(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
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