EXPERIMENTAL STUDY
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
Manuscript received December 28, 1999;
revised manuscript received May 25, 2000,
accepted July 13, 2000.
Reprint requests and correspondence: Dr. Juan J. Badimon, Cardiovascular Institute, The Mount Sinai Medical Center, One Gustave L. Levy Place, Box #1030, New York, New York 10029-6574
juan.badimo{at}mssm.edu
OBJECTIVES
We investigated the in vivo effects of tissue factor (TF) inhibition with recombinant tissue factor pathway inhibitor (rTFPI) on acute thrombus formation and intimal hyperplasia and the in vitro effects on smooth muscle cell migration and proliferation.
BACKGROUND
Inhibition of TF with TFPI has been shown to reduce intimal hyperplasia in experimental models. However, its effects after coronary angioplasty and the cellular mechanisms involved have not been investigated.
METHODS
Twenty-three swine underwent multivessel coronary angioplasty. Fifteen (n = 25 arteries) were euthanized at 72 h to assess thrombus formation and eight (n = 24 arteries) at 28 days to assess intimal hyperplasia. Animals in the 72-h time point received: 1) human rTFPI (0.5 mg bolus plus 25 µg/kg/min continuous infusion for 3 days) plus heparin (150 IU/kg intravenous bolus) plus acetyl salicylic acid (ASA) (325 mg/day); 2) rTFPI regimen plus ASA and 3) heparin (150 IU/kg intravenous bolus) plus ASA.
RESULTS
On histology the control group had evidence of mural thrombus (area 0.8 ± 0.4 mm2). Treatment with TFPI plus heparin abolished thrombus formation (mean area: 0.0 ± 0.0 mm2, p < 0.05) but was associated with prolonged activated partial thromboplastin time and extravascular hemorrhage. Recombinant TFPI alone inhibited thrombosis without bleeding complications (mean area: 0.03 ± 0.02 mm2, p < 0.05 vs. control). Animals in the 28-day time point received continuous intravenous infusion of rTFPI or control solution for 14 days. Tissue factor pathway inhibitor reduced neointimal formation with mean intimal area of 1.2 ± 0.3 mm2 versus 3.2 ± 0.4 mm2 in the control group; p < 0.01. Recombinant TFPI had no effect on human aortic smooth muscle cell growth but inhibited platelet-derived growth factor BB-induced migration.
CONCLUSIONS
Inhibition of TF with rTFPI can prevent acute thrombosis and intimal hyperplasia after injury. Tissue factor plasma inhibitor may prove useful as an adjunct to intracoronary interventions.
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Abbreviations and Acronyms
| | aPTT | = activated partial thromboplastin time | | ASA | = acetyl salicylic acid | | BSA | = bovine serum albumin | | DMEM | = Dulbecco’s modified essential medium | | FBS | = fetal bovine serum | | IEL | = internal elastic lamina | | I/M | = intima-to-media | | PDGF | = platelet-derived growth factor | | rTFPI | = recombinant tissue factor pathway inhibitor | | SMC | = smooth muscle cell | | TF | = tissue factor | | TFPI | = tissue factor pathway inhibitor |
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