© 1998 American Heart Association, Inc.
Original Contributions |
Sequential Injury of the Rabbit Abdominal Aorta Induces Intramural Coagulation and Luminal Narrowing Independent of Intimal Mass
Extrinsic Pathway Inhibition Eliminates Luminal Narrowing
From the Department of Pathology, University of Washington (D.W.C., S.M.S.), and ZymoGenetics (C.E.H.), Seattle, Wash.
Correspondence to Dr Charles E. Hart, ZymoGenetics, 1201 Eastlake Ave East, Seattle, WA 98102. E-mail HARTC{at}zgi.com
Abstract—We hypothesized that activation of the coagulation cascade is involved in arterial remodeling in response to sequential injury. An active site–inhibited recombinant human factor VIIa (FVIIai) was used to inhibit tissue factor, the primary cofactor in the extrinsic pathway of coagulation, in a sequential balloon injury model of the rabbit abdominal aorta. Single balloon injury produced limited intimal thickening at 3 weeks (intimal area, 0.40±0.05 mm2) and no loss in luminal area (12.2±0.9 mm2 before injury and 12.1±0.9 mm2 at 6 weeks after injury). Sequential balloon injury, 3 weeks after the first balloon denudation, produced a progressive loss of lumen, with 22% and 47% loss of luminal area, respectively, at 3 and 6 weeks. Luminal loss could not be accounted for by intimal growth (at 3 weeks after sequential injury, the intimal area was 0.47±0.08 mm2, <4% of the initial luminal area). Sequential injury acutely produced extensive mural and intramural fibrin deposition. Treatment with FVIIai inhibited both the fibrin deposition and the chronic loss of lumen. At 3 weeks after sequential injury, luminal cross-sectional areas were 9.8±0.6 mm2 for control rabbits and 14.3±1.4 mm2 for FVIIai-treated rabbits. Neither neointimal area nor cell proliferation was reduced by FVIIai treatment. The intimal cell proliferation index 3 days after injury was 7.6±1.1% in control rabbits versus 5.8±1.1% in treated rabbits (P>0.05). These results indicate that tissue factor is an important mediator of coagulation in repeat injury and implicate the extrinsic coagulation cascade in a blood vessel remodeling response that is independent of neointimal growth but leads to extensive loss of lumen.
Key Words: factor VII • tissue factor • fibrin • arteries • tunica intima
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