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Anticoagulant Activities of a Monoclonal Antibody That Binds of Exosite II of Thrombin

机译:与凝血酶的Exosite II结合的单克隆抗体的抗凝血活性

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A monoclonal IgG isolated from a patient with multiple myeloma has been shown to bind to exosite II of thrombin, prolong both the thrombin time and the activated partial thromboplastin time (aPTT) when added to normal plasma, and alter the kinetics of hydrolysis of synthetic peptide substrates. Although the IgG does not affect cleavage of fibrinogen by thrombin, it increases the rate of inhibition of thrombin by purified antithrombin '...'3-fold. Experiments with plasma imrnunodepleted of antithrombin or heparin cofactor II confirm that prolongation of the thrombin time requires antithrombin. By contrast, prolongation of the aPTT requires neither antithrombin nor heparin cofactor II. The IgG delays clotting of plasma initiated by purified factor IXa but has much less of an effect on clotting initiated by factor Xa. In a purified system, the IgG decreases the rate of activation of factor VIII by thrombin. These studies indicate that binding of a monoclonal IgG to exosite II prolongs the thrombin time indirectly by accelerating the thrombin-antithrombin reaction and may prolong the aPTT by interfering with activation of factor VIII, thereby diminishing the catalytic activity of the factor IXa/VIIIa complex.
机译:从多发性骨髓瘤患者中分离出的单克隆IgG已显示与凝血酶的exosite II结合,当添加至正常血浆中时可延长凝血酶时间和活化的部分凝血活酶时间(aPTT),并改变合成肽的水解动力学基材。尽管IgG不影响凝血酶对血纤蛋白原的切割,但是它增加了纯化抗凝血酶“ ...” 3倍对凝血酶的抑制率。用抗凝血酶或肝素辅因子II进行核素不饱和的血浆实验证实,延长凝血酶时间需要使用抗凝血酶。相反,延长aPTT既不需要抗凝血酶,也不需要肝素辅因子II。 IgG延迟了由纯化的因子IXa引发的血浆的凝结,但是对由因子Xa引发的凝结的影响小得多。在纯化的系统中,IgG会降低凝血酶对因子VIII的活化率。这些研究表明,单克隆IgG与外位蛋白II的结合通过加速凝血酶-抗凝血酶反应间接地延长了凝血酶时间,并可能通过干扰因子VIII的活化而延长了aPTT,从而降低了因子IXa / VIIIa复合物的催化活性。

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