Statins in prevention of thromboembolic events: from seminal studies to recent advances

Statins, 3‑hydroxy‑methylglutaryl coenzyme A reductase inhibitors, reduce the rate of cardiovascular events in primary and secondary prevention, and represent a cornerstone in the management of atherosclerotic vascular disease. Statins were also shown to be effective in lowering the risk of venous thromboembolism (VTE) in its primary and secondary prevention, but their use in VTE prophylaxis is still not approved and recommended in current guidelines. Several antithrombotic mechanisms of these cholesterol‑lowering agents, largely independent of the magnitude of low‑ density lipoprotein cholesterol reduction, were demonstrated in a broad spectrum of experimental in vitro and in vivo models. However, these studies yielded inconsistent results, such as substantial differences related to the use of specific statins, their dose or final concentration, and even the clinical setting (patients with cardiovascular disease or VTE vs healthy subjects). Anticoagulant properties of statins, reported for the first time 25 years ago, involve downregulation of tissue factor expression with a subsequent decreased thrombin generation and inhibition of thrombin‑mediated reactions, including factor V and factor XIII activation, and enhanced endothelial thrombomodulin expression resulting in increased protein C activation. Enhanced fibrinolysis was also reported partly as a result of reduced activity of fibrinolysis inhibitors such as plasminogen activator inhibitor‑1 (PAI‑1) and thrombin‑activatable fibrinolysis inhibitor. This review summarizes the findings of the studies from the 1990s until the most recent reports to update our knowledge on the impact of statins on blood coagulation and its potential clinical relevance.