title: Prolonged bleeding time induced by anticoagulant glycosaminoglycans in dogs is associated with the inhibition of thrombin-induced platelet aggregation.
abstract: BACKGROUND
  The clinical use of unfractionated heparin (UFH) is complicated by hemorrhage. This has led to a search for safer alternatives, one of which, the recently identified depolymerized holothurian glycosaminoglycan (DHG), causes less bleeding and exhibits a better antithrombotic-hemorrhagic ratio in rats and dogs than UFH and low-molecular-weight heparin (LMWH). In contrast to UFH and LMWH, which exert their anticoagulant effects by inhibiting thrombin in the presence of antithrombin III (AT), DHG exerts its anticoagulant effect by inhibiting the intrinsic factor Xase complex and thrombin in the presence of heparin cofactor II (HCII).
  
  
  METHODS
  The hemorrhagic effect of DHG was compared with those of UFH and LMWH in healthy dogs, and the mechanism responsible for prolonging bleeding time was examined both in dogs and with human platelets.
  
  
  RESULTS
  DHG prolonged template-bleeding time in dogs less than UFH and LMWH do. Although the maximum noneffective concentrations of each glycosaminoglycan (GAG) that prolong the bleeding time are almost the same as the concentrations that inhibit thrombin-induced platelet aggregation, they are not related to those that inhibit ADP-induced platelet aggregation. Results of experiments on gel-filtered platelets from humans indicate that the inhibition of thrombin-induced platelet aggregation caused by UFH and LMWH in the presence of AT is more prominent than that caused by DHG with HCII.
  
  
  CONCLUSIONS
  These results suggest that the prolongation of bleeding time caused by GAGs are associated with the inhibition of thrombin-induced platelet aggregation, and DHG may cause less bleeding than UFH and LMWH because of its different thrombin inhibition mechanism in platelet-rich plasma (PRP).
authors.affiliation: Cancer Research Laboratory, Hannno Research Center, Taiho Pharmaceutical, 1-27, Misugidai, Hanno, Saitama, 357-8527, Japan. taiho.kitazato@nifty.ne.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitazato
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.forename: Eiji
authors.initials: E
authors.lastname: Sasaki
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Minamiguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001760:Bleeding Time / Q000379:methods*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000097:blood* / Q000494:pharmacology*; D006493:Heparin / Q000097:blood* / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D006025:Glycosaminoglycans; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin; D013917:Thrombin