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 si te-inhibited recombinant human factor VIIa (FVIIai) was used to inhibi t tissue factor, the primary cofactor in the extrinsic pathway of coag ulation, 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 mm(2)) and no loss in luminal area (1 2.2+/-0.9 mm(2) before injury and 12.1+/-0.9 mm(2) at 6 weeks after in jury). Sequential balloon injury, 3 weeks after the first balloon denu dation, 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 mm(2), <4% of the initial luminal a rea). Sequential injury acutely produced extensive mural and intramura l fibrin deposition. Treatment with FVIIai inhibited both the fibrin d eposition and the chronic loss of lumen. At 3 weeks after sequential i njury, luminal cross-sectional areas were 9.8+/-0.6 mm(2) for control rabbits and 14.3+/-1.4 mm(2) for FVIIai-treated rabbits. Neither neoin timal area nor cell proliferation was reduced by FVIIai treatment. The intimal cell proliferation index 3 days after injury was 7.6+/-1.1% i n control rabbits versus 5.8+/-1.1% in treated rabbits (P>0.05). These results indicate that tissue factor is an important mediator of coagu lation in repeat injury and implicate the extrinsic coagulation cascad e in a blood vessel remodeling response that is independent of neointi mal growth but leads to extensive loss of lumen.