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测试我们的中心假设，即 凝血与医疗器械表面的接触激活系统有助于 病理机制包括炎症反应和设备相关血栓形成。 尽管使用了抗凝和抗血小板药物，但许多广泛使用的血管装置会导致 血栓形成。抗凝可以减少血栓的形成，尽管不是完全的，因此 血栓形成是一种持续存在的风险，具有重大的临床后果，包括血栓栓塞症、设备 失败，中风，甚至死亡。虽然目前的抗凝形式可以降低这些风险，但它们 普遍增加出血的风险，自相矛盾地导致患者发病率和死亡率。 我们小组已经广泛评估了接触途径因子XI(FXI)和XII(FXII)，它们似乎 参与设备相关血栓形成的发展，但对于止血却是可有可无的。我们的 中心假说是机械装置诱导和传播局部血液凝结和血栓 以依赖于FXIIa的方式传播。在我们之前成功的基础上，我们将在体外利用AIM 1 和非人灵长类动物模型，以及外周植入中枢神经系统的患者的样本 导管(PICCs)作为一种定义接触途径和装置相互作用的模型医疗设备 血液微环境中的表面。在AIM中使用一种新的FXII介导的FXI激活抑制剂 2我们将确定接触激活在设备相关血栓形成发展中的作用 使用外周插入中心静脉导管(PICCs)的患者。PICCs在门诊中经常使用。 需要定期静脉给药的内科患者，但受到高 血栓形成导致局部症状、血栓栓塞症和延误医疗的比率。 矛盾的是，用现代形式的抗凝剂治疗导管相关血栓形成 大出血的显著发病率，以及迄今为止预防CAT的传统抗凝剂试验 没有显示出良好的风险/收益状况。有一种未得到满足的医疗需求，即开发更安全的 这一领域的有效疗法。 综上所述，这些分析将是第一次定义FXI和FXI激活的机制 设备表面的FXII有助于人类设备相关的血栓形成。生成的数据 这一分析将提供适用于多种医疗设备的新的机械见解 现代医疗保健实践，并在确定安全和可用药方面具有很大的翻译相关性 联系人激活系统内的目标。

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.