的目的是确定止血功能是否因性别而异 在没有外源性生化激动剂的动脉高剪切活化环境下。我会 还讨论了与动脉粥样硬化相关的血小板生物学方面是否存在性别差异， 血栓形成，包括血小板机械受体GPIbα和整合素的机械活化性 αIIbβ3、流动中的血小板粘附和血小板收缩力。这次调查很重要 因为了解男性和女性之间血栓形成的差异将影响 健康血小板功能的表征，未来研究的设计，抗血小板药物的应用， 血小板治疗以及未来预防性和治愈性治疗的发展。

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.