Active site-blocked factor Xa prevents thrombus formation in the coronary
vasculature in parallel with inhibition of extravascular coagulation in a
canine thrombosis model
CR Benedict, J Ryan, J Todd, K Kuwabara, P Tijburg, J Cartwright and D Stern
Division of Cardiology, University of Texas Medical School, Houston 77225.
Factor Xa is a central procoagulant enzyme, linking the intrinsic and
extrinsic activation mechanisms to the final common pathway of coagulation.
To assess its contribution to pathologic thrombosis, studies were performed
in a canine coronary thrombosis model. Thrombus formation was initiated by
the application of electric current via a needle electrode placed in the
lumen of the left circumflex coronary artery. When 50% occlusion of the
vessel developed, the current was stopped and animals received an
intravenous bolus of either saline, bovine glutamyl-glycinyl-arginyl-factor
Xa (Xai), a competitive inhibitor of factor Xa assembly into the
prothrombinase complex, Factor X, or heparin. Animals infused with saline
or factor X (300 micrograms/kg) developed total occlusion of the vessel due
to a fibrin/platelet thrombus in 70 +/- 11 minutes (36 of 36 animals) and
74 +/- 13 minutes (8 of 8 animals), respectively. In contrast, infusion of
Xai prevented thrombus formation completely at a dose of 300 micrograms/kg
(8 of 8 animals). As the dose of Xai was decreased, its antithrombotic
effect was diminished, with a patency rate of only 2 of 6 animals at a dose
of 90 micrograms/kg. Xai at 300 micrograms/kg prevented the accumulation of
125I-fibrinogen/fibrin at the site of the coronary thrombus by
approximately 63% and decreased deposition of 111In-labeled platelets by
approximately 57%. Hemostatic parameters of animals infused with Xai
demonstrated prolongation of the PT and dose- dependent increased
extravascular bleeding tendency. These data indicate that factor Xa has a
comparably important role in thrombus formation and extravascular
hemostasis, and contrast with previous results in this same animal model in
which IXai selectively prevented clotting in the coronary vasculature.
Volume 81,
Issue 8,
pp. 2059-2066,
04/15/1993
Copyright © 1993 by The American Society of Hematology
