Influence of Blockade at Specific Levels of the Coagulation Cascade on Restenosis in a Rabbit Atherosclerotic Femoral Artery Injury Model

Abstract

Treatment with DEGR-VIIa or TFPI for 3 days in this rabbit atherosclerotic injury model reduced angiographic restenosis and decreased neointimal hyperplasia compared with controls. These findings highlight the importance of early initiators of the extrinsic coagulation pathway, especially factor VII and tissue factor, in the response to arterial injury.

Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries

“…In healthy vessels, TF is present in the adventitia and in the deep tunica media (9,10) but increases in the vascular intima and media after arterial injury (11) and in atherosclerotic states, where TF accumulates especially in lipid-laden plaques (10,12,13). In animal models of vascular injury, systemic administration of the inhibitor of TF (TF pathway inhibitor, or TFPI) (14)(15)(16), or of inhibitors of factor Xa (17) or thrombin (18), has suggested a role for the TF pathway of blood coagulation and thrombosis in the pathogenesis of postinjury intimal hyperplasia. However, these studies have not distinguished between the local influence of TF inhibition in the injured vessel wall and the systemic anticoagulant effects achieved with i.v.…”

Initial Inhibition of Tissue Factor Signalling Reduces Chronic Vascular Changes in Isogenic Rat Aortic Transplants

“…The impact of blockade of the TF pathway on re-stenosis and the development of intimal hyperplasia was previously investigated using two different models of arterial injury (28,38). In both these studies, initial treatment with rFVIIai, given as bolus injections alone (38) or as injections followed by intravenous infusions (28), was sufficient to reduce longterm proliferative vascular lesions, emphasizing the potential importance of inhibiting transiently expressed TF at the time of injury.…”

“…In both these studies, initial treatment with rFVIIai, given as bolus injections alone (38) or as injections followed by intravenous infusions (28), was sufficient to reduce longterm proliferative vascular lesions, emphasizing the potential importance of inhibiting transiently expressed TF at the time of injury. This has not been demonstrated for inhibitors of FXa or thrombin.…”

“…Jang et al (28) blocked the protease cascade at different levels and found that the inhibition of TF with tissue factor pathway inhibitor (TFPI) or rFVIIai reduced the development of intimal hyperplasia to a significantly higher degree than when using inhibitors of thrombin and/or FXa. This indicates that FVIIa/TF signalling in itself may be important for cell growth regulation in the vessel wall.…”

“…The formed complexes are catalytically inactive, thereby preventing generation of FXa and thrombin with subsequent fibrin precipitation (37). A high dose of rFVIIai (1 mg/kg), which previously was shown to prevent local thrombosis and re-stenosis, was used (28,38).…”