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：
9381316
负责人：
Owen J McCarty
金额：
$ 1.51万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-03 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381316
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

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

展开

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（由应用提供）：止血塞形式和血栓形成都需要依赖凝血酶的纤维蛋白形成，血小板募集和聚集。虽然止血是一个必不可少的过程，但病理血栓形成会导致中风，心脏病发作和其他血管占性疾病。凝血因子XI和XII（FXI，FXII）通过凝结级联反应促进凝血酶产生。我们发现FXI和FXII均有助于实验性血栓形成，并且流行病学数据表明FXI缺乏症受到保护，以防止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缺陷仅引起轻度止血疾病，而FXII缺乏显然是不对称的，没有FXII在正常止血中没有明显的作用。我们的最初发现为开发新的安全抗血栓形成策略开辟了新的窗口。在我的第一个R01赠款的这种续签应用中，我们解决了有关FXI在血栓形成中作用的主要尚未解决的问题，包括绕过固定介导的内在的活动凝血酶生成途径。我们将检验我们的假设，即FXI还通过局部内源性抗凝剂的灭活来促进凝血酶产生中起关键作用。在AIM 1中，我们将表征FXI-Platelet串扰促进血栓形成过程中血小板的凝聚活性的机制。我们将通过血小板组织因子途径抑制剂（TFPI）的失活来促进FXIA促进凝块形成的假设。在AIM 2中，我们将定义FXIA在中性粒细胞外陷阱（NETS）的促血栓性活性中的作用，并将确定NETS对接触途径的激活是否促进了血小板激活和微聚集的形成与流动下的血栓形成部位不同。在AIM 3中，我们将利用体外和体内模型来定义FXI促进内皮细胞上组织因子依赖性凝血的分子机制。拟议的研究的目的是更好地理解接触激活在血栓形成的主动性和传播中的作用，这可以为FXI轴的治疗靶向提供进一步的理由，以此作为对抗血栓形成的新策略。