Characterization of a tissue factor/factor VIIa-dependent model of thrombosis in hypercholesterolemic rabbits.
Tissue factor (TF) expressed in arterial atherosclerotic plaque plays a key role in activating the extrinsic coagulation pathway and triggering acute coronary syndromes. In this study, we developed and characterized a TF-factor (F)VIIa-mediated thrombosis model in rabbits. Balloon catheter-induced endothelial denudation in the femoral artery and a 4-week high cholesterol diet produced a localized atherosclerotic plaque at the injured site. High levels of TF mRNA and TF protein antigen (152 +/- 25 vs. 49 +/- 12 pg mg-1 protein in normal vessels) were detected in these atherosclerotic plaques. Plasma FVII coagulant activity (FVII:C) was significantly increased in the hypercholesterolemic rabbits (36 +/- 1 s) compared with the normal rabbits (44 +/- 1 s, P < 0.0001). Plaque rupture was induced by balloon angioplasty, which resulted in thrombus formation in the injured vessel segment after a brief period of stasis. FVIIai, a specific TF-FVIIa inhibitor, was administered intravenously to rabbits before plaque rupture at 0.3 and 1.0 mg kg-1. FVIIai dose-dependently reduced thrombus mass (14.7 +/- 2.5 and 5.9 +/- 2.2 mg, respectively, vs. 21.6 +/- 1.9 mg in the control group). PD198961, a novel factor Xa inhibitor, and argatroban, a thrombin inhibitor, also dose-dependently inhibited thrombosis. These results indicate that thrombus formation in this model is initiated by the activation of TF-FVIIa pathway, which is attributed to TF expression in the atherosclerotic plaque and enhanced plasma FVII coagulant activity. This model may be useful for evaluating in vivo efficacy of new antithrombotic drugs, particularly TF-FVIIa inhibitors.
Chi
L
L
Pfizer Global R&D, Ann Arbor Laboratories, Cardiovascular Pharmacology, Ann Arbor, MI 48105, USA. liguo.chi@pfizer.com
Gibson
G
G
Peng
Y-W
YW
Bousley
R
R
Brammer
D
D
Rekhter
M
M
Chen
J
J
Leadley
R
R
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D015942:Factor VIIa / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D015870:Gene Expression; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications*; D008055:Lipids / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D013925:Thromboplastin / Q000235:genetics / Q000502:physiology*; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology
D005343:Fibrinolytic Agents; D008055:Lipids; D012333:RNA, Messenger; D013925:Thromboplastin; D015942:Factor VIIa