Download PDF
Semin Vasc Med 2004; 4(4): 407-415
DOI: 10.1055/s-2004-869598
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Statins in Atherothrombosis

Susanna Colli1 , José Pablo Werba2 , Elena Tremoli1 , 2
  • 1E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan
  • 2Department of Cardiac Surgery, Centro Cardiologico Fondazione Monzino I.R.C.C.S., Milan, Italy
Further Information

Publication History

Publication Date:
29 April 2005 (online)

    Permissions and Reprints

ABSTRACT

Clinical studies have shown that hydroxy-methyl glutaryl coenzyme A reductase inhibitors (statins) may favorably affect atherothrombosis. In addition to their potent cholesterol-lowering properties, statins reduce atheroma progression as well as the incidence of acute thrombosis-related vascular events and their dreadful clinical consequences. Available data indicate that statins exert significant antithrombotic effects in clinical practice by reducing the occurrence of vascular atherothrombotic events, with a more prominent effect in high-risk patients. The mechanisms by which statins inhibit thrombosis have been extensively investigated, and several pathways appear to be involved. In particular, statins have been proposed to reduce platelet activation and to exert favorable effects on fibrinolysis, but no clear-cut conclusion can be drawn from available studies. Moreover, statins do not consistently influence fibrinogen or factor VII levels in plasma. In contrast, in vitro and in vivo data indicate that these compounds profoundly affect thrombin generation driven by tissue factor/factor VII pathway. In vitro studies indicate that this effect is not dependent on plasma cholesterol lowering but, rather, on the inhibition of isoprenoid biosynthesis. The relative contribution of reduced levels of prenylated proteins and of cholesterol pathway to the modulation of tissue factor expression is, however, hardly to be established in clinical settings.

KEYWORDS

Atherosclerosis - thrombosis - statins - coagulation - fibrinolysis

REFERENCES

  • 1 Downs J R, Clearfield M, Weis S et al.. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.  JAMA. 1998;  279 1615-1622
    CrossrefPubMedGoogle Scholar
  • 2 Sever P S, Dahlof B, Poulter N R et al.. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.  Lancet. 2003;  361 1149-1158
    CrossrefPubMedGoogle Scholar
  • 3 Shepherd J, Cobbe S M, 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 1301-1307
    CrossrefPubMedGoogle Scholar
  • 4 Heart Protection Study Collaborative Group . MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.  Lancet. 2002;  360 7-22
    CrossrefPubMedGoogle Scholar
  • 5 Sacks F M, Pfeffer M A, Moye L A 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 1001-1009
    CrossrefPubMedGoogle Scholar
  • 6 Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels . The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.  N Engl J Med. 1998;  339 1349-1357
    CrossrefPubMedGoogle Scholar
  • 7 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;  344 1383-1389
    PubMedGoogle Scholar
  • 8 Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study . FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators.  Lancet. 1999;  354 708-715
    CrossrefPubMedGoogle Scholar
  • 9 Juul-Moller S, Edvardsson N, Jahnmatz B, Rosen A, Sorensen S, Omblus R. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Swedish Angina Pectoris Aspirin Trial (SAPAT) Group.  Lancet. 1992;  340 1421-1425
    CrossrefPubMedGoogle Scholar
  • 10 Stenestrand U, Wallentin L. Swedish Register of Cardiac Intensive Care (RIKS-HIA). Early statin treatment following acute myocardial infarction and 1-year survival.  JAMA. 2001;  285 430-436
    CrossrefPubMedGoogle Scholar
  • 11 Aronow H D, Topol E J, Roe M T et al.. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study.  Lancet. 2001;  357 1063-1068
    CrossrefPubMedGoogle Scholar
  • 12 Fonarow G C, Gawlinski A, Moughrabi S, Tillisch J H. Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP).  Am J Cardiol. 2001;  87 819-822
    CrossrefPubMedGoogle Scholar
  • 13 Schwartz G G, Olsson A G, Ezekowitz M D et al.. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.  JAMA. 2001;  285 1711-1718
    CrossrefPubMedGoogle Scholar
  • 14 Cannon C P, Braunwald E, McCabe C H et al.. Pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;  350 1495-1504
    CrossrefPubMedGoogle Scholar
  • 15 Tremoli E, Maderna P, Sirtori M, Sirtori C R. Platelet aggregation malondialdehyde formation in type IIA hypercholesterolemic patients.  Haemostasis. 1979;  8 47-53
    PubMedGoogle Scholar
  • 16 Oliva D W, Maderna P, Accomazzo M R, Nicosia S, Tremoli E. Iloprost binding and inhibition of aggregation in platelet rich plasma. Differences between normal and type IIa hypercholesterolemic subjects.  Biochem Pharmacol. 1989;  38 39-45
    CrossrefPubMedGoogle Scholar
  • 17 Tremoli E, Maderna P, Colli S, Morazzoni G, Sirtori M, Sirtori C R. Increased platelet sensitivity and thromboxane B2 formation in type-II hyperlipoproteinaemic patients.  Eur J Clin Invest. 1984;  14 329-333
    PubMedGoogle Scholar
  • 18 Tremoli E, Folco G, Agradi E, Galli C. Platelet thromboxanes and serum-cholesterol.  Lancet. 1979;  1 107-108
    PubMedGoogle Scholar
  • 19 Davi G, Averna M, Catalano I et al.. Increased thromboxane biosynthesis in type IIa hypercholesterolemia.  Circulation. 1992;  85 1792-1798
    PubMedGoogle Scholar
  • 20 Reilly M P, Pratico D, Delanty N et al.. Increased formation of distinct F2 isoprostanes in hypercholesterolemia.  Circulation. 1998;  98 2822-2828
    CrossrefPubMedGoogle Scholar
  • 21 Davi G, Romano M, Mezzetti A et al.. Increased levels of soluble P-selectin in hypercholesterolemic patients.  Circulation. 1998;  97 953-957
    PubMedGoogle Scholar
  • 22 Tremoli E, Colli S, Maderna P, Baldassarre D, Di Minno G. Hypercholesterolemia and platelets.  Semin Thromb Hemost. 1993;  19 115-121
    PubMedGoogle Scholar
  • 23 Beigel Y, Fuchs J, Snir M, Green P, Lurie Y, Djaldetti M. Lovastatin therapy in hypercholesterolemia: effect on fibrinogen, hemorrheologic parameters, platelet activity, and red blood cell morphology.  J Clin Pharmacol. 1991;  31 512-517
    PubMedGoogle Scholar
  • 24 Mayer J, Eller T, Brauer P et al.. Effects of long-term treatment with lovastatin on the clotting system and blood platelets.  Ann Hematol. 1992;  64 196-201
    CrossrefPubMedGoogle Scholar
  • 25 Kaczmarek D, Hohlfeld T, Wambach G, Schror K. The actions of lovastatin on platelet function and platelet eicosanoid receptors in type II hypercholesterolaemia. A double-blind, placebo-controlled, prospective study.  Eur J Clin Pharmacol. 1993;  45 451-457
    CrossrefPubMedGoogle Scholar
  • 26 Osamah H, Mira R, Sorina S, Shlomo K, Michael A. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets.  Br J Clin Pharmacol. 1997;  44 77-83
    CrossrefPubMedGoogle Scholar
  • 27 Broijersen A, Eriksson M, Larsson P T et al.. Effects of selective LDL-apheresis and pravastatin therapy on platelet function in familial hypercholesterolaemia.  Eur J Clin Invest. 1994;  24 488-498
    PubMedGoogle Scholar
  • 28 Milani M, Cimminiello C, Merlo B, Lorena M, Arpaia G, Bonfardeci G. Effects of fluvastatin and pravastatin on lipid profiles and thromboxane production in type IIa hypercholesterolemia.  Am J Cardiol. 1995;  76 51A-53A
    CrossrefPubMedGoogle Scholar
  • 29 Davi G, Averna M, Novo S et al.. Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients.  Atherosclerosis. 1989;  79 79-83
    PubMedGoogle Scholar
  • 30 Notarbartolo A, Davi G, Averna M et al.. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 1995;  15 247-251
    PubMedGoogle Scholar
  • 31 Schror K, Lobel P, Steinhagen-Thiessen E. Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia.  Eicosanoids. 1989;  2 39-45
    PubMedGoogle Scholar
  • 32 Broijersen A, Eriksson M, Leijd B, Angelin B, Hjemdahl P. No influence of simvastatin treatment on platelet function in vivo in patients with hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 1997;  17 273-278
    PubMedGoogle Scholar
  • 33 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;  48 183-189
    PubMedGoogle Scholar
  • 34 Aoki I, Aoki N, Kawano K et al.. Platelet-dependent thrombin generation in patients with hyperlipidemia.  J Am Coll Cardiol. 1997;  30 91-96
    CrossrefPubMedGoogle Scholar
  • 35 Lacoste L, Lam J Y, Hung J, Letchacovski G, Solymoss C B, Waters D. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction.  Circulation. 1995;  92 3172-3177
    PubMedGoogle Scholar
  • 36 Lacoste L, Lam J YT. Comparative effect of pravastatin and simvastatin on platelet-thrombus formation in hypercholesterolemic coronary patients.  J Am Coll Cardiol. 1996;  27 413 , Abstract
    PubMedGoogle Scholar
  • 37 Alfon J, Royo T, Garcia-Moll X, Badimon L. Platelet deposition on eroded vessel walls at a stenotic shear rate is inhibited by lipid-lowering treatment with atorvastatin.  Arterioscler Thromb Vasc Biol. 1999;  19 1812-1817
    PubMedGoogle Scholar
  • 38 Meade T W, Mellows S, Brozovic M et al.. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.  Lancet. 1986;  2 533-537
    PubMedGoogle Scholar
  • 39 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction.  N Engl J Med. 1984;  311 501-505
    CrossrefPubMedGoogle Scholar
  • 40 Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update.  Arterioscler Thromb Vasc Biol. 1999;  19 1368-1377
    CrossrefPubMedGoogle Scholar
  • 41 Ericsson C G, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients.  Lancet. 1996;  347 849-853
    CrossrefPubMedGoogle Scholar
  • 42 Krysiak R, Okopien B, Herman Z. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes.  Drugs. 2003;  63 1821-1854
    CrossrefPubMedGoogle Scholar
  • 43 Edgington T S, Mackman N, Brand K, Ruf W. The structural biology of expression and function of tissue factor.  Thromb Haemost. 1991;  66 67-79
    PubMedGoogle Scholar
  • 44 Broze Jr G J. Tissue factor pathway of coagulation: factor VII, tissue factor, and tissue factor pathway inhibitor. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD Haemostasis and Thrombosis, vol. 2. 3rd ed. Singapore; Churchill Livingstone 1994: 349-377
    Google Scholar
  • 45 Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis.  Atherosclerosis. 1999;  144 273-283
    CrossrefPubMedGoogle Scholar
  • 46 Camera M, Frigerio M, Toschi V et al.. Platelet activation induces cell-surface immunoreactive tissue factor expression, which is modulated differently by antiplatelet drugs.  Arterioscler Thromb Vasc Biol. 2003;  23 1690-1696
    CrossrefPubMedGoogle Scholar
  • 47 Fuster V, Fallon J T, Badimon J J, Nemerson Y. The unstable atherosclerotic plaque: clinical significance and therapeutic intervention.  Thromb Haemost. 1997;  78 247-255
    PubMedGoogle Scholar
  • 48 Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis.  Arterioscler Thromb Vasc Biol. 1997;  17 265-272
    PubMedGoogle Scholar
  • 49 Eto M, Kozai T, Cosentino F, Joch H, Luscher T F. Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways.  Circulation. 2002;  105 1756-1759
    CrossrefPubMedGoogle Scholar
  • 50 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;  103 276-283
    PubMedGoogle Scholar
  • 51 Camera M, Toschi V, Comparato C et al.. Cholesterol-induced thrombogenicity of the vessel wall: inhibitory effect of fluvastatin.  Thromb Haemost. 2002;  87 748-755
    PubMedGoogle Scholar
  • 52 Baetta R, Camera M, Comparato C, Altana C, Ezekowitz M D, Tremoli E. 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;  22 692-698
    PubMedGoogle Scholar
  • 53 Sukhova G K, Williams J K, Libby P. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.  Arterioscler Thromb Vasc Biol. 2002;  22 1452-1458
    PubMedGoogle Scholar
  • 54 Ferro D, Basili S, Alessandri C, Mantovani B, Cordova C, Violi F. Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia.  Lancet. 1997;  350 1222
    CrossrefPubMedGoogle Scholar
  • 55 Cortellaro M, Cofrancesco E, Arbustini E et al.. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study.  Thromb Haemost. 2002;  88 41-47
    PubMedGoogle Scholar
  • 56 Hansen J B, Huseby K R, Huseby N E, Sandset P M, Hanssen T A, Nordoy A. Effect of cholesterol lowering on intravascular pools of TFPI and its anticoagulant potential in type II hyperlipoproteinemia.  Arterioscler Thromb Vasc Biol. 1995;  15 879-885
    CrossrefPubMedGoogle Scholar
  • 57 Lorena M, Perolini S, Casazza F, Milani M, Cimminiello C. Fluvastatin and tissue factor pathway inhibitor in type IIA and IIB hyperlipidemia and in acute myocardial infarction.  Thromb Res. 1997;  87 397-403
    CrossrefPubMedGoogle Scholar
  • 58 Nordoy A, Bonaa K H, Sandset P M, Hansen J B, Nilsen H. 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;  20 259-265
    PubMedGoogle Scholar
  • 59 Morishita E, Asakura H, Saito M et al.. Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients.  Atherosclerosis. 2001;  154 203-212
    CrossrefPubMedGoogle Scholar
  • 60 Dahlback B. Blood coagulation.  Lancet. 2000;  355 1627-1632
    CrossrefPubMedGoogle Scholar
  • 61 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 47-51
    PubMedGoogle Scholar
  • 62 Di Garbo V, Bono M, Di Raimondo D, De Simone R, Raneli G, Avellone G. Non lipid, dose-dependent effects of pravastatin treatment on hemostatic system and inflammatory response.  Eur J Clin Pharmacol. 2000;  56 277-284
    CrossrefPubMedGoogle Scholar
  • 63 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;  11 378-387
    PubMedGoogle Scholar
  • 64 Undas A, Brummel K E, Musial J, Mann K G, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation.  Circulation. 2001;  103 2248-2253
    CrossrefPubMedGoogle Scholar
  • 65 Libby P, Mach F, Schonbeck U, Bourcier T, Aikawa M. Regulation of the thrombotic potential of atheroma.  Thromb Haemost. 1999;  82 736-741
    PubMedGoogle Scholar
  • 66 Juhan-Vague I, Alessi M C. Plasminogen activator inhibitor 1 and atherothrombosis.  Thromb Haemost. 1993;  70 138-143
    PubMedGoogle Scholar
  • 67 Robbie L A, Booth N A, Brown A J, Bennett B. Inhibitors of fibrinolysis are elevated in atherosclerotic plaque.  Arterioscler Thromb Vasc Biol. 1996;  16 539-545
    CrossrefPubMedGoogle Scholar
  • 68 Booth N A, Simpson A J, Croll A, Bennett B, MacGregor I R. Plasminogen activator inhibitor (PAI-1) in plasma and platelets.  Br J Haematol. 1988;  70 327-333
    CrossrefPubMedGoogle Scholar
  • 69 Essig M, Nguyen G, Prie D, Escoubet B, Sraer J D, Friedlander G. 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;  83 683-690
    CrossrefPubMedGoogle Scholar
  • 70 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;  20 556-562
    PubMedGoogle Scholar
  • 71 Mussoni L, Banfi C, Sironi L, Arpaia M, Tremoli E. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells.  Thromb Haemost. 2000;  84 59-64
    PubMedGoogle Scholar
  • 72 Wiesbauer F, Kaun C, Zorn G, Maurer G, Huber K, Wojta J. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins.  Br J Pharmacol. 2002;  135 284-292
    PubMedGoogle Scholar
  • 73 Markle R A, Han J, Summers B D et al.. Pitavastatin alters the expression of thrombotic and fibrinolytic proteins in human vascular cells.  J Cell Biochem. 2003;  90 23-32
    CrossrefPubMedGoogle Scholar
  • 74 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. Human umbilical vein endothelial cells.  J Atheroscler Thromb. 2002;  9 178-183
    PubMedGoogle Scholar
  • 75 Zambrana J L, 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;  80 836-840
    CrossrefPubMedGoogle Scholar
  • 76 Mitropoulos K A, Armitage J M, 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;  18 235-241
    PubMedGoogle Scholar
  • 77 Seljeflot I, Tonstad S, Hjermann I, Arnesen H. Improved fibrinolysis after 1-year treatment with HMG CoA reductase inhibitors in patients with coronary heart disease.  Thromb Res. 2002;  105 285-290
    CrossrefPubMedGoogle Scholar
  • 78 Bevilacqua M, Bettica P, Milani M et al.. Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease.  Am J Cardiol. 1997;  79 84-87
    CrossrefPubMedGoogle Scholar
  • 79 Wada H, Mori Y, Kaneko T et al.. Hypercoagulable state in patients with hypercholesterolemia: effects of pravastatin.  Clin Ther. 1992;  14 829-834
    PubMedGoogle Scholar
  • 80 Dangas G, Smith D A, Badimon J J et al.. Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin.  Am J Cardiol. 1999;  84 639-643
    CrossrefPubMedGoogle Scholar
  • 81 Dangas G, Badimon J J, Smith D A et al.. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile.  J Am Coll Cardiol. 1999;  33 1294-1304
    CrossrefPubMedGoogle Scholar
  • 82 Dangas G, Smith D A, Unger A H et al.. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect.  Thromb Haemost. 2000;  83 688-692
    PubMedGoogle Scholar
  • 83 Hoekstra T, Geleijnse J M, Schouten E G, Kluft C. Plasminogen activator inhibitor-type 1: its plasma determinants and relation with cardiovascular risk.  Thromb Haemost. 2004;  91 861-872
    PubMedGoogle Scholar

Elena Tremoli

Department of Pharmacological Sciences

via Balzaretti 9, 20133 Milano, Italy