title: Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems. Comparison with heparin and low-molecular-weight heparin.
abstract: The abilities of three synthetic oligosaccharides to accelerate antithrombin inhibition of ten clotting or fibrinolytic proteinases were compared with those of unfractionated, fractionated high-affinity and low-molecular-weight heparins. The results show that the anticoagulant effects of the latter three heparins under conditions approximating physiologic are exerted almost exclusively by acceleration of the inactivation of thrombin, factor Xa and factor IXa to near diffusion-controlled rate constants of approximately 10(6) - 10(7) M(-1).s(-1). All other proteinases are inhibited with at least 20-fold lower rate constants. The anti-coagulant ability of the synthetic regular (fondaparinux) and high-affinity (idraparinux) pentasaccharides is due to a common mechanism, involving acceleration of only factor Xa inhibition to rate constants of approximately 10(6) M(-1).s(-1) . A synthetic hexadecasaccharide, containing both the pentasaccharide sequence and a proteinase binding site, exerts its anticoagulant effect by accelerating antithrombin inactivation of both thrombin and factor Xa to rate constants of approximately 10(6) - 10(7) M(-1).s(-1), although thrombin appears to be the more important target. In contrast, factor IXa inhibition is appreciably less stimulated. The conformational change of antithrombin induced both by the pentasaccharides and longer heparins contributes substantially, approximately 150-500-fold, to accelerating the inactivation of factors Xa, IXa and VIIa and moderately, approximately 50-fold, to that of factor XIIa and tissue plasminogen activator inhibition. The bridging effect due to binding of antithrombin and proteinase to the same, long heparin chain is dominating, approximately 1000-3000-fold, for thrombin inhibition and is appreciably smaller, although up to approximately 250-350-fold, for the inactivation of factors IXa and XIa. These results establish the proteinase targets of heparin derivatives currently used in or considered for thrombosis therapy and give new insights into the mechanism of heparin acceleration of antithrombin inhibition of proteinases.
authors.affiliation: Center for Molecular Biology of Oral Diseases, University of Illinois-Chicago, Illinois, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Olson
authors.forename: Richard
authors.initials: R
authors.lastname: Swanson
authors.forename: Elke
authors.initials: E
authors.lastname: Raub-Segall
authors.forename: Tina
authors.initials: T
authors.lastname: Bedsted
authors.forename: Morvardi
authors.initials: M
authors.lastname: Sadri
authors.forename: Maurice
authors.initials: M
authors.lastname: Petitou
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Hérault
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björk
mesh_terms: D000990:Antithrombin III / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000187:drug effects / Q000302:isolation & purification; D005342:Fibrinolysis / Q000187:drug effects; D000077425:Fondaparinux; D006487:Hemostasis / Q000187:drug effects*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000302:isolation & purification; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001779:Blood Coagulation Factors; D009844:Oligosaccharides; D011134:Polysaccharides; D015842:Serine Proteinase Inhibitors; C479958:idraparinux; D000990:Antithrombin III; D006493:Heparin; D012697:Serine Endopeptidases; D000077425:Fondaparinux