title: On the role of coagulation and fibrinolysis in atherosclerosis.
abstract: Atherosclerosis is probably caused by multiple interacting factors such as disturbed lipid metabolism; endothelial cell damage, leading to platelet aggregation and monocyte invasion with the release of mitogenic factors; and disorders of fibrin balance, leading to persisting fibrin deposits. Deficient fibrinolysis may (1) predispose to fibrin deposition and contribute to the pathogenesis of atherosclerosis and (2) contribute to occlusive thrombus formation on fissured plaque, provoking atherothrombosis. Prospective epidemiologic studies have so far not provided definitive evidence that deficient fibrinolysis constitutes a significant risk factor for the development of atherosclerosis. Two recent findings, however, strongly suggest a contribution: (1) Increased lipoprotein(a) levels that reduce tissue-type plasminogen activator (t-PA)-mediated clot lysis are a clear risk factor for atherosclerosis; and (2) increased plasminogen activator inhibitor-1 (PAI-1) levels in patients with disturbed glucose tolerance predispose to an accelerated development of atherosclerotic disease. However, deficient fibrinolysis constitutes a risk factor for the development of thrombotic complications (acute myocardial infarction) in patients with coronary artery disease. The potential role of deficient fibrinolysis in the pathogenesis of atherosclerosis and of atherothrombosis suggests that drugs normalizing deficient endogenous fibrinolysis by either reducing PAI-1 synthesis or by stimulating endogenous t-PA synthesis may be of clinical value. Although regulation of the gene expression of PAI-1 and t-PA is presently under active investigation, no potent specific and safe agents to downregulate PAI-1 or to upregulate t-PA have as yet been identified. Retinoic acid appears to be a specific inducer of t-PA synthesis in human endothelial cells in culture and may constitute a model for the development of drugs that stimulate endogenous t-PA synthesis.
authors.affiliation: Laboratoire d'Hématologie, Centre Hospitalier Universitaire, Hôpital de la Timone, Marseille, France.
authors.forename: I
authors.initials: I
authors.lastname: Juhan-Vague
authors.forename: D
authors.initials: D
authors.lastname: Collen
mesh_terms: D001161:Arteriosclerosis / Q000097:blood* / Q000503:physiopathology; D001777:Blood Coagulation / Q000502:physiology*; D005337:Fibrin / Q000502:physiology; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D017270:Lipoprotein(a) / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000503:physiopathology
chemical_list: D017270:Lipoprotein(a); D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin