Statins Therapy: Effects on Plasma Fibrinogen Levels and Fibrinolysis

Abstract

Elevated plasma fibrinogen levels have been identified as an independent and strong risk factor for cardiovascular disease. At present, there are no selective oral agents that lower fibrinogen; however different drugs can influence its levels as ticlopidine (inhibitor of platelet aggregation) and fibrates (lipid lowering drugs). Statins lower cholesterol by inhibiting HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, the rate limiting step in cholesterol biosynthesis. In addition to lowering cholesterol, several non-lipids related benefits of statins have been reported. Briefly, statins improve endothelial function, modulate the inflammatory response, may stabilize atherosclerotic plaques, restrain thrombus formation, and others. Many of these are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules (Rho, Ras, and Rac). The beneficial effect of statin on plasma fibrinogen concentration still controversial. Although several studies have shown a mild decrease in plasma fibrinogen (mostly when the Clauss method is used), many others fail to find an effect of statins on plasma fibrinogen concentration. In vitro studies using different cell types have shown that statins increase tPA and decrease PAI-1 levels; however, clinical results are ambiguous. Statins modify fibrin structure leading to increased clot lysis rate and clot permeability, by decreasing tissue factor expression that alters thrombin formation.

Pleiotropic Effects of Atorvastatin Result in a Downregulation of the Carboxypeptidase U System (CPU, TAFIa, CPB2) in a Mouse Model of Advanced Atherosclerosis

“…Moreover, Masuda et al reported on the downregulation of the CPB2 gene expression in HepG2 cells and decreases in both CPB2 mRNA and proCPU antigen levels, mediated by the PPARα signaling pathway upon treatment with the PPARα agonist WY14643 [ 17 ]. Since it has been described that statins increase PPARα expression (although they are not direct ligands for PPARα), the hypothesis that statin therapy could increase PPARα expression—which in turn could lead to reduced CPB2 gene expression and thus lower plasma proCPU levels—seems plausible but was not further explored in the current work [ 6 , 18 , 19 , 20 ].…”

“…Statins (inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase) exert cardiovascular protective effects that are independent of the lowering of LDL-cholesterol, including profibrinolytic effects such as the reduction of proCPU levels in hypercholesterolemic patients [ 5 , 6 , 7 , 8 ]. However, it is challenging to prove whether this is a lipid or a non-lipid-related pleiotropic effect, since lowering cholesterol is inherent to statin treatment in humans.…”

Fibrin Clot Formation under Oxidative Stress Conditions

“…The concentration of fibrinogen and alterations in fibrin clot properties could also be mediated by statins, which are used in the management of hyperlipidemia. Statins are associated with the modulation of PAI-1 and tPA activity, influence fibrinogen concentration, and have an impact on fibrinolysis [29][30][31]. Statins could increase the permeability of clots and thus enhance fibrinolysis [30].…”