Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty
Mercè Roqué, MD*,
Ernane D. Reis, MD ,
Valentin Fuster, MD, PhD*,
Adrian Padurean, MD*,
John T. Fallon, MD*  ,
Mark B. Taubman, MD, PhD*  ,
James H. Chesebro, MD* and
Juan J. Badimon, PhD*
* Zena and Michael A. Wiener Cardiovascular Institute, New York, New York, USA
Department of Surgery, Mount Sinai School of Medicine, New York, New York, USA
Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA
Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York, USA
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Figure 1 The histology of porcine coronary arteries 72 h after angioplasty. (A and B) coronary sections of vehicle-treated animals showing the presence of mural thrombus (red arrows). (C and D) sections of recombinant tissue factor pathway inhibitor plus heparin-treated animals. Note the hemorrhagic area surrounding the coronary wall (yellow arrows). (E and F) sections of recombinant tissue factor pathway inhibitor alone-treated animals, with no mural thrombosis and no periarterial hemorrhage. Note the comparable degrees of injury, with disruption of the internal elastic lamina in all sections. (All sections photographed at 40x).
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Figure 2 The morphometry of coronary arteries from control and rTFPI-treated swine. (A) Standardized intimal area or intima-to-media ratio of control and rTFPI-treated animals. (B) percentage luminal narrowing in both treatment groups, control and rTFPI. I/M = intima-to-media; rTFPI = recombinant tissue factor pathway inhibitor.
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Figure 3 The proliferative response in porcine coronary arteries 28 days after angioplasty. Representative coronary sections of control (A to C) and recombinant tissue factor pathway inhibitor-treated (D to F) animals. Note the internal elastic lamina disruption in all sections and larger amounts of intimal hyperplasia in the sections from controls compared with tissue factor pathway inhibitor-treated group. (All sections photographed at 40x.)
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Figure 4 Plasma levels of TFPI. Plasma levels of TFPI at different times before and after angioplasty during continuous intravenous administration of recombinant TFPI. PTCA = percutaneous transluminal coronary angioplasty; TFPI = tissue factor pathway inhibitor.
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Figure 5 Activated partial thromboplastin time monitoring during TFPI treatment. Activated partial thromboplastin time values at baseline and different times over a 72-h period after angioplasty for the three treatment groups (UFH plus ASA, heparin bolus plus aspirin; UFH plus ASA plus TFPI, heparin bolus plus ASA plus TFPI; ASA plus TFPI, ASA plus rTFPI). Note the synergistic anticoagulant effect of TFPI and heparin compared with the modest increase in aPTT elicited by TFPI alone. Long-dash line = UFH+ASA; solid line = UFH+ASA+TFPI; short-dash line = ASA+TFPI. aPTT = activated partial thromboplastin time; ASA = acetyl salicylic acid; PTCA = percutaneous transluminal coronary angioplasty; TFPI = tissue factor pathway inhibitor; UFH = unfractionated heparin.
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Figure 6 The effect of tissue factor pathway inhibitor on smooth muscle cell proliferation. Seven-day growth curve of human aortic smooth muscle cells in the presence or absence of rTFPI. Short-dash line = 1% FBS; solid line = 10% FBS; long-dash line = 10% FBS + rTFPI. FBS = fetal bovine serum; rTFPI = recombinant tissue factor pathway inhibitor.
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Figure 7 The effect of TFPI on smooth muscle cell migration. Concentration-dependent inhibition of human aortic smooth muscle cell migration by recombinant TFPI. All concentrations expressed as nM. BSA = bovine serum albumin; HPF = high power field; TFPI = tissue factor pathway inhibitor.
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