Suppression by antithrombotic agents of pseudointimal hyperplasia of polytetrafluoroethylene graft implanted into venous system

Abstract

The lumen of the polytetrafluoroethylene graft (PTFE) implanted into a rabbit inferior vena cava (IVC) was markedly narrowed by 4 weeks after grafting. This was due to initial thrombosis on the luminal surface of the graft, which was followed by pseudointimal hyperplasia (PIH). To elucidate the role of the initial thrombosis in subsequent PIH, the effect of ticlopidine (T) and/or warfarin (W) on PIH was studied in an animal model. A PTFE tube graft was implanted into a rabbit IVC. Twenty eight rabbits were randomly assigned to the following experimental groups. Eight rabbits without antithrombotic agents were observed for 2 weeks (A, n=4) and 4 weeks (B, n=4) after grafting. T (100mg/kg/day) and W (0.33mg/kg/day) were orally administered for 4 weeks to group C (n=4) and group D (n=4), respectively. A combination of a half dose of T and W ((T+W)/2) was given for 2 weeks (E, n=4) and 4 weeks (F,n=4) after grafting. Four rabbits in group G received the combination of T and W for the first 2 weeks and were observed for an additional 2 weeks without medication. All the grafts were patent at time of harvest. The dry weight of the intraluminal deposit (DW) was determined as an indicator of PIH (A:35±1 mg/graft, B:40±8, C:22±3, D:22±3, E: 14±2, F: 15±3, G:23±2). Administration of T or W was equally effective in reducing DW and (T+W)/2 was more effective, than a single agent. The initial two weeks' administration of (T+W)/2 was not only effective in the first 2 weeks but also in the next 2 weeks to a significant extent. The ultrastructural analysis of the harvested grafts revealed that subendothelial layer of PIH was composed of smooth muscle cells, myofibroblasts and fibroblasts. The reduction of PIH by antithrombotic agents was likely due to suppression of the proliferation and transformation of these cells. Endothelial coverage of the luminal surface was not altered by administration of any antithtrombotic agent. From these observations, it was concluded that administration of antithrombotic agents is beneficial for prevention of not only initial thrombosis but also of PIH.