Selective factor Xa inhibition by recombinant antistasin prevents vascular graft thrombosis in baboons.
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.
Schaffer
L W
LW
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, Pa. 19486.
Davidson
J T
JT
Vlasuk
G P
GP
Dunwiddie
C T
CT
Siegl
P K
PK
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001808:Blood Vessels / Q000637:transplantation*; D065427:Factor Xa Inhibitors; D006487:Hemostasis / Q000187:drug effects; D007447:Invertebrate Hormones / Q000627:therapeutic use*; D008297:Male; D010215:Papio; D011183:Postoperative Complications / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013917:Thrombin / Q000502:physiology; D013927:Thrombosis / Q000517:prevention & control*
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007447:Invertebrate Hormones; D011994:Recombinant Proteins; C053155:antistasin; D013917:Thrombin