Characterization of coagulation factor-platelet interactions: role of FXI

凝血因子-血小板相互作用的表征：FXI 的作用

基本信息

批准号：
9241431
负责人：
Owen J McCarty
金额：
$ 44.3万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241431
关键词：
Activated Partial Thromboplastin Time measurement Address Affect Anticoagulants Attenuated Binding Blood Blood Coagulation Factor Blood Platelets Blood Vessels Blood coagulation Bypass Cardiovascular system Chronic Cleaved cell Coagulation Process Complex Consequentialism Data Deep Vein Thrombosis Development Disease Distal Endothelial Cells Endothelium Enzymes Event Extracellular Matrix Proteins F8 gene FXII deficiency Factor IX Factor XI Factor XII Fibrin Fibrinolytic Agents Functional disorder Generations Goals Grant Hematological Disease Hemophilia A Hemorrhage Hemostatic Agents Hemostatic function Human In Vitro Industrialization Inflammation Injury Interruption Investigation Ischemic Stroke Knockout Mice Laminin Lead Leukocytes Maintenance Mediating Medicine Molecular Molecular Target Morbidity - disease rate Mus Myocardial Infarction Nuclear Pathogenesis Pathologic Pathway interactions Peptide Hydrolases Peritonitis Pharmacology Plasma Platelet Activation Play Polyphosphates Primates Process Protein C Recruitment Activity Research Resistance Role Site Stroke TFPI Testing Thrombin Thromboplastin Thrombosis Thrombus Work apolipoprotein E receptor 2 cofactor combat epidemiologic data extracellular granulocyte improved in vivo Model migration mortality neutralizing antibody neutrophil public health relevance receptor therapeutic target

项目摘要

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.

描述（由申请人提供）：止血栓形成和血栓形成都需要凝血酶依赖性纤维蛋白形成、血小板募集和聚集，虽然止血是一个重要过程，但病理性血栓形成可导致中风、心脏病和其他凝血因子XI和XII。 (FXI、FXII) 通过凝血级联促进凝血酶生成我们发现 FXI 和 FXII 都有助于实验。血栓形成和流行病学数据表明，FXI 缺乏可预防深静脉血栓形成和缺血性中风，然而，与其他凝血因子不同，FXI 缺乏仅导致轻度止血障碍，而 FXII 缺乏显然无症状，FXII 在正常止血中没有明显作用。我们最初的发现为开发新的安全抗血栓策略打开了新的窗口。在我的第一笔 R01 资助的续签申请中，我们解决了这一重大问题。关于 FXI 在血栓形成中的作用的未解决问题，包括绕过 FIX 介导的内在机制的活动我们将检验我们的假设，即 FXI 还通过局部内源性抗凝剂失活而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 FXI 与血小板串扰在血栓过程中促进血小板促凝活性的机制。我们将测试我们的假设，即 FXIa 通过使血小板组织因子途径抑制剂 (TFPI) 失活来促进血栓形成。我们将定义 FXIa 在中性粒细胞胞外陷阱 (NET) 的促血栓形成活动中的作用，并将确定 NET 激活接触途径是否会促进血流下血栓形成部位远端的血小板活化和微聚集体形成。利用体外和体内模型来定义 FXI 促进内皮细胞组织因子依赖性凝血的分子机制。拟议研究的目的是更好地了解其作用。接触激活在血栓形成的起始和传播过程中的作用，这可能为 FXI 轴的治疗靶向作为一种更安全的抗血栓形成新策略提供进一步的理论依据。