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Anticoagulant Effects of Statins and Their Clinical Implications

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Anticoagulant Effects of Statins and Their Clinical Implications Review Article 1 Anticoagulant effects of statins and their clinical implications Anetta Undas1; Kathleen E. Brummel-Ziedins2; Kenneth G. Mann2 1Institute of Cardiology, Jagiellonian University School of Medicine, and John Paul II Hospital, Krakow, Poland; 2Department of Biochemistry, University of Vermont, Colchester, Vermont, USA Summary cleavage, factor V and factor XIII activation, as well as enhanced en- There is evidence indicating that statins (3-hydroxy-methylglutaryl dothelial thrombomodulin expression, resulting in increased protein C coenzyme A reductase inhibitors) may produce several cholesterol-inde- activation and factor Va inactivation. Observational studies and one ran- pendent antithrombotic effects. In this review, we provide an update on domized trial have shown reduced VTE risk in subjects receiving statins, the current understanding of the interactions between statins and blood although their findings still generate much controversy and suggest that coagulation and their potential relevance to the prevention of venous the most potent statin rosuvastatin exerts the largest effect. thromboembolism (VTE). Anticoagulant properties of statins reported in experimental and clinical studies involve decreased tissue factor ex- Keywords pression resulting in reduced thrombin generation and attenuation of Blood coagulation, statins, tissue factor, thrombin, venous throm- pro-coagulant reactions catalysed by thrombin, such as fibrinogen boembolism Correspondence to: Received: August 30, 2013 Anetta Undas, MD, PhD Accepted after major revision: October 15, 2013 Institute of Cardiology, Jagiellonian University School of Medicine Prepublished online: November 28, 2013 80 Pradnicka St., 31–202 Krakow, Poland doi:10.1160/TH13-08-0720 Tel.: +48 12 6143004, Fax: +48 12 4233900 Thromb Haemost 2014; 111: ■■■ E-mail: [email protected] Introduction Most of these additional statin-mediated actions reported are independent of blood cholesterol reduction. Statins reduce Statins (3-hydroxy-methylglutaryl coenzyme A [HMG-CoA] re- formation of isoprenoids, altering protein prenylation, a critical ductase inhibitors), both lipophilic agents – atorvastatin, simvas- event in the posttranslational modification of proteins involved in tatin and fluvastatin, and hydrophilic agents – rosuvastatin and the regulation of cell cycle progression, proliferation and signalling pravastatin, are effective in reducing low-density lipoprotein pathways (7, 8). Inhibition of mevalonic acid synthesis blocks the (LDL) cholesterol. At typical daily doses statins result in reduc- synthesis of isoprenoid intermediates of the cholesterol biosyn- tion in total and LDL cholesterol by 18–60% with decreases in thetic pathway (e.g. farnesyl pyrophosphate and geranylgeranylpy- triglycerides by 10–30% and slight increases in high-density lipo- rophosphate [GGPP]). These compounds permit the attachment protein (HDL) cholesterol (8%). Data from the Cholesterol of signalling proteins for the posttranslational modification of Treatment Trialists’ Collaboration found that statins reduced the GTP-binding protein Ras and Ras-like proteins to the cell mem- risk of major vascular events by 22% (1). Compelling clinical evi- brane. The inhibition of Rho, Ras, and Rac, whose localisation and dence indicates that statins also decrease cardiovascular and all- functions are dependent on isoprenylation, is perceived to be a key cause death (2). process in mediating the statins pleiotropic effects (8). Statins also A number of ’pleiotropic’ effects of statins have been suggested reduce the stability of lipid raft formation and modulate immune to contribute to their efficacy in cardiovascular disease (3). The activation and regulation (6). first clinical data suggesting that statins have benefits beyond lipid Antithrombotic properties of statins were recently reviewed by lowering came from the Heart Protection Study, in which simvas- Violi et al. (9) and previously by us (10). In this review, we focus on tatin reduced mortality and morbidity even in patients with ’nor- the effect of statins on blood coagulation and their potential rel- mal’ LDL-cholesterol levels (<2.6 mmol/l or 100 mg/dl) (4). Ancil- evance for the prevention of venous thromboembolism (VTE). lary effects of statins included 1) improvement in endothelial func- tion via increased nitric oxide (NO) bioavailability, 2) suppression of inflammation via reduction in proinflammatory cytokines, Tissue factor (TF) chaemokines and adhesion molecule expression, lowering C-reac- tive protein (CRP), 3) stabilisation of atherosclerotic plaques in- TF is the major initiator of blood clotting in vivo. The formation of cluding modification of the physiochemical properties of the lipid the Ca2+-dependent complex between TF and plasma factor core, 4) reducing smooth muscle cell proliferation, 5) immuno- (F)VIIa on the cell surfaces leads to the activation of FX and FIX, modulation, and 6) inhibition of cardiac hypertrophy (5, 6). and subsequent thrombin generation and fibrin formation (▶ Fig- © Schattauer 2014 Thrombosis and Haemostasis TH111.3/2014 Downloaded from www.thrombosis-online.com on 2013-12-01 | IP: 88.162.114.204 Note: Uncorrected proof, prepublished online For personal or educational use only. No other uses without permission. All rights reserved. 2 Undas et al. Statins and coagulation ure 1) (11, 12). In healthy individuals, TF is associated with ex- lin-1 membrane microdomains. Banfi et al. (18) have shown that travascular tissue and expressed in monocytes. TF expression fluvastatin and rosuvastatin block this mechanism of induction of within atherosclerotic plaques and an increased number of TF- TF expression by inhibition of ERK1/2 phosphorylation, and positive microparticles promote intravascular thrombosis (11, 12). PAR1 relocation. This statin-induced effect is independent of iso- Colli et al. (13) demonstrated that simvastatin and fluvastatin, de- prenoids and may be mediated by decreasing the cholesterol con- creased TF mRNA expression and activity in cultured human mono- tent of the cell membrane (18). Statin-induced suppression of the cytes/macrophages stimulated by lipopolysaccharides (LPS). This ef- decryption of TF remains controversial (19, 20). fect was reversed by co-incubation with mevalonate or GGPP, but Down-regulation of TF associated with suppressed inflam- not by cholesterol. In contrast, pravastatin at concentrations 100 mation, but not with cholesterol levels, has been documented for times greater than effective for lipophilic statins, did not affect TF various statins in animal models, such as apolipoprotein E-defi- mRNA expression or activity on monocytes (13). Inhibition of tran- cient mice and in cholesterol-fed rabbits (21–24). A substantial re- scription nuclear factor κB (NF-κB) activation has been reported as duction in vascular TF expression, up to 70%, was observed for ro- the mechanism underlying down-regulation of TF expression (13). suvastatin (22). In patients, 4–6 months of treatment with atorvas- Down-regulation of TF expression has also been observed on en- tatin resulted in 29% lower TF antigen levels and 56% lower TF ac- dothelial and vascular smooth muscle cells. Further studies reported tivity in atherosclerotic plaques removed during endarterectomy that cerivastatin (paper withdrawn, 2001), atorvastatin, simvastatin, compared with the values for subjects receiving placebo (25). Sta- pravastatin, lovastatin, and fluvastatin, in this order, suppress NF-κB tin-induced decrease in TF expression has also been reported in activation in human monocytes stimulated by LPS from 45% in- atherosclerotic plaques removed from coronary arteries (26). hibition for cerivastatin to 5% for fluvastatin (14). A three-fold reduc- The effect of simvastatin on coagulation in LDL receptor-defi- tion in TF expression and activity was observed in human LPS- cient mice on a four-week high-fat diet plus simvastatin decreased stimulated monocytes isolated from hypercholesterolaemic subjects oxidised LDL (oxLDL), white blood cell TF expression and the treated with 20 mg/day simvastatin (15). number of TF+ microparticles. Administration of simvastatin also Simvastatin has been shown to inhibit thrombin-induced TF reduced TF-containing microparticles and circulating thrombin expression in human aortic endothelial cells and aortic smooth generation markers despite unaltered blood cholesterol levels. The muscle cells (16) while mevalonate reversed this effect. The in- simvastatin-induced changes were associated with prolonged time hibition of Rho-kinase-dependent Akt dephosphorylation me- from arterial injury to the vessel closure. TF expression in hyper- diates, at least in part, the inhibitory effect of statins on TF ex- cholesterolaemic mice and monkeys was mediated by the mono- pression in the endothelium (16, 17). cyte CD36/TLR4/TLR6 heterotrimeric complex enhanced by Activation of protease activated receptors (PAR) by thrombin oxLDL and simvastatin reduced expression of TF and interleu- induces TF expression in endothelial cells, which requires caveo- kin-6 through lowering oxLDL in these animal models (27). It re- Figure 1: The blood coagulation cascade and proteins or reactions reportedly af- fected by statin therapy. The inventory and connectivity of the vitamin K dependent com- plexes (squares; intrinsic tenase, extrinsic tenase, prothrombinase and protein Case) leading to the generation of thrombin (IIa) and the formation of a fibrin clot are illustrated. The square in each of the complexes
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