Author + information
- Received December 28, 1999
- Revision received May 25, 2000
- Accepted July 13, 2000
- Published online December 1, 2000.
- 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∗,* ()
- ↵*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
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.
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.
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.
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.
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.
☆ Supported, in part, by a grant-in-aid from the Spanish Heart Association to Dr. Roqué.
Presented, in part, at the 71st Scientific Sessions of the American Heart Association, Dallas, Texas, November 1998, and published in abstract form (Circulation 1998;98 Suppl I:I–727).
- Received December 28, 1999.
- Revision received May 25, 2000.
- Accepted July 13, 2000.
- American College of Cardiology