| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2001;103:2248.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Simvastatin Depresses Blood Clotting by Inhibiting Activation of Prothrombin, Factor V, and Factor XIII and by Enhancing Factor Va Inactivation
From the Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland (A.U., J.M., A.S.), and the Department of Biochemistry, University of Vermont, Burlington (K.E.B., K.G.M.).
Correspondence to Kenneth G. Mann, PhD, University of Vermont, Department of Biochemistry, Given Bldg, Room E407, Burlington, VT 05405. E-mail kmann{at}protein.uvm.edu
Background—The mechanism of the antithrombotic action of statins is unclear. The aim of this study was to evaluate the effects of simvastatin on the coagulation process at sites of microvascular injury.
Methods and
Results—Tissue factor–initiated coagulation
was assessed in blood samples collected every 30 seconds from
bleeding-time wounds of 17 patients who had advanced coronary
artery disease and total cholesterol levels of 224.6±11.8
mg/dL (mean±SEM). Quantitative Western blotting for time courses of
fibrinogen depletion and activation of prothrombin, factor V, and
factor XIII was performed before and after 3 months of
simvastatin treatment (20 mg/d). Simvastatin
induced reductions in total cholesterol (23%) and
LDL-cholesterol (36%), which were accompanied by
significant decreases in the rates of prothrombin activation
(16.2±2.1%; P=0.004),
formation of 
-thrombin B-chain (27.4±1.8%;
P=0.001), generation of factor
Va heavy chain (29.7±3.1%;
P=0.007) and factor Va light
chain (18.9±1.2%; P=0.02),
factor XIII activation (19.8±1.3%;
P=0.001), and fibrinogen
conversion to fibrin (72.2±3%;
P=0.002). Posttreatment
fibrinopeptides A and B concentrations, determined by
using high-performance liquid chromatography,
were reduced within the last 30 seconds of bleeding. The 30-kDa
fragment of the factor Va heavy chain (residues 307 to 506), produced
by activated protein C, and the 97-kDa fragment of the factor
Va heavy chain (residues 1 to 643) were released more rapidly after
simvastatin treatment. The antithrombotic actions of
simvastatin showed no relationship to its
cholesterol-lowering action.
Conclusions—Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and an increased rate of factor Va inactivation. These effects are not related to cholesterol reduction.
Key Words: simvastatin • thrombin • factor V • factor XIII • fibrinogen
This article has been cited by other articles:
 |
|
 |
|
  M. Rodriguez-Yanez, J. Agulla, R. Rodriguez-Gonzalez, T. Sobrino, and J. Castillo Review: Statins and stroke Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 157 - 166. [Abstract] [PDF]
|
|
|
|
 |
|
 D. D. Waters, J. C. LaRosa, P. Barter, J.-C. Fruchart, A. M. Gotto Jr, R. Carter, A. Breazna, J. J.P. Kastelein, and S. M. Grundy Effects of High-Dose Atorvastatin on Cerebrovascular Events in Patients With Stable Coronary Disease in the TNT (Treating to New Targets) Study J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1793 - 1799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. N. Boushra and M. Muntazar Review article: The role of statins in reducing perioperative cardiac risk: physiologic and clinical perspectives: [Le role des statines dans la reduction du risque cardiaque perioperatoire : perspectives physiologiques et cliniques]. Can J Anesth, November 1, 2006; 53(11): 1126 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Douketis, K. Arneklev, S. Z. Goldhaber, J. Spandorfer, F. Halperin, and J. Horrow Comparison of Bleeding in Patients With Nonvalvular Atrial Fibrillation Treated With Ximelagatran or Warfarin: Assessment of Incidence, Case-Fatality Rate, Time Course and Sites of Bleeding, and Risk Factors for Bleeding. Arch Intern Med, April 24, 2006; 166(8): 853 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lopez-Pedrera, P Buendia, M A Aguirre, F Velasco, and M J Cuadrado Antiphospholipid syndrome and tissue factor: a thrombotic couple Lupus, March 1, 2006; 15(3): 161 - 166. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Pignatelli, V. Sanguigni, B. Buchetti, L. Lenti, F. Violi, A. Undas, and K. G. Mann Early Anticoagulant Effect of Atorvastatin Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): e145 - e146. [Full Text] [PDF]
|
|
|
|
|
|
K. K. Ray and C. P. Cannon The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1425 - 1433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Undas, M. Celinska-Lowenhoff, K. E. Brummel-Ziedins, J. Brozek, A. Szczeklik, and K. G. Mann Simvastatin Given for 3 Days Can Inhibit Thrombin Generation and Activation of Factor V and Enhance Factor Va Inactivation in Hypercholesterolemic Patients Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1524 - 1525. [Full Text] [PDF]
|
|
|
|
|
|
K. O'Neil-Callahan, G. Katsimaglis, M. R. Tepper, J. Ryan, C. Mosby, J. P.A. Ioannidis, and P. G. Danias Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery: The Statins for Risk Reduction in Surgery (StaRRS) study J. Am. Coll. Cardiol., February 1, 2005; 45(3): 336 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Undas, K. E. Brummel-Ziedins, and K. G. Mann Statins and Blood Coagulation Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 287 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Tousoulis, C Antoniades, E Bosinakou, M Kotsopoulou, C Tsioufis, C Tentolouris, A Trikas, C Pitsavos, and C Stefanadis Effects of atorvastatin on reactive hyperaemia and the thrombosis-fibrinolysis system in patients with heart failure Heart, January 1, 2005; 91(1): 27 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Scott, R. A.S. Ariens, and P. J. Grant Genetic and Environmental Determinants of Fibrin Structure and Function: Relevance to Clinical Disease Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1558 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Balk, J. Lau, L. C. Goudas, H. S. Jordan, B. Kupelnick, L. U. Kim, and R. H. Karas Effects of Statins on Nonlipid Serum Markers Associated with Cardiovascular Disease: A Systematic Review Ann Intern Med, October 21, 2003; 139(8): 670 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kadikoylu, V. Yukselen, I. Yavasoglu, and Z. Bolaman Hemostatic Effects of Atorvastatin Versus Simvastatin Ann. Pharmacother., April 1, 2003; 37(4): 478 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Masamura, K. Oida, H. Kanehara, J. Suzuki, S. Horie, H. Ishii, and I. Miyamori Pitavastatin-Induced Thrombomodulin Expression by Endothelial Cells Acts Via Inhibition of Small G Proteins of the Rho Family Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 512 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rezaie-Majd, G. W. Prager, R. A. Bucek, G. H. Schernthaner, T. Maca, H.-G. Kress, P. Valent, B. R. Binder, E. Minar, and M. Baghestanian Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 397 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. C. Lau, L. A. Waskell, P. B. Watkins, C. J. Neer, K. Horowitz, A. S. Hopp, A. R. Tait, D. G.M. Carville, K. E. Guyer, and E. R. Bates Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation: A New Drug-Drug Interaction Circulation, January 7, 2003; 107(1): 32 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. Mann, S. Butenas, and K. Brummel The Dynamics of Thrombin Formation Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 17 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Szczeklik, J. Musial, A. Undas, J. W. Eikelboom, J. Hirsh, J. I. Weitz, M. Johnston, Q. Yi, and S. Yusuf Reasons for Resistance to Aspirin in Cardiovascular Disease * Response Circulation, November 26, 2002; 106 (22): e181 - e182. [Full Text] [PDF]
|
|
|
|
|
|
A. C. Sposito and M. J. Chapman Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1524 - 1534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Waters, G. G. Schwartz, A. G. Olsson, A. Zeiher, M. F. Oliver, P. Ganz, M. Ezekowitz, B. R. Chaitman, S. J. Leslie, T. Stern, et al. Effects of Atorvastatin on Stroke in Patients With Unstable Angina or Non-Q-Wave Myocardial Infarction: A Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Substudy Circulation, September 24, 2002; 106(13): 1690 - 1695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rezaie-Majd, T. Maca, R. A. Bucek, P. Valent, M. R. Muller, P. Husslein, A. Kashanipour, E. Minar, and M. Baghestanian Simvastatin Reduces Expression of Cytokines Interleukin-6, Interleukin-8, and Monocyte Chemoattractant Protein-1 in Circulating Monocytes From Hypercholesterolemic Patients Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1194 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Newby, A. Kristinsson, M. V. Bhapkar, P. E. Aylward, A. P. Dimas, W. W. Klein, D. K. McGuire, D. J. Moliterno, F. W. A. Verheugt, W. D. Weaver, et al. Early Statin Initiation and Outcomes in Patients With Acute Coronary Syndromes JAMA, June 19, 2002; 287(23): 3087 - 3095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.F. Gensini and B. Dilaghi The unstable plaque Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B22 - B27. [Abstract] [PDF]
|
|
|
|
|
|
A. Undas, K. Brummel, J. Musial, K. G. Mann, and A. Szczeklik PlA2 Polymorphism of {beta}3 Integrins Is Associated With Enhanced Thrombin Generation and Impaired Antithrombotic Action of Aspirin at the Site of Microvascular Injury Circulation, November 27, 2001; 104(22): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Brummel, S. G. Paradis, R. F. Branda, and K. G. Mann Oral Anticoagulation Thresholds Circulation, November 6, 2001; 104(19): 2311 - 2317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J Miller Emerging mechanisms for secondary cardioprotective effects of statins Cardiovasc Res, October 1, 2001; 52(1): 5 - 7. [Full Text] [PDF]
|
|