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

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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.