Active site-blocked factor Xa prevents thrombus formation in the coronary vasculature in parallel with inhibition of extravascular coagulation in a canine thrombosis model

C. R. Benedict, J. Ryan, J. Todd, K. Kuwabara, P. Tijburg, J. Cartwright, David Stern

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 μg/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 μg/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 μg/kg. Xai at 300 μg/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.

Original languageEnglish (US)
Pages (from-to)2059-2066
Number of pages8
JournalBlood
Volume81
Issue number8
StatePublished - Jan 1 1993
Externally publishedYes

Fingerprint

Factor Xa
Coagulation
Canidae
Catalytic Domain
Animals
Thrombosis
Factor X
Fibrin
Platelets
Blood Platelets
Coronary Thrombosis
Hemostatics
Hemostasis
Electric currents
Fibrinogen
Needles
Heparin
Coronary Vessels
Electrodes
Animal Models

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Active site-blocked factor Xa prevents thrombus formation in the coronary vasculature in parallel with inhibition of extravascular coagulation in a canine thrombosis model. / Benedict, C. R.; Ryan, J.; Todd, J.; Kuwabara, K.; Tijburg, P.; Cartwright, J.; Stern, David.

In: Blood, Vol. 81, No. 8, 01.01.1993, p. 2059-2066.

Research output: Contribution to journalArticle

Benedict, C. R. ; Ryan, J. ; Todd, J. ; Kuwabara, K. ; Tijburg, P. ; Cartwright, J. ; Stern, David. / Active site-blocked factor Xa prevents thrombus formation in the coronary vasculature in parallel with inhibition of extravascular coagulation in a canine thrombosis model. In: Blood. 1993 ; Vol. 81, No. 8. pp. 2059-2066.
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abstract = "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 μg/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 μg/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 μg/kg. Xai at 300 μg/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.",
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