Active site-blocked factor Xa prevents thrombus formation in the coronary vasculature in parallel with inhibition of extravascular coagulation in a canine thrombosis model.
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.
Benedict
C R
CR
Division of Cardiology, University of Texas Medical School, Houston 77225.
Ryan
J
J
Todd
J
J
Kuwabara
K
K
Tijburg
P
P
Cartwright
J
J
Stern
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology; D002417:Cattle; D003328:Coronary Thrombosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D005170:Factor X / Q000494:pharmacology; D015951:Factor Xa / Q000494:pharmacology / Q000502:physiology; D065427:Factor Xa Inhibitors; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D008854:Microscopy, Electron; D008969:Molecular Sequence Data
D065427:Factor Xa Inhibitors; C080817:factor Xa, Glu-Gly-Arg-; D005170:Factor X; D005337:Fibrin; D005340:Fibrinogen; D006493:Heparin; D015951:Factor Xa