Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration
Year: 2024
Type: article
Abstract: BACKGROUND: Immediate activated factor (F)X (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. OBJECTIVES: Therefore, we analyzed platelet-derived effects of long-term FXa inhibition in the setting of acute myocardial infarction (AMI) and stroke. METHODS: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following AMI and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa nonvitamin K antagonist oral anticoagulant treatment and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of patients with AMI, we determined cardiovascular magnetic resonance based cardiac endpoints under FXa nonvitamin K antagonist oral anticoagulant effects on clinical endpoints in a cohort of patients with AMI. RESULTS: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24 hours after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced neutrophil extracellular trap 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 α and dense granule release. Subsequent, thromboinflammatory neutrophil extracellular trap density in thrombi isolated from stroke and myocardial infarction patients was reduced. Patients with AMI treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment. CONCLUSION: Long-term FXa inhibition induces antithromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.
Authors: Amin Polzin, Marcel Benkhoff, Manuela Thienel, Maike Barcik, Philipp Mourikis, Khrystyna Shchurovska, Carolin Helten, Vincent Ehreiser, Zhang Zhe, Franziska von Wulffen, Alexander Theiss, Sameera Peri, Sophie Cremer, Samantha Ahlbrecht, Saif Zako, Laura Wildeis, Gabrielle Al-Kassis, Daniel Metzen, Amelie Utz, Hao Hu, Lilian Vornholz, Goran Pavic, Enzo Lüsebrink, Jan Strecker, Steffen Tiedt, Mareike Cramer, Michael Gliem, Tobias Ruck, Sven G. Meuth, Tobias Zeus, Christoph Mayr, Herbert B. Schiller, Lukas Simon, Steffen Massberg, Malte Kelm, Tobias Petzold
Institutions: Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, Imperial College London, University of Vienna, Ludwig-Maximilians-Universität München, Deutsches Herzzentrum der Charité, Stiftung Charité, Charité - Universitätsmedizin Berlin, Institut für Schlaganfall- und Demenzforschung, Helmholtz Munich, German Center for Lung Research, Institut für Experimentelle Pneumologie, Baylor College of Medicine, German Centre for Cardiovascular Research
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,750
Awards: G3449116857, G42791754, G5127947741, Lipidom‐Analyse bei EPA‐Medikation und akutem Myokardinfarkt, Die Auswirkung von Sphingosin1Phosphat Rezeptor Modulatoren auf das postischämische Remodeling nach akutem Myokardinfarkt, SFB 1116: Master switches bei kardialer Ischämie, Faktor Xa Hemmer als Regulatoren von Proteom und Funktion der Thrombozyten, Dyslipidämie reduziert die Thrombozytenmembranfluidität und erhöht die Thrombozytenreaktivität
OpenAlex ID: W4404408311