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
- 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
- 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
- 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
- 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
- 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
- 7
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease:
the Scandinavian Simvastatin Survival Study (4S).
Lancet.
1994;
344
1383-1389
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 15
Tremoli E, Maderna P, Sirtori M, Sirtori C R.
Platelet aggregation malondialdehyde formation in type IIA hypercholesterolemic patients.
Haemostasis.
1979;
8
47-53
- 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
- 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
- 18
Tremoli E, Folco G, Agradi E, Galli C.
Platelet thromboxanes and serum-cholesterol.
Lancet.
1979;
1
107-108
- 19
Davi G, Averna M, Catalano I et al..
Increased thromboxane biosynthesis in type IIa hypercholesterolemia.
Circulation.
1992;
85
1792-1798
- 20
Reilly M P, Pratico D, Delanty N et al..
Increased formation of distinct F2 isoprostanes in hypercholesterolemia.
Circulation.
1998;
98
2822-2828
- 21
Davi G, Romano M, Mezzetti A et al..
Increased levels of soluble P-selectin in hypercholesterolemic patients.
Circulation.
1998;
97
953-957
- 22
Tremoli E, Colli S, Maderna P, Baldassarre D, Di Minno G.
Hypercholesterolemia and platelets.
Semin Thromb Hemost.
1993;
19
115-121
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 42
Krysiak R, Okopien B, Herman Z.
Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes.
Drugs.
2003;
63
1821-1854
- 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
- 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
- 45
Tremoli E, Camera M, Toschi V, Colli S.
Tissue factor in atherosclerosis.
Atherosclerosis.
1999;
144
273-283
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 60
Dahlback B.
Blood coagulation.
Lancet.
2000;
355
1627-1632
- 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
- 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
- 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
- 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
- 65
Libby P, Mach F, Schonbeck U, Bourcier T, Aikawa M.
Regulation of the thrombotic potential of atheroma.
Thromb Haemost.
1999;
82
736-741
- 66
Juhan-Vague I, Alessi M C.
Plasminogen activator inhibitor 1 and atherothrombosis.
Thromb Haemost.
1993;
70
138-143
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 79
Wada H, Mori Y, Kaneko T et al..
Hypercoagulable state in patients with hypercholesterolemia: effects of pravastatin.
Clin Ther.
1992;
14
829-834
- 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
- 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
- 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
- 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
Elena Tremoli
Department of Pharmacological Sciences
via Balzaretti 9, 20133 Milano, Italy
