Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of balloon-induced arterial injury in pigs.
Intravenous infusion of recombinant tissue factor pathway inhibitor (rTFPI) for 24 hours decreases neointimal thickening and luminal stenosis 1 month after balloon-induced injury to the carotid arteries in minipigs. This study was designed to determine whether the effect of rTFPI is accounted for by early decreases in procoagulant activity and thrombosis on the injured vessel wall. Vascular injury was induced by balloon hyperinflations in both carotid arteries of anesthetized pigs given no anticoagulant as a control (n=16), an intravenous infusion for 24 hours of rTFPI (0.5 mg/kg bolus and 25 microg. kg(-1). min(-1), n=14), or an intravenous infusion of unfractionated heparin (100 U. kg(-1). h(-1), n=19). Accumulation of radiolabeled autologous platelets was markedly decreased over 24 hours on injured arteries from animals given rTFPI (0.6x10(6)/cm(2)) compared with controls (2.5x10(6)/cm(2), P=0.0004). Deposition of radiolabeled fibrin was also decreased in rTFPI-treated animals (269+/-266 microg/cm(2)) compared with controls (2389+/-1673 microg/cm(2), P=0.04). Similar effects were observed with heparin. However, factor Xa activity, assayed after 24 hours by incubation of the injured arterial segments with the chromogenic substrate S-2222, was decreased more markedly on arteries from rTFPI-treated animals (0.14+/-0.13 OD) than those from heparin-treated animals (0.29+/-0.18 OD) compared with controls (0. 47+/-0.24 OD, P=0.0007). In addition, arteries from rTFPI-treated animals showed a 4-fold lower induction of tissue factor protein compared with controls (P=0.0002). Attenuation of procoagulant activity and tissue factor-mediated thrombin generation in response to injury may account for the promising results with rTFPI in the porcine angioplasty model.
St Pierre
J
J
Cardiovascular Division, Washington University School of Medicine, St Louis, MO 63110, USA.
Yang
L Y
LY
Tamirisa
K
K
Scherrer
D
D
De Ciechi
P
P
Eisenberg
P
P
Tolunay
E
E
Abendschein
D
D
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D020212:Carotid Artery Injuries; D002404:Catheterization; D065427:Factor Xa Inhibitors; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000494:pharmacology*; D008297:Male; D011994:Recombinant Proteins; D013552:Swine; D013925:Thromboplastin / Q000378:metabolism*; D013927:Thrombosis / Q000517:prevention & control; D014947:Wounds and Injuries / Q000209:etiology
D065427:Factor Xa Inhibitors; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin