Sequential injury of the rabbit abdominal aorta induces intramural coagulation and luminal narrowing independent of intimal mass: extrinsic pathway inhibition eliminates luminal narrowing.
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.
Courtman
D W
DW
Department of Pathology, University of Washington, Seattle, USA.
Schwartz
S M
SM
Hart
C E
CE
D000818:Animals; D001012:Aorta, Abdominal / Q000293:injuries* / Q000473:pathology; D001777:Blood Coagulation; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division; D005167:Factor VII / Q000037:antagonists & inhibitors; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D008855:Microscopy, Electron, Scanning; D011817:Rabbits; D013925:Thromboplastin / Q000037:antagonists & inhibitors; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D005167:Factor VII; D005337:Fibrin; D013925:Thromboplastin