Evaluating the Safety and Efficacy of Targeting the Contact Pathway to Prevent Device Associated Thrombosis.

项目摘要 我们的研究项目旨在验证我们的中心假设，即 血液凝固的接触活化系统和医疗装置的表面有助于 病理机制包括炎症反应和器械相关血栓形成。 尽管使用抗凝和抗血小板剂，但许多广泛使用的血管装置诱导 血栓形成抗凝可以减轻血栓形成，尽管不是完全的，因此 血栓形成是一种具有显著临床后果的持续性风险，包括血栓栓塞、器械 失败中风甚至死亡虽然目前的抗凝形式可以减少这些风险，但它们 普遍增加出血的风险，矛盾地导致患者发病率和死亡率。 我们的小组已经广泛地评估了接触途径因子Xi（FXi）和XII（FXII），它们似乎 参与器械相关血栓形成的发展，但仍需止血。我们 中心假设是机械装置诱导并传播局部血液凝固和血栓 以FXIIa依赖的方式传播。在我们先前成功的基础上，在AIM 1中，我们将利用体外 和非人灵长类动物模型，沿着来自外周插入中心静脉导管的患者的样品， 导管（PICC）作为模型医疗器械，以定义接触路径和器械的相互作用 血液微环境中的表面。在AIM中使用FXII介导的FXI活化的新型抑制剂 我们将确定接触激活在器械相关血栓形成中的作用， 外周插入中心静脉导管（PICC）患者。PICC经常用于门诊 需要定期给予静脉内药物的内科患者，但受到高血压的困扰， 导致局部症状、血栓栓塞和医疗护理延迟的血栓形成率。 特别是，用现代形式的抗凝治疗导管相关血栓形成导致 大出血的发病率很高，迄今为止，传统抗凝剂预防CAT的试验 尚未显示出有利的风险/受益概况。有一个未满足的医疗需求，以开发更安全的 有效的治疗方法。 总之，这些分析将是第一个定义FXI激活机制的分析， 器械表面的FXII导致人体内器械相关血栓形成。生成的数据 这种分析将提供适用于许多医疗器械的新的机理见解， 现代医疗保健实践，并在确定安全和可药用方面具有很大的翻译相关性 接触激活系统内的目标

Project Summary Our research project is designed to test our central hypothesis that the interaction between the contact activation system of blood coagulation and the surfaces of medical devices contributes to pathologic mechanisms including inflammatory responses and device associated thrombosis. Despite the use of anticoagulation and antiplatelet agents, many widely used vascular devices induce thrombus formation. Anticoagulation can mitigate thrombus formation, though not completely, and thus thrombosis is a persistent risk with significant clinical consequences including thromboembolism, device failure, stroke and even death. While current forms of anticoagulation can lessen these risks, they universally increase the risk of bleeding, paradoxically contributing to patient morbidity and mortality. Our group has extensively evaluated the contact pathway factors XI (FXI) and XII (FXII) which appear to be complicit in the development of device-associated thrombosis, yet dispensable for hemostasis. Our central hypothesis is that mechanical devices induce and propagate local blood coagulation and thrombus propagation in a FXIIa-dependent manner. Building on our prior successes, in AIM 1 we will utilize in vitro and non-human primate models, along with samples from patients with peripherally inserted central catheters (PICCs) as a model medical device to define the interaction of the contact pathway and device surfaces in the blood microenvironment. Using a novel inhibitor of FXII-mediated activation of FXI, in AIM 2 we will determine the role of contact activation in the development of device-associated thrombosis in patients with peripherally inserted central catheters (PICCs). PICCs are frequently used in ambulatory medical patients who require regular administration of intravenous medications, but are plagued by high rates of thrombosis leading to local symptoms, thromboembolism and delays in medical care. Paradoxically, the treatment of catheter associated thrombosis with modern forms of anticoagulation leads to significant morbidity from major bleeding, and to date trials of traditional anticoagulants to prevent CAT have not shown a favorable risk/benefit profile. There is an unmet medical need to develop safer more effective therapies in this space. Taken together, these analyses will be the first to define the mechanisms of by which activation of FXI and FXII by device surfaces contributes to device-associated thrombosis in humans. The data generated from this analysis will provide new mechanistic insights applicable to numerous medical devices used in modern health care practices and has large translational relevance in identifying safe and druggable targets within the contact activation system.