SearchPublisher and Institutes
You are here: Home :: Area NEM :: Medical science :: Human medicine
Steven T. Olson, Richard Swanson, Elke Raub-Segall, Tina Bedsted, Morvardi Sadri, Maurice Petitou, Jean-Pascal Hrault, Jean-Marc Herbert, Ingemar Bjrk
Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems. Comparison with heparin and low-molecular-weight heparin
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 106 107 M1s1. 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 106 M1s1 . 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 106 107 M1s1, 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, 150500-fold, to accelerating the inactivation of factors Xa, IXa and VIIa and moderately, 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, 10003000-fold, for thrombin inhibition and is appreciably smaller, although up to 250350-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.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 92, 11/2004
Pages: 929 - 939