Abstract
Heparin is a highly sulfated, linear polysaccharide that has been used clinically in order to prevent the recurrence of venous thromboembolism because of its anticoagulant effect [1]. In the blood coagulation cascade, it binds with antithrombin III (AT III) [2], a serine protease inhibitor, and the reaction of AT III with serine proteases such as thrombin and factor Xa is dramatically accelerated [3]. It has been well established that there is a critical pentasaccharidic sequence in heparin named as an antithrombin-binding domain (A-domain) [4], which exhibits a high affinity to hAT III. The binding of A-domain to AT III strongly increases the inhibitory activity of AT III toward factor Xa, although not toward factor IIa [5]. On the other hand, the binding of AT III to another sequence, i.e.the thrombin-binding domain (T-domain) coupled to the A-domain in heparin causes an inhibitory effect on hAT III toward factor IIa. In the heparinotherapy, the T-domain in heparin caused significant side effects such as thrombocytopaenia and haemorrhages. Therefore, attention has been drawn to the structure and activity of the A-domain, and a lot of work has already been carried out to identify the high affinity binding site for the A-domain of heparin in AT III. However, these investigations are not sufficient to characterize the heparin-binding site. It is the purpose of this study to clarify, with use of a novel physicochemical and biochemical method, the heparin binding sites of AT III in relation to the inhibition of coagulation involving factor Xa.
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