Tissue-type plasminogen activator (tPA) catalyzes the rate-limiting initial step in the fibrinolytic cascade. Systemic infusion of tPA has become the standard of care for acute myocardial infarction. However, even the relatively short duration protocols currently employed have encountered significant hemorrhagic complications as well as complications from rebound thrombosis. Gene therapy offers a method of local high level tPA expression over a prolonged time period to potentially avoid both systemic hemorrhage and local rebound thrombosis. To examine the impact of local tPA overexpression, an adenoviral vector expressing tPA was created. The construct was functionally characterized in vitro, and the function of the vector was confirmed by in vivo delivery to the rabbit common femoral artery. Systemic coagulation parameters were not perturbed at any of the doses examined. The impact of local overexpression of tPA on in vivo thrombus formation was subsequently examined in a stasis/injury model of arterial thrombosis. The construct effectively prevented arterial thrombosis formation in treated animals, while viral and nonviral controls typically developed occluding thrombi (P<0.01 relative to viral and nonviral controls. Across all sections, buffer treated animals averaged 66.5% (+/-13.7%) cross sectional thrombus, while viral controls rose to 78.2% (+/-7.1%). Vessels treated with the adenoviral-tPA construct, in contrast, averaged 19.3% (+/-3.2%). These results remained after three days, during which most rebound thrombosis would have occurred. Thus a locally thromboresistant small caliber artery with minimal risk of systemic hemorrhagic complications can be produced using this construct.
|Original language||English (US)|
|State||Published - Mar 20 1998|
ASJC Scopus subject areas
- Molecular Biology