Characterization of coagulation factor-platelet interactions: role of FXI

 描述（由申请方提供）：止血栓形成和血栓形成均需要凝血酶依赖性纤维蛋白形成、血小板募集和聚集。虽然止血是一个必要的过程，但病理性血栓形成可导致中风、心脏病发作和其他血管闭塞性疾病。凝血因子Xi和XII（FXi，FXII）通过凝血级联促进凝血酶产生。我们发现，FXI和FXII都有助于实验性血栓形成，流行病学数据表明，FXI缺乏对深静脉血栓形成和缺血性卒中具有保护作用。然而，与其他凝血因子不同，FXI缺乏仅引起轻度止血障碍，FXII缺乏明显无症状，在正常止血中没有FXII的明显作用。我们最初的发现为开发新的安全抗血栓策略打开了一扇新的窗口。在我的第一个R 01资助的更新申请中，我们解决了关于FXI在血栓形成中的作用的主要未解决问题，包括绕过FIX介导的内源性血栓形成的活动。 凝血酶生成途径。我们将检验我们的假设，即FXI也通过灭活局部内源性抗凝剂在促进凝血酶生成中发挥关键作用。在目标1中，我们将描述血栓形成期间FXI-血小板串扰促进血小板促凝活性的机制。我们将检验我们的假设，即FXIa通过血小板组织因子途径抑制物（TFPI）的失活促进凝块形成。在目的2中，我们将定义FXIa在中性粒细胞胞外陷阱（NET）的促血栓形成活性中的作用，并将确定NET激活接触途径是否促进血小板活化和流动下血栓形成部位远端的微聚集体形成。在目标3中，我们将利用体外和体内模型来确定FXI促进内皮细胞上组织因子依赖性凝血的分子机制。拟定研究的目的是更好地了解接触激活在血栓形成的启动和传播中的作用，这可能为FXI轴作为更安全的抗血栓形成新策略的治疗靶向提供进一步的依据。

 DESCRIPTION (provided by applicant): Both hemostatic plug formation and thrombosis require thrombin-dependent fibrin formation, platelet recruitment and aggregation. While hemostasis is an essential process, pathologic thrombosis can cause stroke, heart attack and other vasoocclusive diseases. Coagulation factors XI and XII (FXI, FXII) promote thrombin generation through the coagulation cascade. We found that both FXI and FXII contribute to experimental thrombosis, and epidemiologic data suggest that FXI deficiency is protective against deep vein thrombosis and ischemic stroke. Yet, unlike other coagulation factors, FXI-deficiency causes only a mild hemostasis disorder and FXII deficiency is apparently asymptomatic without a demonstrable role for FXII in normal hemostasis. Our original findings have opened a new window towards the development of new safe antithrombotic strategies. In this renewal application of my first R01 grant, we address the major unresolved questions on the role of FXI in thrombus formation, including activities that bypass the FIX- mediated intrinsic thrombin generation pathway. We will test our hypothesis that FXI also plays a key role in promoting thrombin generation through the inactivation of local endogenous anticoagulants. In Aim 1 we will characterize the mechanisms by which FXI-platelet crosstalk promotes the procoagulant activities of platelets during thrombus formation. We will test our hypothesis that FXIa promotes the clot formation through the inactivation of platelet tissue factor pathway inhibitor (TFPI). In Aim 2 we will define the role of FXIa in the prothrombotic activities of neutrophil extracellular traps (NETs), and will determine whether activation of the contact pathway by NETs promotes platelet activation and microaggregate formation distal to sites of thrombus formation under flow. In Aim 3 we will utilize in vitro and in vivo models to define the molecular mechanisms by which FXI promotes tissue factor-dependent coagulation on endothelial cells. The goal of the proposed studies is to better understand the role of contact activation in the initiation and propagation of thrombus formation, which may provide further rationale for therapeutic targeting of the FXI axis as a safer new strategy to combat thrombosis.