The Role of Coagulation Factor XII in Hemostasis and Thrombosis

凝血因子 XII 在止血和血栓形成中的作用

• 批准号: 10194578
• 负责人: Pavan Bendapudi
• 金额: $ 16.34万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194578
• 关键词: Address; Advisory Committees; Antibodies; Anticoagulation; Binding; Biology; Blood Platelets; Clinical; Coagulation Process; Communities; Confocal Microscopy; Custom; Disease; Disease susceptibility; Dose; Endothelium; Environment; Factor XII; Factor XII Deficiency; Feedback; Fibrin; Five-Year Plans; Generations; Goals; Hematology; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; Impairment; In Vitro; Injury; International; Israel; Laser injury; Maps; Mechanics; Mediating; Medical center; Mentors; Mentorship; Modeling; Molecular; Monitor; Mus; Myocardial Infarction; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphatidylserines; Phospholipids; Physicians; Physiological; Plasma; Plasma Kallikrein; Platelet Activating Factor; Play; Process; Proteins; Reagent; Research; Risk; Role; Scientist; Serine Protease; Site; Stroke; Surface; System; Testing; Therapeutic antibodies; Thrombin; Thrombosis; Thrombus; Treatment Efficacy; Veins; Wild Type Mouse; Work; base; career; career development; cofactor; experimental study; in vitro Assay; in vivo; in vivo Model; innovation; insight; mouse model; novel; novel strategies; novel therapeutics; preservation; prevent; receptor; recruit; synergism; vascular injury

Project Summary/Abstract Discovery of an antithrombotic therapy that does not cause bleeding would be a transformative advance in the management of millions of patients with conditions such as myocardial infarction, thromboembolic disease, and stroke who require anticoagulation but are put at risk of major hemorrhage with currently available medications. One highly promising target is coagulation factor XII (FXII/FXIIa), based on the recent finding that mice lacking FXII are strikingly protected from thrombosis without increased bleeding. Because it has long been known that severe congenital FXII deficiency in humans does not cause bleeding, these results make FXII a potentially groundbreaking antithrombotic target that could “decouple” efficacy from bleeding complications. As proof of concept, we have shown that X210-C01, a novel therapeutic antibody against murine FXIIa, prevents arterial thrombus formation in mice while preserving hemostasis. However, the mechanism by which FXII is recruited, activated, and propagated during arterial thrombosis but not hemostasis remains poorly understood. Our central hypothesis is that platelets bind and activate FXII in arterial thrombi but not in hemostatic plugs, after which FXIIa is amplified by positive feedback via a plasma cofactor. To define the molecular mechanisms underlying FXII function in vivo, we propose the following aims: 1) Test whether plasma kallikrein (PK) is an essential cofactor for FXIIa in thrombus formation. We will use a novel anti-PK antibody (M202-H03) to evaluate the effect of dual PK and FXIIa blockade on thrombus formation in vivo. We will also study the mechanism by which PK interacts with and activates FXII. 2) Define mechanisms of FXII activation during thrombus formation in vivo. We will test whether phosphatidylserine and platelet GPIbα are necessary and sufficient to activate FXII at the platelet surface. We will then use intravital confocal microscopy to localize FXII during thrombus formation. 3) Using in vivo models, test whether FXII inhibition impairs hemostasis and determine if platelets in hemostatic plugs are phenotypically distinct from those in arterial thrombi. The applicant, Dr. Pavan Bendapudi, is well qualified to execute the proposed experiments. He is committed to pursuing a scientific career in hemostasis and thrombosis and has proposed a comprehensive five-year plan to meet his goal of becoming an independent physician-scientist. Dr. Bendapudi will be working under the primary mentorship of Dr. Robert Flaumenhaft with Dr. Bruce Furie serving as co-mentor. He has enlisted a research advisory committee of internationally-recognized experts in hematology to support him. The Division of Hemostasis and Thrombosis at Beth Israel Deaconess Medical Center is an ideal environment for completion of his scientific and career development objectives given its outstanding research community and tradition of scientific discovery and trainee mentorship in this field.

项目概要/摘要 发现一种不会引起出血的抗血栓疗法将是医学领域的革命性进步。 管理数百万患有心肌梗塞、血栓栓塞性疾病和心脏病等疾病的患者 需要抗凝治疗但使用现有药物有大出血风险的中风患者。 一个非常有希望的目标是凝血因子 XII (FXII/FXIIa)，这是基于最近发现缺乏凝血因子 XII 的小鼠 FXII 可显着防止血栓形成，且不会增加出血。因为人们早就知道 人类严重的先天性 FXII 缺陷不会导致出血，这些结果使 FXII 成为潜在的治疗选择 突破性的抗血栓目标，可以将疗效与出血并发症“脱钩”。作为证明 概念，我们已经证明 X210-C01，一种针对小鼠 FXIIa 的新型治疗性抗体，可以预防动脉粥样硬化 小鼠体内血栓形成，同时保持止血。然而，FXII 的招募机制， 在动脉血栓形成过程中被激活和传播，但在止血过程中却没有被激活和传播，人们对此仍知之甚少。我们的 中心假设是，血小板在动脉血栓中结合并激活 FXII，但在止血塞中则不然。 其中 FXIIa 通过血浆辅助因子的正反馈被放大。定义分子机制 为了了解 FXII 体内的潜在功能，我们提出以下目标： 1) 测试血浆激肽释放酶 (PK) 是否是一种 FXIIa 在血栓形成过程中的重要辅助因子。我们将使用一种新型抗 PK 抗体 (M202-H03) 评估双重 PK 和 FXIIa 阻断对体内血栓形成的影响。我们还将研究 PK 与 FXII 相互作用并激活 FXII 的机制。 2) 定义 FXII 激活机制 体内血栓形成。我们会测试磷脂酰丝氨酸和血小板GPIbα是否必要， 足以激活血小板表面的 FXII。然后我们将使用活体共聚焦显微镜来定位 FXII 血栓形成过程中。 3) 使用体内模型，测试 FXII 抑制是否会损害止血和 确定止血塞中的血小板在表型上是否与动脉血栓中的血小板不同。 申请人 Pavan Bendapudi 博士完全有资格执行所提议的实验。他是 致力于追求止血和血栓形成方面的科学事业，并提出了全面的 实现他成为一名独立医师科学家的目标的五年计划。 Bendapudi 博士将开始工作 在 Robert Flaumenhaft 博士的主要指导下，Bruce Furie 博士担任联合导师。他有 招募了一个由国际公认的血液学专家组成的研究咨询委员会来支持他。 贝斯以色列女执事医疗中心的止血和血栓科是一个理想的环境 鉴于其杰出的研究社区，完成了他的科学和职业发展目标 以及该领域的科学发现和实习生指导的传统。

项目成果

Persistence of endothelial thrombomodulin in a patient with infectious purpura fulminans treated with protein C concentrate.

使用浓缩蛋白 C 治疗的传染性暴发性紫癜患者中内皮血栓调节蛋白的持续存在。

• DOI: 10.1182/bloodadvances.2018024430
• 发表时间: 2018
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Bendapudi,PavanK;Robbins,Alissa;LeBoeuf,Nicole;Pozdnyakova,Olga;Bhatt,Ami;Duke,Fujiko;Sells,Ryan;McQuiston,John;Humrighouse,Ben;Rouaisnel,Betty;Colling,Meaghan;Stephenson,KathrynE;Saavedra,Arturo;Losman,Julie-Aurore
• 通讯作者: Losman,Julie-Aurore