Abstract-The formation of fibrin clots that are relatively resistant to lysis represents the final step in blood coagulation. We discuss the genetic and environmental regulators of fibrin structure in relation to thrombotic disease. In addition, we discuss the implications of fibrin structure for treatment of thrombosis. Fibrin clots composed of compact, highly branched networks with thin fibers are resistant to lysis. Altered fibrin structure has consistently been reported in patients with several diseases complicated by thromboembolic events, including patients with acute or prior myocardial infarction, ischemic stroke, and venous thromboembolism. Relatives of patients with myocardial infarction or venous thromboembolism display similar fibrin abnormalities. Low-dose aspirin, statins, lowering of homocysteine, better diabetes control, smoking cessation, and suppression of inflammatory response increase clot permeability and susceptibility to lysis. Growing evidence indicates that abnormal fibrin properties represent a novel risk factor for arterial and venous thrombotic events, particularly of unknown etiology in young and middle-aged patients. (Arterioscler Thromb Vasc Biol. 2011;31:e88-e99.)

Abstract-The 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) have been shown to exhibit several vascular protective effects, including antithrombotic properties, that are not related to changes in lipid profile. There is growing evidence that treatment with statins can lead to a significant downregulation of the blood coagulation cascade, most probably as a result of decreased tissue factor expression, which leads to reduced thrombin generation. Accordingly, statin use has been associated with impairment of several coagulant reactions catalyzed by this enzyme. Moreover, evidence indicates that statins, via increased thrombomodulin expression on endothelial cells, may enhance the activity of the protein C anticoagulant pathway. Most of the antithrombotic effects of statins are attributed to the inhibition of isoprenylation of signaling proteins. These novel properties of statins, suggesting that these drugs might act as mild anticoagulants, may explain, at least in part, the therapeutic benefits observed in a wide spectrum of patients with varying cholesterol levels, including subjects with acute coronary events. Key Words: statins Ⅲ blood coagulation Ⅲ thrombin Ⅲ protein C T he 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors, the so-called statins, have been proven to be highly effective in the management of hyperlipidemia and the prevention of atherosclerotic vascular disease, especially coronary artery disease (CAD). 1,2 The therapeutic benefits from statin therapy, however, are only poorly correlated with cholesterol lowering, suggesting other mechanisms are at play. Mevalonate, the product of HMGCoA reductase, is the precursor of not only cholesterol but also isoprenoid compounds that permit the attachment of signaling proteins to the cell membrane. 3,4 Abundant experimental and clinical evidence in this rapidly expanding field has resulted in the widely accepted concept of cholesterol-independent pleiotropic effects produced by statins that include alteration of endothelial dysfunction, leading to increased nitric oxide (NO) bioavailability, atherosclerotic plaque stabilization, regulation of angiogenesis, reduction of the inflammatory response, and antithrombotic properties. [5][6][7] Apart from profibrinolytic and antiplatelet effects, reported in several studies, 5,7-9 increasing evidence indicates that the HMG-CoA reductase inhibitors also modulate the blood coagulation cascade at multiple levels, leading to reduced thrombogenicity.The activation of the extrinsic coagulation pathway initiated by an exposure or expression of tissue factor (TF) plays a key role in hemostasis (Figure). The localized process involves multiple components, including blood coagulation factors, platelets, blood cells, the endothelium, and sublayers of a damaged vessel. Platelets provide the catalytic surface for the formation of the procoagulant complexes; the intrinsic factor Xase (FIXa-FVIIIa) and prothrombinase (prothrombin, FXa-FVa). These complexes accelerate thrombin ge...

To cite this article: Undas A, Celinska-Lö wenhoff M, Lö wenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 4: 1029-36.Summary. Background: Aspirin increases fibrin clot porosity and susceptibility to lysis. It is unknown whether other drugs, in combination with aspirin, used in the treatment of coronary artery disease (CAD) might affect clot structure and resistance to lysis. Aim: The aim of the study was to assess the effects of statins, fibrates, or angiotensin-converting enzyme inhibitors (ACEIs) on fibrin clot properties. Patients and methods: In a randomized double-blind study, men with advanced CAD taking low-dose aspirin were assigned to receive one of the four drugs: simvastatin 40 mg day )1 (n ¼ 13), atorvastatin 40 mg day )1 (n ¼ 12), fenofibrate 160 mg day )1 (n ¼ 12), and quinapril 10 mg day )1 (n ¼ 11) for 28 ± 2 days. Moreover, CAD patients (n ¼ 13) taking aspirin (75 mg day) for 8 weeks were studied after additional 4 weeks on an open-label basis. Thirty men served as healthy controls. Plasma clot permeability and tissue plasminogen activator-induced fibrinolysis were evaluated at baseline and after drug administration. Results: Permeability increased following the administration of simvastatin (by 20%; P ¼ 0.01), atorvastatin (by 22%; P ¼ 0.001), fenofibrate (by 16%; P ¼ 0.02), and quinapril (by 13%; P ¼ 0.04) like for aspirin (P < 0.001). Turbidity analysis showed that administration of any of the drugs was associated with higher maximum absorbancy, suggesting thicker fibers, and shorter fibrinolysis time (P < 0.001). Post-treatment reduction in lysis time correlated with an increase in clot porosity in all the groups (r from 0.42 to 0.61; P from 0.01 to 0.001). Conclusions: Statins, fibrates, and ACEIs may increase plasma clot permeability and susceptibility to fibrinolysis in CAD patients receiving aspirin. This novel antithrombotic mechanism might contribute to clinical benefits of the drugs tested.