The use of aspirin is widely recommended for the prevention of heart attacks owing to its ability to inhibit platelet activation by irreversibly blocking cyclooxygenase 1. However, aspirin also affects the fibrinolytic and hemostatic pathways by mechanisms that are not well understood, causing severe hemorrhagic complications. Here, we investigated the ability of aspirin and aspirin metabolites to inhibit thrombin-activatable fibrinolysis inhibitor (TAFI), the major inhibitor of plasma fibrinolysis. TAFI is activated via proteolytic cleavage by the thrombin-thrombomodulin complex to TAFIa, a carboxypeptidase B-like enzyme. TAFIa modulates fibrinolysis by removing the C-terminal arginine and lysine residues from partially degraded fibrin, which in turn inhibits the binding of plasminogen to fibrin clots. Aspirin and its major metabolites, salicylic acid, gentisic acid, and salicyluric acid, inhibit TAFIa carboxypeptidase activity. Salicyluric acid effectively blocks activation of TAFI by thrombin-thrombomodulin; however, salicylates do not inhibit carboxypeptidase N or pancreatic carboxypeptidase B. Aspirin and other salicylates accelerated the dissolution of fibrin clots and reduced thrombus formation in an in vitro model of fibrinolysis. Inhibition of TAFI represents a novel hemostatic mechanism that contributes to aspirin's therapy-associated antithrombotic activity and hemorrhagic complications.

Objective: To examine whether co-administration of clopidogrel and omeprazole affects the clinical outcomes of clopidogrel treatment. Design and Methods: A retrospective cross-sectional study of 4078 patients after a percutaneous coronary intervention and stent implantation. Seven hundred twenty-three clopidogrel-treated patients who fulfilled the inclusion criteria of the study were included: 318 treated only with clopidogrel; 405 treated with clopidogrel and omeprazole (study group). The interaction between the drugs was examined in relation to adverse clinical outcomes such as all-cause mortality, Major Adverse Cardiovascular Events (MACE) and cardiac hospitalizations during one year. Results: No significant difference was detected between the groups regarding the primary outcomes of the study. Regression models adjusted to basic characteristics and clinical variables showed a significant association between the study group and the primary outcomes through interactions with specific covariates: “all-cause mortality” through interaction with the covariate ethnicity (not-Jewish) (OR = 43.12, 95% CI 1.19-1567.8, P = 0.04), “MACE” through interaction with the covariates gender (female) and complicated angioplasty (OR= 9.36, 95% CI 2.04-42.94, P= 0.04); and “cardiac hospitalizations” through interaction with the covariates extent of artery stenosis and hypertension (OR= 2.65, 95% CI 1.043-6.76, P = 0.04). Conclusion: Addition of omeprazole to clopidogrel may be associated with increased incidence of negative clinical outcomes, including death and MACE. These findings underscore the need for conduction of prospective randomized controlled trials that will examine the association between addition of omeprazole to clopidogrel and the incidence of clinical outcomes.

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