Effect of atorvastatin on different fibrinolyis mechanisms in hypercholesterolemic subjects F. Bruni, A.L. Pasqui, M. Pastorelli, G. Bova, M. Di Renzo, M. Cercigani, A. Leo, A. Auteri, L. Puccetti * Department of Clinical Medicine and Immunological Sciences, Internal Medicine Division, Center for Metabolic Diseases and Atherosclerosis, University of Siena, Policlinico Le Scotte, V.le Bracci, 53100 Siena, Italy Received 22 April 2003; accepted 11 August 2003 Abstract Background: Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular events by cholesterol lowering as well as non-lipid related actions. Among them, the modulation of fibrinolysis could play a relevant role in vascular protection. Atorvastatin is able of reducing platelet activity and thrombin generation before low-density lipoprotein cholesterol (LDL-C) decrease in hypercholesterolemic subjects in which coagulation and fibrinolysis are linked by the activation of thrombin activable fibrinolysis inhibitor (TAFI). The aim of our study was to evaluate whether atorvastatin could modulate fibrinolysis by interactions with endothelial mechanisms and thrombin generation. Methods: Forty-four pure hypercholesterolemic subjects (26 M, 18 F, mean age 52.7 F 13.7, LDL-C 194.8 F 9.3t mg/dl) were evaluated for plasmin–antiplasmin complexes (PAP), tissue-plasminogen acivator (t-PA) and its inhibitor (PAI-1) (ELISA), TAFI activity (HPLC), platelet P-selectin (P-sel) (cytofluorymetric detection), platelet-dependent thrombin generation (PDTG, coagulative-chromogenic method) and lipid profile at baseline and after 7, 14, 28 and 90 days of atorvastatin (10 mg/die) treatment. Results: PAP were significantly reduced at baseline in hypercholesterolemic versus control subjects ( P < 0.05) and were related to P-sel ( P < 0.01), PDTG ( P < 0.01) and its inhibitor (PAI-1) after venous occlusion (VO) ( P < 0.05). Atorvastatin induced a significant increase of PAP at T 2 related to modifications of P-sel ( P < 0.01) and PDTG ( P < 0.01) before significant LDL-C reduction ( P = 0.132). PAI-1 was significantly changed at T 3 with relation to LDL-C ( P < 0.01), Von Willebrand factor (VWF) ( P < 0.01) and sE-sel ( P < 0.05). Conclusions: The profibrinolytic activity of atorvastatin in hypercholesterolemic subjects is related, initially, to the positive effects exerted on platelet function and thrombin generation which can modulate fibrinolysis by TAFI activity. D 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Atorvastatin; Fibrinolyis mechanisms; Hypercholesterolemic subjects 1. Introduction Impairment of fibrinolytic endogenous activity has been associated with either venous thromboembolism or acute thrombotic complications of atherosclerosis [1]. Furthermore the relation between fibrinolysis and cardiovascular disease is an open debate either in terms of pathogenetic mechanisms or as evaluation of possible prognostic factors [2,3]. Fibri- nolysis is related to endothelial function and presents mo- lecular links with platelet and coagulation activity by way of thrombin generation and thrombin-acitvable fibrinolysis inhibitor (TAFI) activity [4,5]. We have previously shown the latter findings in hypercholesterolemic subjects, whereas endothelial dysfunction associated to PAI-1 hyperactivity share a prominent role in hypertrigliceridaemia/low high- density lipoprotein cholesterol (HDL-C) and/or combined hyperlipoproteinaemia [6]. Furthermore reduced fibrinolysis has been reported in other dysmetabolic conditions associ- ated with atherosclerosis such as diabetes mellitus [7]. HMG-CoA reductase inhibitors (statins) are described to reduce the vascular risk of dysmetabolic and/or atheroscler- ois affected subjects also by possible mechanisms not completely related to low-density lipoprotein cholesterol (LDL-C) reduction [8]. Indeed possible direct antithrombotic effects of statins could be responsible of this action [8]. We have recently shown that atorvastatin reduces platelet activ- ity and platelet-dependent thrombin generation (PDTG) by direct cellular mechanisms partially independent from LDL- 0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.08.003 * Corresponding author. Tel.: +39-05-7758-5741; fax: +39-05-774- 4114. E-mail address: puccetti@unisi.it (L. Puccetti). www.elsevier.com/locate/ijcard International Journal of Cardiology 95 (2004) 269 – 274