Language
English
Publication Date
2-1-2025
Journal
Journal of Thrombosis and Haemostasis
DOI
10.1016/j.jtha.2024.10.025
PMID
39551435
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.
Keywords
Animals, Blood Platelets, Humans, Myocardial Infarction, Proteome, Male, Factor Xa Inhibitors, Thrombosis, Stroke, Mice, Inbred C57BL, Mice, Female, Inflammation, Disease Models, Animal, Middle Aged, Aged, Time Factors, Platelet Aggregation Inhibitors, Proteomics, Platelet Activation, factor Xa, myocardial infarction, platelets, thromboinflammation
Published Open-Access
yes
Recommended Citation
Polzin, Amin; Benkhoff, Marcel; Thienel, Manuela; et al., "Long-Term FXa Inhibition Attenuates Thromboinflammation After Acute Myocardial Infarction and Stroke by Platelet Proteome Alteration" (2025). Faculty, Staff and Students Publications. 6559.
https://digitalcommons.library.tmc.edu/baylor_docs/6559