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

血小板和止血因子作为经导管主动脉瓣置换术后炎症反应的促进剂

• 批准号: 10439593
• 负责人: Donald Ray Lynch
• 金额: $ 17.96万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439593
• 关键词: Acute; Affect; Aortic Valve Stenosis; Blood Platelets; Blood flow; Characteristics; Clinical; Clinical Research; Coagulation Process; Data; Development; Event; FDA approved; Foundations; Functional disorder; Generations; Goals; Guidelines; Healthcare Systems; Heart; Heart Valve Diseases; Heart Valves; Hemorrhage; Hemostatic Agents; Hospitalization; Hour; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Knowledge; Mass Spectrum Analysis; Measures; Mediating; National Heart, Lung, and Blood Institute; Observational Study; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Platelet aggregation; Procedures; Protein Disulfide Isomerase; Public Health; Research; Risk; Risk Factors; Role; Sampling; Surrogate Markers; System; Technology; Testing; Thrombin Receptor; Thrombocytopenia; Thromboplastin; Time; Work; adverse outcome; aortic valve; aortic valve replacement; calcification; cost; efficacious treatment; improved; innovation; insight; monocyte; mortality; patient subsets; prospective; response; secondary analysis; surgical risk; thromboinflammation; thrombotic; treatment choice

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.

摘要 主动脉瓣置换术（AVR）仍然是严重心脏病患者的唯一明确和有效的治疗方法。 主动脉瓣狭窄（AS）是一种常见的瓣膜异常，与高死亡率，频繁住院， 以及每年超过10亿美元的医疗系统成本。但大量患者并不适合 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FDA批准用于 中等或更高手术风险的患者。尽管在经导管瓣膜技术方面取得了进展， 血栓栓塞和出血问题仍然是TAVR术后的主要并发症， 短期和长期生存。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，这已被证明会影响 生存我们强有力的初步数据表明，TAVR与血小板源性 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，我们证明，TAVR术后的生存率由以下因素预测： 发生持续性血小板减少症和基线血小板聚集降低。因此，中央 该建议假设是凝结的活化，特别是通过接触活化，且所得的 血小板功能障碍对于急性心肌梗死患者病理性血栓炎性反应的发展至关重要， TAVR后的患者亚组，并与不良结局直接相关。这一假设将由以下人员进行检验： 追求三个具体目标：1）确定血小板反应性增加的机制， TAVR促进急性炎症反应，2）确定止血因子对 炎症反应，和3）定义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）对30天存活率的影响。TAVR术后血栓形成和出血事件的机制 以及基线原发性止血异常和最佳术后 程序抗血栓治疗。拟议的研究是重要和创新的，因为它们将提供 对止血因子、血小板和炎症因子之间相互作用的机制理解 TAVR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局。