A baboon model of high-shear, platelet-dependent vascular graft
thrombosis was used to assess the antithrombotic effect of recombinant
antistasin (rATS), a 119-amino
acid protein with selective, subnanomolar inhibitory potency against
coagulation factor Xa. In this model, a
Dacron vascular graft segment of a femoral arteriovenous (AV) shunt provided the thrombogenic stimulus. Antithrombotic efficacy of rATS was assessed by continuous monitoring of 111In-labeled platelet and 125I-labeled
fibrin(
ogen) deposition onto the graft surface and blood flow through the vascular shunt. Systemic
intravenous administration of rATS (2 or 4 micrograms/kg.min-1) dose dependently decreased both platelet and
fibrin(
ogen) deposition onto the graft. Vascular graft
thrombus formation was completely inhibited at a systemic dose of rATS of 4 micrograms/kg.min-1. None of the AV shunts in animals receiving rATS at either dose occluded, and blood flow was maintained at 81 +/- 4% (2 micrograms/kg.min-1 rATS) or 96 +/- 3% (4 micrograms/kg.min-1 rATS) of basal flow. Systemic
fibrinopeptide A elevations in response to exposure to the
Dacron graft segment were completely suppressed by both doses of rATS. The ex vivo activated partial
thromboplastin times were extended to greater than 150 seconds during infusion of both doses of rATS; however, even at fully antithrombotic doses, template bleeding times were not significantly increased. Thus, in this baboon model, rATS is a potent
antithrombotic agent that inhibits both platelet and
fibrin(
ogen) deposition onto a
Dacron vascular graft segment. Furthermore, these results demonstrate that selective inhibition of
coagulation factor Xa by rATS can completely prevent vascular graft
thrombus formation without significantly compromising primary hemostasis as measured by template bleeding time.