The formation of an obstructive thrombus within an artery remains a major cause of mortality and morbidity worldwide. [1] Despite effective inhibition of platelet function by modern antiplatelet therapies, these agents fail to fully eliminate atherothrombotic risk. This may well be related to extensive vascular disease, beyond the protective abilities of the treatment agents used. However, recent evidence suggests that residual vascular risk in those treated with modern antiplatelet therapies is related, at least in part, to impaired fibrin clot lysis. Along these lines, thrombosis is the result of several changes in local homeostasis: endothelial dysfunction, changes in the fibrinolytic system, increased content of some coagulation factors, decreased natural inhibitors, platelet hyperactivity [2] [3]. In this review, we attempt to shed more light on the role of hypofibrinolysis in predisposition to arterial vascular events. We provide a brief overview of the coagulation system followed by addressing the role of impaired coagulation, anticoagulation, and fibrinolysis in acute vascular conditions, including coronary artery disease. We also discuss the prognostic implications of coagulation biomarkers regarding arterial thrombotic events, addressing, in particular, people who are exposed to metabolic risks (hyperlipidemia, hypertension, and diabetes). We conclude that affecting coagulation appears to contribute to residual thrombosis risk in individuals with arterial disease on antiplatelet therapy, and targeting proteins in the fibrinolytic and coagulant system represents a viable strategy to improve outcomes in this population. Future work is required to refine the antithrombotic approach by modulating pathological abnormalities in the fibrinolytic and anticoagulant system and tailoring the therapy according to the need of each individual