Plasminogen Activator Inhibitor-1–Positive Platelet-Derived Extracellular Vesicles Predicts MACE and the Proinflammatory SMC Phenotype

•This study shows the existence of PAI-1+ PEVs. Approximately 20% of plasma PAI-1 is composed of PAI-1+ PEVs.•Elevated PAI-1+ PEV levels were predictive of 1-year major adverse cardiac events in both the discovery and the validation cohort, with larger effect sizes than other clinical biomarkers.•High PAI-1+ PEV levels did not affect thrombogenicity.•Increasing doses of PAI-1+ PEVs promoted the proinflammatory VSMC state by enhancing proliferation and migration. Inhibition of the PAI-1:low-density lipoprotein–related receptor-1 pathway dampened the proinflammatory VSMC changes.•PAI-1+ PEV is a promising biomarker for major adverse cardiac events, and targeting the PAI-1+ PEV–VSMC interaction may offer a novel target to modulate cardiac events in patients with coronary artery disease.