Drugs

, Volume 63, Issue 17, pp 1821–1854 | Cite as

Effects of HMG-CoA Reductase Inhibitors on Coagulation and Fibrinolysis Processes

  • Robert Krysiak
  • Boguslaw Okopień
  • Zbigniew S. Herman
Review Article

Abstract

Recent large clinical trials have demonstrated that HMG-CoA reductase inhibitors, or statins, markedly reduce morbidity and mortality when used in the primary and secondary prevention of cardiovascular disease. It has been established that the benefits of statin therapy in cardiovascular disease can be explained not only by the lipid-lowering potential of statins but also by nonlipid-related mechanisms (so-called ‘pleiotropic effects’) that contribute to the positive effect of statins on the incidence of cardiovascular events.

The coagulation and fibrinolytic systems are two separate but reciprocally linked enzyme cascades that regulate the formation and breakdown of fibrin. Numerous studies have demonstrated that disturbances of coagulation and fibrinolysis contribute to the development and progression of atherosclerosis, and that they affect the incidence of atherosclerosis-related clinical events. High plasma levels or activities of fibrinogen, factor VII, factor VIII, von Willebrand factor (vWF), soluble thrombomodulin, tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are thought to be associated with increased morbidity and mortality related to cardiovascular disease.

Experimental studies and many clinical studies have recently shown that statins produce favourable effects on haemostatic parameters, including those that are risk factors for cardiovascular disease. Statins diminish procoagulant activity, which is observed at different stages of the coagulation cascade, including tissue factor (TF) activity, conversion of prothrombin to thrombin and thrombin activity. In some studies, statins also reduced fibrinogen levels. By altering the levels and activities of tPA and PAI-1, statins seem to stimulate fibrinolysis. The data on the effects of combined treatment with statins and other drugs on haemostasis are rather limited. They suggest that statins combined with fibric acid derivatives, omega-3 fatty acids and 17β-estradiol are superior to statins alone. The only two clinical studies performed in patients with acute coronary syndromes showed a relatively weak effect of statins on haemostasis in those patients. Although various statins may produce different effects on individual variables, there are no convincing data showing that differences in their physicochemical and pharmacokinetic properties significantly alter their net effect on excessive procoagulant activity. Apart from the lipid-lowering effect, statins suppress the synthesis of several important nonsterol isoprenoids derived from the mevalonate pathway, especially farnesyl and geranylgeranyl pyrophosphates, which via enhanced protein prenylation, are involved in the regulation of many cellular processes. It is presumed that the inhibitory effect of statins on the mevalonate pathway is involved in the regulation of some key steps of coagulation and fibrinolysis processes. In this way they probably regulate the synthesis of TF, tPA and PAI-1, and perhaps they also control the generation and activity of thrombin.

The beneficial effects of statins on coagulation and fibrinolysis may be responsible for their ability to decrease the number of cardiovascular events. The lipid-independent effects of statins on haemostasis may contribute to the marked decrease in the incidence rates of mortality, hospitalisation and revascularisation in patients treated with these drugs.

Keywords

Simvastatin Atorvastatin Pravastatin Human Umbilical Vein Endothelial Cell Tissue Factor 

Notes

Acknowledgements

This work was supported by the statutory grant NN-1-012/01 of the Medical University of Silesia. The authors wish to thank Katarzyna Wilgus-Kubica and Maciej Haberka for their excellent technical assistance in the preparation of the manuscript. The authors have provided no information on conflicts of interest directly relevant to the content of this review.

References

  1. 1.
    Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study Group. Lancet 1994; 344: 1383–9Google Scholar
  2. 2.
    Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333: 1301–7Google Scholar
  3. 3.
    Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–9Google Scholar
  4. 4.
    Wheeler DC. Are there potential non-lipid-lowering uses of statins? Drugs 1998; 56: 517–22PubMedCrossRefGoogle Scholar
  5. 5.
    Bellosta S, Ferri N, Bernini F, et al. Non-lipid-related effects of statins. Ann Med 2000; 32: 164–76PubMedCrossRefGoogle Scholar
  6. 6.
    Koh KK. Effects of statins on vascular wall: vasomotoric function, inflammation, and plaque stability. Cardiovasc Res 2000; 47: 648–57PubMedCrossRefGoogle Scholar
  7. 7.
    Rosenson RS. Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. Am J Cardiovasc Drugs 2001; 1: 411–20PubMedCrossRefGoogle Scholar
  8. 8.
    Warkentin TE. Hemostasis and atherosclerosis. Can J Cardiol 1995; 11 Suppl. C: 29C–34CPubMedGoogle Scholar
  9. 9.
    Gensini GF, Comeglio M, Colella A. Classical risk factors and emerging elements in the risk profile for coronary artery disease. Eur Heart J 1998; 19 Suppl. A: A53–61PubMedGoogle Scholar
  10. 10.
    Folsom AR. Hemostatic risk factors for atherothrombotic disease: an epidemiologic view. Thromb Haemost 2001; 86: 366–73PubMedGoogle Scholar
  11. 11.
    Libby P. Changing concepts of atherogenesis. J Intern Med 2000; 247: 349–58PubMedCrossRefGoogle Scholar
  12. 12.
    Heinrich J, Assmann G. Fibrinogen and cardiovascular risk. J Cardiovasc Risk 1995; 2: 197–205PubMedCrossRefGoogle Scholar
  13. 13.
    Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; II: 533–7CrossRefGoogle Scholar
  14. 14.
    Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, et al. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501–5PubMedCrossRefGoogle Scholar
  15. 15.
    Kannel WB, Wolf PA, Castelli WP, et al. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA 1987; 258: 1183–6PubMedCrossRefGoogle Scholar
  16. 16.
    Davidson M, McKenney J, Stein E, et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia: Atorvastatin Study Group I. Am J Cardiol 1997; 79: 1475–81PubMedCrossRefGoogle Scholar
  17. 17.
    Marais AD, Firth JC, Bateman ME, et al. Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997; 17: 1527–31PubMedCrossRefGoogle Scholar
  18. 18.
    Wierzbicki AS, Lumb PJ, Semra YK, et al. Effect of atorvastatin on plasma fibrinogen. Lancet 1998; 351: 569–70PubMedCrossRefGoogle Scholar
  19. 19.
    Nair DR, Papadakis JA, Jagroop IA, et al. Statins and fibrinogen. Lancet 1998; 351: 1430PubMedCrossRefGoogle Scholar
  20. 20.
    Bertolotto A, Bandinelli S, Ruocco L, et al. More on the effect of atorvastatin on plasma fibrinogen levels in primary hypercholesterolemia. Atherosclerosis 1999; 143: 455–7PubMedCrossRefGoogle Scholar
  21. 21.
    Bairaktari ET, Tzallas CS, Tsimihodimos VK, et al. Comparison of the efficacy of atorvastatin and micronized fenofibrate in the treatment of mixed hyperlipidemia. J Cardiovasc Risk 1999; 6: 113–6PubMedGoogle Scholar
  22. 22.
    Dujovne CA, Harris WS, Altman R, et al. Effect of atorvastatin on hemorheologic-hemostatic parameters and serum fibrinogen levels in hyperlipidemic patients. Am J Cardiol 2000; 85: 350–3PubMedCrossRefGoogle Scholar
  23. 23.
    Gentile S, Turco S, Guarino G, et al. Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia. Diabetes Obes Metab 2000; 2: 355–62PubMedCrossRefGoogle Scholar
  24. 24.
    Joukhadar C, Klein N, Prinz M, et al. Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia. Thromb Haemost 2001; 85: 47–51PubMedGoogle Scholar
  25. 25.
    Kiortsis DN, Millionis H, Bairaktari E, et al. Efficacy of combination of atorvastatin and micronised fenofibrate in the treatment of severe mixed hyperlipidemia. Eur J Clin Pharmacol 2000; 56: 631–5CrossRefGoogle Scholar
  26. 26.
    Frost RJ, Otto C, Geiss HC, et al. Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia. Am J Cardiol 2001; 87: 44–8PubMedCrossRefGoogle Scholar
  27. 27.
    Goudevenos JA, Bairaktari ET, Chatzidimou KG, et al. The effect of atorvastatin on serum lipids, lipoprotein(a) and plasma fibrinogen levels in primary dyslipidaemia: a pilot study involving serial sampling. Curr Med Res Opin 2001; 16: 269–75PubMedCrossRefGoogle Scholar
  28. 28.
    Malik J, Melenovsky V, Wichterle D, et al. Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial — FAT). Cardiovasc Res 2001; 52: 290–8PubMedCrossRefGoogle Scholar
  29. 29.
    Bo M, Nicolello MT, Fiandra U, et al. Treatment of heterozygous familial hypercholesterolemia: atorvastatin vs simvastatin. Nutr Metab Cardiovasc Dis 2001; 11: 17–24PubMedGoogle Scholar
  30. 30.
    Wierzbicki AS, Lumb PJ, Chik G, et al. Fibrinogen response with simvastatin versus atorvastatin in familial hypercholesterolemia. Am J Cardiol 2001; 87: 338–40PubMedCrossRefGoogle Scholar
  31. 31.
    Banyai S, Banyai M, Falger J, et al. Atorvastatin improves blood rheology in patients with familial hypercholesterolemia (FH) on long-term LDL apheresis treatment. Atherosclerosis 2001; 159: 513–9PubMedCrossRefGoogle Scholar
  32. 32.
    Seljeflot I, Tonstad S, Hjermann I, et al. Improved fibrinolysis after 1-year treatment with HMG-CoA reductase inhibitors in patients with coronary heart disease. Thromb Res 2002; 105: 285–90PubMedCrossRefGoogle Scholar
  33. 33.
    Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin versus four statin-fibrate combinations in patients with familial combined hyperlipidaemia. J Cardiovasc Risk 2002; 9: 33–9PubMedCrossRefGoogle Scholar
  34. 34.
    Atalar E, Ozmen F, Haznedaroglu I, et al. Effect of short-term atorvastatin treatment on global fibrinolytic capacity, and sL-selectin and sFas levels in hyperlipidemic patients with coronary artery disease. Int J Cardiol 2002; 84: 227–31PubMedCrossRefGoogle Scholar
  35. 35.
    Velussi M. Long-term (18-month) efficacy of atorvastatin therapy in type 2 diabetics at cardiovascular risk. Nutr Metab Cardiovasc Dis 2002; 12: 29–35PubMedGoogle Scholar
  36. 36.
    Ural AU, Yilmaz MI, Avcu F, et al. Treatment with cerivastatin in primary mixed hyperlipidemia induces changes in platelet aggregation and coagulation system components. Int J Hematol 2002; 76: 279–83PubMedCrossRefGoogle Scholar
  37. 37.
    Gottsater A, Anwaar I, Lind P, et al. Increasing plasma fibrinogen, but unchanged levels of intraplatelet cyclic nucleotides, plasma endothelin-1, factor VII, and neopterin during cholesterol lowering with fluvastatin. Blood Coagul Fibrinolysis 1999; 10: 133–40PubMedCrossRefGoogle Scholar
  38. 38.
    Tan K, Janus ED, Lam KS. Effects of fluvastatin on prothrombotic and fibrinolytic factors in type 2 diabetes mellitus. Am J Cardiol 1999; 84: 934–7PubMedCrossRefGoogle Scholar
  39. 39.
    Cortellaro M, Cofrancesco E, Boschetti C, et al. Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Thromb Haemost 2000; 83: 549–53PubMedGoogle Scholar
  40. 40.
    Lin TH, Huang CH, Voon WC, et al. The effect of fluvastatin on fibrinolytic factors in patients with hypercholesterolemia. Kaohsiung J Med sci 2000; 16: 600–6PubMedGoogle Scholar
  41. 41.
    Rizos E, Miltiadous G, Elisaf M. The effect of fluvastatin on plasma fibrinogen levels. Curr Med Res Opin 2002; 18: 154–5PubMedCrossRefGoogle Scholar
  42. 42.
    Koppensteiner R, Minar E, Ehringer H. Effect of lovastatin on hemorheology in type II hyperlipoproteinemia. Atherosclerosis 1990; 83: 53–8PubMedCrossRefGoogle Scholar
  43. 43.
    Beigel Y, Fuchs J, Snir M, et al. Lovastatin therapy in hypercholesterolemia: effect on fibrinogen, hemorrheologic parameters, platelet activity, and red blood cell morphology. J Clin Pharmacol 1991; 31: 512–7PubMedGoogle Scholar
  44. 44.
    Koenig W, Hehr R, Ditschuneit HH, et al. Lovastatin alters blood rheology in primary hyperlipoproteinemia: dependence on lipoprotein(a)? J Clin Pharmacol 1992; 32: 539–45PubMedCrossRefGoogle Scholar
  45. 45.
    Isaacsohn JL, Setaro JF, Nicholas C, et al. Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels. Am J Cardiol 1994; 74: 735–7PubMedCrossRefGoogle Scholar
  46. 46.
    Zambrana JL, Velasco F, Castro P, et al. Comparison of bezafibrate versus lovastatin for lowering plasma insulin, fibrinogen, and plasminogen activator inhibitor-1 concentrations in hyperlipemic heart transplant patients. Am J Cardiol 1997; 80: 836–40PubMedCrossRefGoogle Scholar
  47. 47.
    Jay RH, Rampling MW, Betteridge DJ. Abnormalities of blood rheology in familial hypercholesterolaemia: effects of treatment. Atherosclerosis 1990; 85: 249–56PubMedCrossRefGoogle Scholar
  48. 48.
    Branchi A, Rovellini A, Sommariva D, et al. Effect of three fibrate derivatives and of two HMG-CoA reductase inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia. Thromb Haemost 1993; 70: 241–3PubMedGoogle Scholar
  49. 49.
    Wada H, Mori Y, Kaneko T, et al. Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia. Am J Hematol 1993; 44: 112–6PubMedCrossRefGoogle Scholar
  50. 50.
    Tsuda Y, Satoh K, Kitadai M, et al. Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia. Atherosclerosis 1996; 122: 225–33PubMedCrossRefGoogle Scholar
  51. 51.
    Fogari R, Marasi G, Vanasia A, et al. Comparative study of acipimox and pravastatin in patients with combined hyperlipidemia. Int J Clin Pharmacol Ther 1997; 35: 61–4PubMedGoogle Scholar
  52. 52.
    Dangas G, Smith DA, Unger AH, et al. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 1999; 33: 1294–304PubMedCrossRefGoogle Scholar
  53. 53.
    Dangas G, Smith DA, Badimon JJ, et al. Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin. Am J Cardiol 1999; 84: 639–43PubMedCrossRefGoogle Scholar
  54. 54.
    Miossec P, Zkhiri F, Paries J, et al. Effect of pravastatin on erythrocyte rheological and biochemical properties in poorly controlled Type 2 diabetic patients. Diabetes Med 1999; 16: 424–30CrossRefGoogle Scholar
  55. 55.
    Di Garbo V, Bono M, Di Raimondo D, et al. Non lipid, dose-dependent effects of pravastatin treatment on hemostatic system and inflammatory response. Eur J Clin Pharmacol 2000; 56: 277–84PubMedCrossRefGoogle Scholar
  56. 56.
    Dangas G, Smith DA, Unger AH, et al. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect. Thromb Haemost 2000; 83: 688–92PubMedGoogle Scholar
  57. 57.
    Bo M, Bonino F, Neirotti M, et al. Hemorheologic and coagulative pattern in hypercholesterolemic subjects treated with lipid-lowering drugs. Angiology 1991; 42: 106–13PubMedCrossRefGoogle Scholar
  58. 58.
    McDowell IF, Smye M, Trinick T, et al. Simvastatin in severe hypercholesterolaemia: a placebo controlled trial. Br J Clin Pharmacol 1991; 31: 340–3PubMedCrossRefGoogle Scholar
  59. 59.
    Steinmetz A, Schwartz T, Hehnke U, et al. Multicenter comparison of micronized fenofibrate and simvastatin in patients with primary type IIA or IIB hyperlipoproteinemia. J Cardiovasc Pharmacol 1996; 27: 563–70PubMedCrossRefGoogle Scholar
  60. 60.
    Jaeger BR, Meiser B, Nagel D, et al. Aggressive lowering of fibrinogen and cholesterol in the prevention of graft vessel disease after heart transplantation. Circulation 1997; 96 Suppl. II: 154–8Google Scholar
  61. 61.
    Mitropoulos KA, Armitage JM, Collins R, et al. Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids. The Oxford Cholesterol Study Group. Eur Heart J 1997; 18: 235–41Google Scholar
  62. 62.
    Szczeklik A, Musial J, Undas A, et al. Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 1999; 33: 1286–93PubMedCrossRefGoogle Scholar
  63. 63.
    Sbarouni E, Melissari E, Kyriakides ZS, et al. Effects of simvastatin or hormone replacement therapy, or both, on fibrinogen, factor VII, and plasminogen activator inhibitor levels in postmenopausal women with proven coronary artery disease. Am J Cardiol 2000; 86: 80–3PubMedCrossRefGoogle Scholar
  64. 64.
    Musial J, Undas A, Undas R, et al. Treatment with simvastatin and low-dose aspirin depresses thrombin generation in patients with coronary heart disease and borderline-high cholesterol levels. Thromb Haemost 2001; 85: 221–5PubMedGoogle Scholar
  65. 65.
    Undas A, Brummel KE, Musial J, et al. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001; 103: 2248–53PubMedCrossRefGoogle Scholar
  66. 66.
    Bickel C, Rupprecht HJ, Blankenberg S, et al. Relation of markers of inflammation (C-reactive protein, fibrinogen, von Willebrand factor, and leukocyte count) and statin therapy to long-term mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 2002; 89: 901–8PubMedCrossRefGoogle Scholar
  67. 67.
    Maison P, Mennen L, Sapinho D, et al. A pharmacoepidemiological assessment of the effect of statins and fibrates on fibrinogen concentration. Atherosclerosis 2002; 160: 155–60PubMedCrossRefGoogle Scholar
  68. 68.
    De Maat MPM. Effects of diet, drugs, and genes on plasma fibrinogen levels. Ann N Y Acad sci 2001; 936: 509–21PubMedCrossRefGoogle Scholar
  69. 69.
    Clauss A. Quick method to estimate fibrinogen by a functional clotting assay [in German]. Acta Haematol 1957; 17: 237–46PubMedCrossRefGoogle Scholar
  70. 70.
    Song JC, White CM. Do HMG-CoA reductase inhibitors affect fibrinogen? Ann Pharmacother 2001; 35: 236–41PubMedCrossRefGoogle Scholar
  71. 71.
    Rosenson RS, Tangney CC, Schaefer EJ. Comparative study of HMG-CoA reductase inhibitors on fibrinogen. Atherosclerosis 2001; 155: 463–6PubMedCrossRefGoogle Scholar
  72. 72.
    Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279: 1643–50PubMedCrossRefGoogle Scholar
  73. 73.
    Dahlback B. Blood coagulation. Lancet 2000; 355: 1627–32PubMedCrossRefGoogle Scholar
  74. 74.
    Colli S, Eligini S, Lalli M, et al. Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997; 17: 265–72PubMedCrossRefGoogle Scholar
  75. 75.
    Ferro D, Basili S, Alessandri C, et al. Inhibition of tissue-factor-mediated thrombin generation by simvastatin. Atherosclerosis 2000; 149: 111–6PubMedCrossRefGoogle Scholar
  76. 76.
    Nagata K, Ishibashi T, Sakamoto T, et al. Rho/Rho-kinase is involved in the synthesis of tissue factor in human monocytes. Atherosclerosis 2002; 163: 39–47PubMedCrossRefGoogle Scholar
  77. 77.
    Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001; 103: 276–83PubMedCrossRefGoogle Scholar
  78. 78.
    Eto M, Kozai T, Cosentino F, et al. Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation 2002; 105: 1756–9PubMedCrossRefGoogle Scholar
  79. 79.
    Camera M, Toschi V, Comparato C, et al. Cholesterol-induced thrombogenicity of the vessel wall: inhibitory effect of fluvastatin. Thromb Haemost 2002; 87: 748–55PubMedGoogle Scholar
  80. 80.
    Corsini A, Bellosta S, Baetta R, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Toxicol 1999; 84: 413–28Google Scholar
  81. 81.
    Desager JP, Horsmans Y. Clinical pharmacokinetics of 3-hy-droxy-3-methylglutaryl-coenzyme A reductase inhibitors. Clin Pharmacokinet 1996; 31: 348–71PubMedCrossRefGoogle Scholar
  82. 82.
    Essig M, Nguyen G, Prie D, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells: role of geranylgeranylation and Rho proteins. Circ Res 1998; 83: 683–90PubMedCrossRefGoogle Scholar
  83. 83.
    Mussoni L, Banfi C, Sironi L, et al. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells. Thromb Haemost 2000; 84: 59–64PubMedGoogle Scholar
  84. 84.
    Seeger H, Wallwiener D, Mueck AO. Lipid-independent effects of an estrogen-statin combination: inhibition of expression of adhesion molecules and plasminogen activator inhibitor-I in human endothelial cell cultures. Climacteric 2001; 4: 209–14PubMedGoogle Scholar
  85. 85.
    Haslinger B, Goedde MF, Toet KH, et al. Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. Kidney Int 2002; 62: 1611–9PubMedCrossRefGoogle Scholar
  86. 86.
    Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes related to inflammation, coagulation and vascular constriction in HUVEC. J Atheroscler Thromb 2002; 9: 178–83PubMedCrossRefGoogle Scholar
  87. 87.
    Lopez S, Peiretti F, Bonardo B, et al. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis 2000; 152: 359–66PubMedCrossRefGoogle Scholar
  88. 88.
    Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20: 556–62PubMedCrossRefGoogle Scholar
  89. 89.
    Ishibashi T, Nagata K, Ohkawara H. Inhibition of Rho/Rhokinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes. Biochim Biophys Acta 2002; 2590: 123–30CrossRefGoogle Scholar
  90. 90.
    Wiesbauer F, Kaun C, Zorn G, et al. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins. Br J Pharmacol 2002; 135: 284–92PubMedCrossRefGoogle Scholar
  91. 91.
    Mueck AO, Seeger H, Deuringer FU, et al. Effect of an estrogen/statin combination on biochemical markers of endothelial function in human coronary artery cell cultures. Menopause 2001; 8: 216–21PubMedCrossRefGoogle Scholar
  92. 92.
    Baetta R, Camera M, Comparato C, et al. Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering. Arterioscler Thromb Vasc Biol 2002; 22: 692–8PubMedCrossRefGoogle Scholar
  93. 93.
    Ferro D, Basili S, Alessandri C, et al. Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia [letter]. Lancet 1997; 350: 1222PubMedCrossRefGoogle Scholar
  94. 94.
    Holschermann H, Hilgendorff A, Kemkes-Matthes B, et al. Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients. Transplantation 2000; 69: 1830–6PubMedCrossRefGoogle Scholar
  95. 95.
    Cortellaro M, Cofrancesco E, Arbustini E, et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost 2002; 88: 41–7PubMedGoogle Scholar
  96. 96.
    Hansen JB, Huseby KR, Huseby NE, etal. Effect of cholesterol lowering on intravascular pools of TFPI and its anticoagulant potential in type II hyperlipoproteinemia. Arterioscler Thromb Vasc Biol 1995; 15: 879–85PubMedCrossRefGoogle Scholar
  97. 97.
    Lorena M, Perolini S, Casazza F, et al. Fluvastatin and tissue factor pathway inhibitor in type IIA and IIB hyperlipidemia and in acute myocardial infarction. Thromb Res 1997; 87: 397–403PubMedCrossRefGoogle Scholar
  98. 98.
    Nordoy A, Bonaa KH, Sandset PM, et al. Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia. Arterioscler Thromb Vasc Biol 2000; 20: 259–65PubMedCrossRefGoogle Scholar
  99. 99.
    Morishita E, Asakura H, Saito M, et al. Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients. Atherosclerosis 2001; 154: 203–12PubMedCrossRefGoogle Scholar
  100. 100.
    Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001; 15: 44–54PubMedCrossRefGoogle Scholar
  101. 101.
    Cipollone F, Mezzetti A, Porreca E, et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia. Circulation 2002; 106: 399–402PubMedCrossRefGoogle Scholar
  102. 102.
    Aoki I, Aoki N, Kawano K, et al. Platelet-dependent thrombin generation in patients with hyperlipidemia. J Am Coll Cardiol 1997; 30: 91–6PubMedCrossRefGoogle Scholar
  103. 103.
    Davi G, Ganci A, Averna M, et al. Thromboxane biosynthesis, neutrophil and coagulative activation in type lia hypercholesterolemia. Thromb Haemost 1995; 74: 1015–9PubMedGoogle Scholar
  104. 104.
    Alessandri C, Basili S, Maurelli M, et al. Relationship between prothrombin activation fragment F1+2 and serum cholesterol. Haemostasis 1996; 26: 214–9PubMedGoogle Scholar
  105. 105.
    Puccetti L, Bruni F, Di Renzo M, et al. Hypercoagulable state in hypercholesterolemic subjects assessed by platelet-dependent thrombin generation: in vitro effect of cerivastatin. Eur Rev Med Pharmacol sci 1999; 3: 197–204PubMedGoogle Scholar
  106. 106.
    Puccetti L, Bruni F, Bova G, et al. Effect of diet and treatment with statins on platelet-dependent thrombin generation in hypercholesterolemic subjects. Nutr Metab Cardiovasc Dis 2001; 11: 378–87PubMedGoogle Scholar
  107. 107.
    Puccetti L, Bruni F, Bova G, et al. Role of platelets in tissue factor expression by monocytes in normal and hypercholesterolemic subjects: in vitro effect of cerivastatin. Int J Clin Lab Res 2000; 30: 147–56PubMedCrossRefGoogle Scholar
  108. 108.
    Porreca E, Di Febbo C, Amore C, et al. Effect of lipid-lowering treatment on factor VII profile in hyperlipidemic patients. Thromb Haemost 2000; 84: 789–93PubMedGoogle Scholar
  109. 109.
    Morishita E, Minami S, Ishino C, et al. Atorvastatin reduces plasma levels of factor VII activity and factor VII antigen in patients with hyperlipidemia. J Atheroscler Thromb 2002; 9: 72–7PubMedCrossRefGoogle Scholar
  110. 110.
    Farrer M, Winocour PH, Evans K, et al. Simvastatin in non-insulin-dependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures. Diabetes Res Clin Pract 1994; 23: 111–9PubMedCrossRefGoogle Scholar
  111. 111.
    Folsom AR, Wu KK, Rosamond WD, et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102–8PubMedCrossRefGoogle Scholar
  112. 112.
    Blann AD, Lip GYH. The endothelium in atherothrombotic disease: assessment of function, mechanisms and clinical implications. Blood Coagul Fibrinolysis 1998; 9: 297–306PubMedCrossRefGoogle Scholar
  113. 113.
    Rairaktari OT, Celermajer DS. Testing for endothelial dysfunction. Ann Med 2000; 32: 293–304CrossRefGoogle Scholar
  114. 114.
    Bickel C, Rupprecht HJ, Blankenberg S, et al. Influence of HMG-CoA reductase inhibitors on markers of coagulation, systemic inflammation and soluble cell adhesion. Int J Cardiol 2002; 82: 25–31PubMedCrossRefGoogle Scholar
  115. 115.
    Blann AD, Gurney D, Hughes E, et al. Influence of pravastatin on lipoproteins, and on endothelial, platelet, and inflammatory markers in subjects with peripheral artery disease. Am J Cardiol 2001; 88: 89–92CrossRefGoogle Scholar
  116. 116.
    Malik J, Wichterle D, Melenovsky V, et al. Von Willebrand factor and assessment of endothelial function. Cardiovasc Res 2002; 54: 193–4CrossRefGoogle Scholar
  117. 117.
    Romano M, Mezzetti A, Marulli C, et al. Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients: role of nitric oxide. J Investig Med 2000; 48: 183–9PubMedGoogle Scholar
  118. 118.
    Seljeflot I, Tonstad S, Hjermann I, et al. Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease. Atherosclerosis 2002; 162: 179–85PubMedCrossRefGoogle Scholar
  119. 119.
    Asberg A, Hartmann A, Fjeldsa E, et al. Atorvastatin improves endothelial function in renal-transplant recipients. Nephrol Dial Transplant 2001; 16: 1920–4PubMedCrossRefGoogle Scholar
  120. 120.
    Ambrosi P, Aillaud MF, Habib G, et al. Fluvastatin decreases soluble thrombomodulin in cardiac transplant recipients. Thromb Haemost 2000; 83: 46–8PubMedGoogle Scholar
  121. 121.
    Dick J, McClaren M, Ford R. The effect of atorvastatin on activated factor XII, fibrinogen and lipid profile [abstract]. Haemostasis 2000; 30: 42Google Scholar
  122. 122.
    Salomaa V, Wu KK. Soluble thrombomodulin as predictor of incident coronary heart disease. Lancet 1999; 353: 1729–34PubMedCrossRefGoogle Scholar
  123. 123.
    Malyszko J, Malyszko JS, Hryszko T, et al. Effects of long-term treatment with simvastatin on some hemostatic parameters in continuous ambulatory peritoneal dialysis patients. Am J Nephrol 2001; 21: 373–7PubMedCrossRefGoogle Scholar
  124. 124.
    Malyszko J, Malyszko JS, Hryszko T, et al. Simvastatin affects TAFI and thrombomodulin in CAPD patients. Thromb Haemost 2001; 86: 930–1PubMedGoogle Scholar
  125. 125.
    Meade TW, Ruddock V, Stirling Y, et al. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076–9PubMedCrossRefGoogle Scholar
  126. 126.
    Folsom AR, Pankow JS, Williams RR, et al. Fibrinogen, plasminogen activator inhibitor-1, and carotid intima-media wall thickness in the NHLBI family heart study. Thromb Haemost 1998; 79: 400–4PubMedGoogle Scholar
  127. 127.
    Nordt TK, Bode C. Impaired endogenous fibrinolysis in diabetes mellitus: mechanisms and therapeutic approaches. Semin Thromb Hemost 2000; 26: 495–501PubMedCrossRefGoogle Scholar
  128. 128.
    Margaglione M, Cappucci G, d’Addedda M, et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18: 562–7PubMedCrossRefGoogle Scholar
  129. 129.
    Juhan-Vague I, Alessi MC, Morange PE. Hipofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med 2000; 32 Suppl. 1: 78–84Google Scholar
  130. 130.
    Ridker PM, Vaughan DE, Stampfer MJ, et al. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993; 341: 1165–8PubMedCrossRefGoogle Scholar
  131. 131.
    Ridker PM, Hennekens CH, Stampfer MJ, et al. Prospective study of endogenous tissue plasminogen activator and risk of stroke. Lancet 1994; 343: 940–3PubMedCrossRefGoogle Scholar
  132. 132.
    Juhan-Vague I, Pyke SDM, Alessi MC, et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057–63PubMedCrossRefGoogle Scholar
  133. 133.
    Bevilacqua M, Bettica P, Milani M, et al. Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease. Am J Cardiol 1997; 79: 84–7PubMedCrossRefGoogle Scholar
  134. 134.
    Newby DE, Witherow FN, Wright RA, et al. Hypercholesterolaemia and lipid lowering treatment do not affect the acute endogenous fibrinolytic capacity in vivo. Heart 2002; 87: 48–53PubMedCrossRefGoogle Scholar
  135. 135.
    Koh KK, Son JW, Ahn JY, et al. Non-lipid effects of statin on hypercholesterolemic patients established to have coronary artery disease who remained hypercholesterolemic while eating a step-II diet. Coron Artery Dis 2001; 12: 305–11PubMedCrossRefGoogle Scholar
  136. 136.
    Tsikouris JP, Suarez JA, Meyerrose GE. Plasminogen activator inhibitor-1: physiological role, regulation, and the influence of common pharmacologic agents. J Clin Pharmacol 2002; 42: 1187–92PubMedCrossRefGoogle Scholar
  137. 137.
    Lopez S, Peiretti F, Bonardo B, et al. Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages. J Cardiovasc Pharmacol 2001; 37: 762–8PubMedCrossRefGoogle Scholar
  138. 138.
    Ito MK. The effects of converting from simvastatin to atorvastatin on plasminogen activator inhibitor type-1. J Clin Pharmacol 2001; 41: 779–82PubMedCrossRefGoogle Scholar
  139. 139.
    Takada A, Takada Y, Urano T. The physiological aspects of fibrinolysis. Thromb Res 1994; 76: 1–31PubMedCrossRefGoogle Scholar
  140. 140.
    Mayer M, Eller T, Brauer P, et al. Effects of long-term treatment with lovastatin on the clotting system and blood platelets. Ann Hematol 1992; 64: 196–201PubMedCrossRefGoogle Scholar
  141. 141.
    Dupuis J, Tardif JC, Cernacek P, et al. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischaemia and Function of the Endothelium) trial. Circulation 1999; 99: 3227–33Google Scholar
  142. 142.
    Olivotti L, Ghigliotti G, Spallarossa P, et al. High doses of atorvastatin do not affect activity of prothrombinase in patients with acute coronary syndromes. Blood Coagul Fibrinolysis 2002; 13: 315–21PubMedCrossRefGoogle Scholar
  143. 143.
    De Matt MPM, Kastelein JJP, Jukema JW, et al. 455G/A polymorphism of the β-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. Arterioscler Thromb Vasc Biol 1998; 18: 265–71CrossRefGoogle Scholar
  144. 144.
    Zito F, Lowe G, Rumley A, et al. Association of the factor XII 46C>T polymorphism with risk of coronary heart disease (CHD) in the WOSCOPS study. Atherosclerosis 2002; 165: 153–8PubMedCrossRefGoogle Scholar
  145. 145.
    Gavish D, Leibovitz E, Shapira I, et al. Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety. J Intern Med 2000; 247: 563–9PubMedCrossRefGoogle Scholar
  146. 146.
    Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997; 80: 608–13PubMedCrossRefGoogle Scholar
  147. 147.
    Papadakis JA, Ganotakis ES, Jagroop IA, et al. Statin + fibrate combination therapy fluvastatin with bezafibrate or ciprofibrate in high risk patients with vascular disease. Int J Cardiol 1999; 69: 237–44PubMedCrossRefGoogle Scholar
  148. 148.
    Hamelin BA, Turgeon J. Hydrophillicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol sci 1998; 19: 26–37PubMedCrossRefGoogle Scholar
  149. 149.
    Koh KK. Effects of HMG-CoA reductase inhibitor on hemostasis. Int J Cardiol 2000; 76: 23–32PubMedCrossRefGoogle Scholar
  150. 150.
    Stickney JT, Buss JE. Murine guanylate-binding protein: incomplete geranylgeranyl isoprenoid modification of an interferon-gamma-inducible guanosine triphosphate-binding protein. Mol Biol Cell 2000; 11: 2191–200PubMedGoogle Scholar
  151. 151.
    Fenton II JW, Shen GX, Minnear FL, et al. Statins induce hypothrombotic states? Clin Appl Thromb Hemost 2000; 6: 18–21PubMedCrossRefGoogle Scholar
  152. 152.
    Fenton II JW, Shen GX, Minnear FL, et al. Statin drugs and dietary isoprenoids as antithrombotic agents. Hematol Oncol Clin North Am 2000; 14: 483–90PubMedCrossRefGoogle Scholar
  153. 153.
    Fenton II JW, Jeske WP, Catalfamo JL, et al. Statin drugs and dietary isoprenoids downregulate protein prenylation in signal transduction and are antithrombotic and prothrombolytic agents. Biochemistry (Mosc) 2002; 67: 85–91CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Robert Krysiak
    • 1
  • Boguslaw Okopień
    • 1
  • Zbigniew S. Herman
    • 1
  1. 1.Department of Clinical PharmacologyMedical University of SilesiaKatowicePoland

Personalised recommendations