Platelets and Hemostatic Factors as Facilitators of the Inflammatory Response Following Transcatheter Aortic Valve Replacement

摘要 主动脉瓣置换术(AVR)仍是重症高血压患者唯一明确有效的治疗方法。 主动脉瓣狭窄(AS)，一种常见的瓣膜异常，与高死亡率，频繁住院， 医疗保健系统每年的成本超过10亿美元。然而，大量的患者并不适合 外科主动脉瓣置换术的候选人。经导管主动脉瓣置换术(TAVR)已经出现 作为症状性AS的替代非手术治疗选择，最近已被FDA批准用于 手术风险中等或更高的患者。尽管经导管瓣膜技术取得了进步， 血栓栓子和出血问题仍然是TAVR后的主要并发症，这对 短期和长期的生存。拟议研究的长期目标是优化以下结果 TAVR通过了解血栓炎症反应的基础，这已被证明影响 生死存亡。我们强有力的初步数据表明，TAVR与血小板衍生的增加有关 炎症介质和明显的急性炎症反应，其程度与 基线血小板反应性。此外，我们还证明了TAVR后的存活率是通过 持续性血小板减少和基线血小板聚集率降低。因此，中央 这一建议的假设是凝血的激活，特别是通过接触激活，并产生 血小板功能障碍对急性脑出血病理性血栓性炎症反应的发生至关重要 TAVR后患者的亚群，并与不良结果直接相关。这一假设将通过以下方式检验 追求三个具体目标：1)确定以下引起血小板反应性增加的机制 TAVR促进急性炎症反应，2)确定止血因素对 炎症反应，以及3)确定血小板衍生的炎症介质(特别是蛋白质)的作用 二硫键异构酶)存活30天。TAVR术后血栓形成和出血事件的发生机制 在很大程度上仍然是未知的，以及基线初级止血异常和最佳岗位的影响 程序性抗血栓治疗。拟议的研究具有重大意义和创新性，因为它们将提供 止血因子、血小板和炎症之间相互作用的机制理解 接受TAVR的患者的系统。这项研究的结果可能为以下方面提供基础 新一代抗血栓策略，如靶向接触因子或凝血酶受体，以优化 经导管心脏瓣膜手术后的结果。

ABSTRACT Aortic valve replacement (AVR) remains the only definitive and efficacious treatment for patients with severe aortic stenosis (AS), a common valvular abnormality associated with high mortality, frequent hospitalizations, and over $1 billion annual cost to the healthcare system. However, a large number of patients are not suitable candidates for surgical aortic valve replacement. Transcatheter aortic valve replacement (TAVR) has emerged as an alternative non-surgical treatment option for symptomatic AS, and has been recently FDA approved for patients with intermediate or higher surgical risk. Despite advances in transcatheter valve technology, thromboembolic and bleeding issues continue to be major complications following TAVR which impact both short and long-term survival. The long-term goal of the proposed research is to optimize outcomes following TAVR by understanding the basis of the thromboinflammatory response, which has been shown to affect survival. Our strong preliminary data suggests that TAVR is associated with an increase in platelet derived inflammatory mediators and a pronounced acute inflammatory response, the degree of which correlates with baseline platelet reactivity. Furthermore, we demonstrated that survival following TAVR is predicted by development of persistent thrombocytopenia and lower baseline platelet aggregation. Accordingly, the central hypothesis of this proposal is that activation of coagulation, particularly via contact activation, and resultant platelet dysfunction are critically important for development of a pathologic thromboinflammatory response in a subset of patients following TAVR and is directly tied to adverse outcomes. This hypothesis will be tested by pursuing three specific aims: 1) determine the mechanism by which an increase in platelet reactivity following TAVR promotes an acute inflammatory response, 2) determine the impact of hemostatic factors on the inflammatory response, and 3) define the role of platelet derived inflammatory mediators (specifically protein disulfide isomerase) on 30 day survival. The mechanism of thrombotic and bleeding events following TAVR remains largely unknown as well as the impact of baseline primary hemostatic abnormalities and optimum post procedure antithrombotic therapy. The proposed studies are significant and innovative in that they will provide a mechanistic understanding of the cross-talk between the hemostatic factors, platelets and inflammatory systems in patients undergoing TAVR. The resulting findings from this study may provide a foundation for newer generation antithrombotic strategies, such as targeting contact factors or thrombin receptors, to optimize outcomes following transcatheter heart valve procedures.