title: Comparison of thrombin active site and exosite inhibitors and heparin in experimental models of arterial and venous thrombosis and bleeding.
abstract: Different pharmacological approaches to thrombin inhibition were compared for their effects on thrombosis and bleeding time in anesthetized rats. Thrombosis was induced in the carotid artery by transmural vessel injury and in the vena cava by partial blood flow stasis combined with mild endothelial disruption. Small mesenteric arteries were punctured with a hypodermic needle to measure the bleeding time. Dose-response relationships were determined with a thrombin active site inhibitor, N-methyl (GYKI 14,766); a thrombin exosite inhibitor, succinyl-Phe-Glu-Pro-Ile-Pro-Glu-Glu-Tyr-cyclohexylalanine-Gln (BMS 180,742); and heparin. BMS 180,742 interferes with fibrinogen binding to the thrombin exosite but, unlike GYKI 14,766, it does not block thrombin's catalytic site. The effects on thrombosis and bleeding time were correlated with ex vivo clotting times using the activated partial thromboplastin time for heparin and the thrombin time for GYKI 14,766 and BMS 180,742. Venous thrombosis was inhibited more than 90% by all three inhibitors at doses that either produced threshold increases or had no effect on bleeding and clotting times. Arterial thrombosis was inhibited 82% by GYKI 14,766 and 63% by heparin but it was not inhibited by BMS 180,742. These antithrombotic activities were accompanied by a maximal activated partial thromboplastin time increase and doubling of the bleeding time with heparin and a maximal thrombin time prolongation and 35% increase in bleeding time with GYKI 14,766. These results suggest that thrombin inhibitors, which act at the active site or exosite or through antithrombin III, are equally efficacious against venous thrombosis but active site inhibitors are the most effective against arterial thrombosis.
authors.affiliation: Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
authors.forename: W A
authors.initials: WA
authors.lastname: Schumacher
authors.forename: T E
authors.initials: TE
authors.lastname: Steinbacher
authors.forename: C L
authors.initials: CL
authors.lastname: Heran
authors.forename: S M
authors.initials: SM
authors.lastname: Seiler
authors.forename: I M
authors.initials: IM
authors.lastname: Michel
authors.forename: M L
authors.initials: ML
authors.lastname: Ogletree
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001665:Binding Sites; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000627:therapeutic use*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013924:Thrombophlebitis / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D009842:Oligopeptides; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; C072028:BMS 180742; D006493:Heparin; D013917:Thrombin; C064289:efegatran