From the Department of Anatomy and Cell Biology (S.D.G., S.B.), The
Hebrew University–Hadassah Medical School, Jerusalem, Israel; Department
of Medicine (S.D.G., M.B.T., Y.N., S.T., J.H.C., V.F., J.J.B.), The
Cardiovascular Institute (J.T.F., R.G., M.B.T., J.H.C., V.F., J.J.B.), and
Department of Pathology (J.T.F., S.S.N.), Mount Sinai Medical Center, New
York, NY; and The Division of Cardiology (W.L.B., L.W.G., I.J.S.), The
University of Virginia, Charlottesville.
Correspondence to S. David Gertz, MD, PhD, Department of Anatomy and Cell Biology, The Hebrew University–Hadassah Medical School, PO Box 12272, Jerusalem 91120 Israel. E-mail gertz{at}cc.huji.ac.il
Background—Tissue factor (TF) is a
transmembrane glycoprotein that, after binding to factor
VII/VIIa, initiates the extrinsic coagulation pathway, resulting in
thrombin generation and its sequelae. Thrombin has been shown to induce
TF mRNA in endothelium, monocytes, and smooth muscle
cells, further perpetuating the thrombogenic cycle. This study was
designed to determine the effect of specific inhibition of thrombin by
recombinant hirudin (r-hirudin) on TF distribution after balloon
angioplasty in the cholesterol-fed rabbit femoral artery
and porcine coronary artery models.
Methods and Results—Thirty-five femoral arteries from 32
cholesterol-fed New Zealand White rabbits and 84
coronary arteries from 55 Yorkshire-Albino swine were studied
by use of a recently developed in situ method of TF localization based
on digoxigenin labeling of recombinant factor VIIa (Dig-VIIa), with
correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1)
or anti-human (sTF) antibodies. At sites of balloon angioplasty in
rabbit femoral or pig coronary arteries (double or single
injury), TF-antibody and Dig-VIIa staining were noted in association
with endothelial cells, smooth muscle cells, and foam
cells and within the fibrous tissue matrix primarily of the adventitia
and neointima. Staining was significantly greater after
balloon angioplasty than in vessels that had not undergone angioplasty
but was similar after single and double balloon injury. Animals treated
with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; pigs, 1
mg/kg bolus plus 0.7 mg · kg-1 ·
d-1 infusion for 14 days with implantable pump) had
diminished TF-antibody and Dig-VIIa staining 28 days after balloon
angioplasty compared with controls (bolus heparin only). This effect
was more prominent on the neointima and was more striking
in the porcine than the rabbit model.
Conclusions—TF expression, persistent 1 month after balloon
angioplasty in rabbit femoral arteries and porcine coronary
arteries, is attenuated by specific thrombin inhibition with hirudin.
These results suggest that thrombin inhibition, in addition to its
effect on acute thrombus formation and its effect on luminal narrowing
by plaque in experimental animals, may result in a prolonged reduction
in thrombogenicity of the restenotic plaque through this effect
on TF expression.
© 1998 American Heart Association, Inc.
Basic Science Reports
Hirudin Reduces Tissue Factor Expression in Neointima After Balloon Injury in Rabbit Femoral and Porcine Coronary Arteries
Key Words: hirudin • tissue factor • restenosis • balloon • plaque
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