(Circulation. 1999;99:1780-1787.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Local Inhibition of Tissue Factor Reduces the Thrombogenicity of Disrupted Human Atherosclerotic Plaques
Effects of Tissue Factor Pathway Inhibitor on Plaque Thrombogenicity Under Flow Conditions
From the Cardiovascular Biology Research Laboratory, Zena and Michael A. Wiener Cardiovascular Institute, New York, NY (J.J.B., M.L., V.T., V.F., J.H.C.), and the Cardiovascular Research Center, CSIC–Hospital Santa Cruz y San Pablo-UAB, Barcelona, Spain (M.B., L.B.).
Correspondence to Juan J. Badimon, PhD, Cardiovascular Biology Research Laboratory, The Zena and Michael A. Wiener Cardiovascular Institute (Box 1030), Mount Sinai School of Medicine, New York, NY 10029. E-mail Jbadimo{at}smtplink.mssm.edu
Background—Plaque disruption and subsequent thrombus formation lead to acute coronary syndromes and progression of atherosclerotic disease. Tissue factor (TF) appears to mediate plaque thrombogenicity. Tissue factor pathway inhibitor (TFPI) is the major physiological inhibitor of TF. This study analyzes the role of TF on thrombogenicity of disrupted human atherosclerotic plaques and the therapeutic possibilities of its specific inhibition.
Methods and Results—Human atherosclerotic and normal arterial segments were exposed to heparinized blood at flow conditions modeling medium-grade coronary stenosis in the Badimon perfusion chamber. The antithrombotic effects of the specific inhibition of plaque TF was assessed by reduction in the deposition of radiolabeled platelets and fibrin(ogen) and immunohistochemical analysis of perfused arteries. TF activity was inhibited by both recombinant TFPI and a polyclonal antibody against human TF. Human lipid-rich plaques were more thrombogenic than less advanced atherosclerotic plaques. Specific inhibition of TF activity reduced plaque thrombogenicity, inhibiting both platelet and fibrin(ogen) deposition (580 versus 194 plateletsx106/cm2; P<0.01, and 652 versus 172x1012 molecules of Fg/cm2; P<0.05, respectively) and thrombosis (immunohistochemistry).
Conclusions—This study documents the key role of TF activity in acute arterial thrombosis after atherosclerotic plaque disruption and provides evidence of the benefit of blocking plaque TF activity. Therefore the inhibition of the TF pathway opens a new therapeutic strategy in the prevention of acute coronary thrombosis after plaque disruption.
Key Words: tissue factor • TFPI • thrombosis • coronary disease • atherosclerosis
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