Inhibition of tissue factor-mediated coagulation markedly attenuates stenosis after balloon-induced arterial injury in minipigs.
BACKGROUND
Exposure and upregulation of tissue factor in the wall of balloon-injured arteries may result in prolonged activation of coagulation contributing to restenosis. This study was designed to determine whether brief or more prolonged inhibition of tissue factor-mediated coagulation with tissue factor pathway inhibitor (TFPI) attenuates neointimal formation and luminal stenosis after balloon-induced arterial injury.


RESULTS
The carotid artery of minipigs fed an atherogenic diet was injured by repetitive balloon hyperinflations, a procedure that rapidly yields complex, plaque-like neointimal lesions and high-grade luminal stenosis. Recombinant TFPI (rTFPI) was administered intravenously beginning 15 minutes before balloon injury as either a high dose (0.5 mg/kg bolus and 100 microg x kg(-1) x min(-1)) for 3 hours (n=7) or 24 hours (n=6) or as a low dose (0.5 mg/kg and 25 microg x kg(-1) x min(-1)) for 24 hours (n=6). Control animals received intravenous heparin (100 U x kg(-1) x h(-1)) for 3 hours (n=6) or 24 hours (n=7) or aspirin (5 mg/kg P.O.) followed by heparin for 24 hours (n=7). Luminal stenosis, assessed histologically 4 weeks after injury, was 73+/-17% and 76+/-18% (mean+/-SEM) in animals that received rTFPI or heparin for 3 hours, respectively. In contrast, luminal stenosis was only 11+/-12% and 6+/-3% in pigs given high and low doses, respectively, of rTFPI for 24 hours compared with 46+/-22% in pigs given heparin for 24 hours and 40+/-19% in those given both heparin and aspirin (P<.0002).


CONCLUSIONS
Inhibition of tissue factor-mediated coagulation during the first 24 hours after deep arterial injury appears to be particularly effective for attenuating subsequent neointimal formation and stenosis.
Oltrona
L
L
Cardiovascular Division, Washington University School of Medicine, St Louis, Mo 63110, USA.
Speidel
C M
CM
Recchia
D
D
Wickline
S A
SA
Eisenberg
P R
PR
Abendschein
D R
DR
D000800:Angioplasty, Balloon; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects*; D002339:Carotid Arteries / Q000473:pathology* / Q000503:physiopathology; D004036:Diet, Atherogenic; D007275:Injections, Intravenous; D008074:Lipoproteins / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013552:Swine; D013556:Swine, Miniature; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000502:physiology; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*
D000925:Anticoagulants; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin