Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model

Endothelial thrombomodulin plays a critical role in hemostasis by binding t hrombin and subsequently converting protein C to its active form, a powerfu l anticoagulant, Thrombomodulin thus represents a central mechanism by whic h patency is maintained in normal vessels. However, thrombomodulin expressi on decreases in perturbed endothelial cells, predisposing to thrombotic occ lusion. An adenoviral construct expressing thrombomodulin (Adv/RSV-THM) was created and functionally characterized in vitro and in vivo. The impact of local overexpression of thrombomodulin on in vivo thrombus formation was s ubsequently examined in a stasis/injury model of arterial thrombosis. The c onstruct prevented arterial thrombosis formation in all animals, while vira l and nonviral controls typically developed occluding thrombi. By histologi cal analysis, nonviral controls exhibited intravascular thrombus occluding a mean of 70.52+/-3.72% of available lumen, while viral controls reached 86 .85+/-2.82% thrombotic occlusion; in contrast, Adv/RSV-THM reduced thrombos is to 28.61+/-3.31% of lumen in cross section. No significant intima-to-med ia ratio was observed in the thrombomodulin group relative to controls. Loc al infiltration of granulocytes and macrophages significantly decreased in the Adv/RSV-THM group relative to controls, while neutrophilic infiltration increased in viral controls relative to nonviral controls, This construct thus offers a viable technique for promoting a locally thromboresistant sma ll-caliber artery, without the inflammatory damage that has limited many ot her adenoviral applications.