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

• 批准号: 8478017
• 负责人: Owen J McCarty
• 金额: $ 7.21万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478017
• 关键词: Adult; Affect; Animals; Apple; Binding; Binding Sites; Biological Assay; Bleeding time procedure; Blood; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular Diseases; Coagulation Process; Collagen; Commit; Deep Vein Thrombosis; Development; Disease; Disease susceptibility; Epidemiology; Event; Exhibits; Factor XI; Factor XI Deficiency; Factor XIIa; Factor XIa; Fibrin; Fibrinolytic Agents; Generations; Genetic; Glycoprotein Ib; Goals; Health; Hemorrhage; Hemostatic function; In Vitro; Individual; Injury; Ischemic Stroke; Ligands; Light; Maintenance; Mediating; Modeling; Molecular; Mus; Myocardial Infarction; Oryctolagus cuniculus; Pathologic; Peptide Hydrolases; Pharmacologic Substance; Phase; Physiological; Platelet Glycoproteins; Play; Population; Primates; Recombinants; Relative (related person); Research; Risk Factors; Role; Solid; Stroke; Surface; System; Testing; Therapeutic; Thrombin; Thrombosis; Thrombus; United States; apolipoprotein E receptor 2; base; combat; design; genetic risk factor; in vivo; inhibitor/antagonist; insight; mutant; neutralizing antibody; neutralizing monoclonal antibodies; novel; oligomycin sensitivity-conferring protein; prevent; public health relevance; receptor; reconstitution

DESCRIPTION (provided by applicant): Elevated coagulation factor XI (FXI) level is an independent risk factor for deep vein thrombosis, ischemic stroke, and myocardial infarction. Inherited FXI-deficiency causes mild bleeding tendency, yet it has also been found to be protective against ischemic stroke. FXI has been shown to play a critical role in the formation of experimental thrombi, as evidenced by the fact that genetic deletion or pharmacological inhibition of FXI prevents vascular occlusions in animal thrombosis models. While these findings implicate an important role for FXI in thrombosis, and a possible role in hemostasis, they do not suggest molecular mechanisms by which FXI differentially contributes to (patho)physiological coagulation. Blood platelets are the essential cellular components of primary hemostasis. FXI has been shown to bind specifically to the platelet surface via the platelet glycoprotein (GP) Ib-IX-V complex; however, the functional significance of this interaction is unclear. Moreover, it is unknown whether shear forces due to blood flow play a role in regulating FXI-platelet binding. It has been suggested that GPIb orchestrates the activation of FXI through the protease thrombin; however, there is considerable controversy surrounding this hypothesis. Moreover, while thrombin, activated FXI (FXIa), or activated factor XII (FXIIa), has been shown to activate FXI in purified systems in vitro, the relative importance of these FXI activators on the platelet surface ex vivo or in vivo has not been established. The objectives of our proposed studies are to elucidate the mechanisms of FXI-platelet interactions and to provide further insight into the physiological role of FXI in normal hemostasis and pathologic coagulation. We hypothesize that FXI-platelet interactions promote clot formation under shear flow conditions. We have identified FXI as a ligand for the platelet apolipoprotein E receptor 2 (ApoER2). We hypothesize that ApoER2 plays a critical role in mediating FXI-platelet binding and in initiating coagulation under flow. These hypotheses will be tested through the following specific aims: Aim 1: Determine the molecular mechanisms and consequences of platelet-FXI interactions. Aim 2: Determine the role of FXI-platelet binding in ex vivo thrombus formation. Aim 3: Determine the role of FXI-platelet binding in thrombus formation in vivo. We are committed to the design and development of novel antithrombotic FXI inhibitors. We believe that therapeutic inhibition of the FXI axis is a promising therapeutic strategy to combat pathological thrombus formation, in light of the strong antithrombotic efficacy and mild bleeding diathesis associated with FXI deficiency. The ultimate goal of this line of research is to establish valuable mechanistic information concerning FXI-platelet interactions and to provide further insight into the physiological role of FXI in normal hemostasis and pathologic coagulation. PUBLIC HEALTH RELEVANCE: Cardiovascular disease and stroke remain major health concerns in the adult population in the United States. To combat these diseases, an ideal antithrombotic agent would selectively target an event crucial for thrombus formation without affecting hemostasis. We propose that elucidation of the role that FXI plays in clot formation may provide the basis for the pharmaceutical development of such a novel class of FXI-targeted anti-thrombotics.

描述（由申请方提供）：凝血因子XI（FXI）水平升高是深静脉血栓形成、缺血性卒中和心肌梗死的独立风险因素。遗传性FXI缺陷导致轻度出血倾向，但它也被发现对缺血性中风有保护作用。已证明FXI在实验血栓形成中起关键作用，如FXI的遗传缺失或药理学抑制可预防动物血栓形成模型中的血管闭塞这一事实所证明。虽然这些发现暗示FXI在血栓形成中的重要作用，以及可能在止血中的作用，但它们并不表明FXI差异性地促进（病理性）生理性凝血的分子机制。血小板是主要止血的基本细胞成分。已证明FXI通过血小板糖蛋白（GP）Ib-IX-V复合物特异性结合血小板表面;然而，这种相互作用的功能意义尚不清楚。此外，尚不清楚血流引起的剪切力是否在调节FXI-血小板结合中起作用。有人认为GPIb通过凝血酶蛋白酶协调FXI的激活;然而，围绕这一假设存在相当大的争议。此外，虽然凝血酶、活化的FXI（FXIa）或活化的因子XII（FXIIa）已显示在体外纯化系统中活化FXI，但这些FXI活化剂在离体或体内血小板表面上的相对重要性尚未确定。我们拟定研究的目的是阐明FXI-血小板相互作用的机制，并进一步了解FXI在正常止血和病理性凝血中的生理作用。我们假设，在剪切流条件下，FXI-血小板相互作用促进凝块形成。我们已经确定FXI为血小板载脂蛋白E受体2（ApoER 2）的配体。我们假设ApoER 2在介导FXI-血小板结合和启动流动下凝血中起关键作用。这些假设将通过以下特定目的进行检验：目的1：确定血小板-FXI相互作用的分子机制和后果。目的2：确定FXI-血小板结合在离体血栓形成中的作用。目的3：确定FXI-血小板结合在体内血栓形成中的作用。我们致力于设计和开发新型抗血栓FXI抑制剂。我们认为，鉴于FXI缺乏相关的强抗血栓形成疗效和轻度出血素质，FXI轴的治疗性抑制是对抗病理性血栓形成的有前景的治疗策略。这一系列研究的最终目标是建立有关FXI-血小板相互作用的有价值的机制信息，并进一步了解FXI在正常止血和病理性凝血中的生理作用。 公共卫生相关性：心血管疾病和中风仍然是美国成年人群的主要健康问题。为了对抗这些疾病，理想的抗血栓剂将选择性地靶向血栓形成的关键事件而不影响止血。我们认为，阐明FXI在凝块形成中的作用可能为此类新型FXI靶向抗血栓药物的药物开发提供基础。