Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration

BACKGROUND AND AIMS: Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases. METHODS: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients. RESULTS: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment. CONCLUSIONS: Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.

• Polzin, A.
• Benkhoff, M.
• Thienel, M.
• Barcik, M.
• Mourikis, P.
• Shchurovska, K.
• Helten, C.
• Ehreiser, V.
• Zhe, Z.
• von Wulffen, F.
• Theiss, A.
• Peri, S.
• Cremer, S.
• Ahlbrecht, S.
• Zako, S.
• Wildeis, L.
• Al-Kassis, G.
• Metzen, D.
• Utz, A.
• Hu, H.
• Vornholz, L.
• Pavic, G.
• Lüsebrink, E.
• Strecker, J.
• Tiedt, S.
• Cramer, M.
• Gliem, M.
• Ruck, T.
• Meuth, S. G.
• Zeus, T.
• Mayr, C.
• Schiller, H. B.
• Simon, L.
• Massberg, S.
• Kelm, M.
• Petzold, T.