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首页> 外文期刊>Thrombosis and Haemostasis: Journal of the International Society on Thrombosis and Haemostasis >Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems. Comparison with heparin and low-molecular-weight heparin.
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Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems. Comparison with heparin and low-molecular-weight heparin.

机译：合成寡糖对凝血酶和纤溶系统蛋白酶抗凝血酶抑制作用的加速能力。与肝素和低分子量肝素的比较。

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摘要

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 intothe mechanism of heparin acceleration of antithrombin inhibition of proteinases.
机译：比较了三种合成寡糖与十种凝血酶或纤溶酶相比，加速抗凝血酶抑制十种凝血酶或纤溶酶的能力。结果表明，后三种肝素在近似生理条件下的抗凝作用几乎完全是通过加速凝血酶，Xa因子和IXa因子的失活达到接近扩散控制的速率常数（约10（6）-10（7））来实现的。 ）M（-1）.s（-1）。所有其他蛋白酶均以至少20倍的较低速率常数受到抑制。合成的常规（磺达肝素）和高亲和力（伊达肝素）五糖的抗凝能力是由于一种共同的机制所致，其中包括仅加速因子Xa抑制至速率常数约为10（6）M（-1）.s。 （-1）。同时包含五糖序列和蛋白酶结合位点的十六碳糖通过加速凝血酶和Xa因子的抗凝血酶失活以达到约10（6）-10（7）M（-1）s的速率常数来发挥其抗凝作用。 （-1），尽管凝血酶似乎是更重要的目标。相比之下，IXa因子抑制作用受到的刺激明显较少。由五糖和更长的肝素诱导的抗凝血酶的构象变化在很大程度上促进了因子Xa，IXa和VIIa的失活，并在一定程度上是对因子XIIa和组织纤溶酶原的约50倍的失活。激活剂抑制。由于抗凝血酶和蛋白酶与相同的长肝素链结合而产生的桥接作用在抑制凝血酶方面占主导地位，约为1000-3000倍，而对于灭活因子则明显较小，尽管高达250-350倍。 IXa和XIa。这些结果确定了目前用于血栓形成治疗或考虑用于血栓形成治疗的肝素衍生物的蛋白酶靶标，并为了解肝素加速抗凝血酶抑制蛋白酶的机制提供了新见解。

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