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.

项目摘要/摘要 发现一种不会导致出血的抗血栓疗法将是 管理数百万患有心肌梗死、血栓栓塞症和 需要抗凝，但目前可用药物有大出血风险的中风患者。 一个非常有希望的靶点是凝血因子XII(FXII/FXIIa)，基于最近的发现，小鼠缺乏 FXII在不增加出血的情况下显著防止血栓形成。因为很早就知道 人类严重的先天性FXII缺乏症不会导致出血，这些结果使FXII成为潜在的 突破性的抗血栓靶点，可将疗效与出血并发症“脱钩”。作为证明 概念，我们已经证明了X210-C01，一种新的抗鼠FXIIa的治疗性抗体，可以防止动脉 在保持止血的同时，在小鼠体内形成血栓。然而，招募FXII的机制， 在动脉血栓形成过程中被激活和传播，但不能止血，目前仍知之甚少。我们的 中心假说是，血小板在动脉血栓中结合并激活FXII，而不是在止血栓中 其中FXIIa通过血浆辅因子进行正反馈扩增。为了定义分子机制 基于FXII在体内的作用，我们提出了以下目标：1)检测血浆激肽释放酶(PK)是否是一种 血栓形成中FXIIa的重要辅因子。我们将使用一种新型的抗PK抗体(M202-H03)来 评价双PK和FXIIa阻断对体内血栓形成的影响。我们亦会研究 PK与FXII相互作用和激活的机制。2)定义FXII的激活机制 体内血栓形成。我们将测试磷脂酰丝氨酸和血小板GPIBα是否必要以及 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 在血栓形成过程中。3)使用体内模型，测试FXII抑制是否损害止血和 确定止血栓中的血小板是否与动脉血栓中的血小板表型不同。 申请者Pavan Bendapudi博士完全有资格执行拟议的实验。他是 致力于止血和血栓形成的科学生涯，并提出了一项全面的 五年计划，以实现他成为一名独立内科科学家的目标。本达普迪博士将致力于 在Robert Flaumenhaft博士的主要指导下，Bruce Furie博士担任联合导师。他有 聘请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。 贝丝以色列女执事医疗中心的止血和血栓科是理想的环境 为了完成他的科学和职业发展目标，考虑到其杰出的研究界 以及这一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