Anticoagulant activities of a monoclonal antibody that binds to exosite II of thrombin.
Anticoagulant activities of a monoclonal antibody that binds to exosite II of thrombin.
复制标题
与凝血酶外位点 II 结合的单克隆抗体的抗凝活性。
DOI：
10.1021/bi0101906
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发表时间：
2001
期刊：
影响因子：
2.9
通讯作者：
Tollefsen,DM
中科院分区：
文献类型：
--
作者：
Lian,F;He,L;Colwell,NS;Lollar,P;Tollefsen,DM
从患有多发性骨髓瘤的患者分离的单克隆IgG已显示与凝血酶的外部位点II结合，当添加到正常血浆中时延长凝血酶时间和活化部分凝血活酶时间（aPTT），并且改变合成肽底物的水解动力学。尽管IgG不影响凝血酶对纤维蛋白原的切割，但它使纯化的抗凝血酶对凝血酶的抑制率增加了约3倍。血浆免疫耗竭抗凝血酶或肝素辅因子II的实验证实，凝血酶时间的延长需要抗凝血酶。相比之下，aPTT的延长既不需要抗凝血酶也不需要肝素辅因子II。IgG延迟由纯化的因子IXa引发的血浆凝血，但对因子Xa引发的凝血的影响小得多。在纯化的系统中，IgG降低凝血酶对因子VIII的活化速率。这些研究表明，单克隆IgG与外部位点II的结合通过加速凝血酶-抗凝血酶反应间接缩短凝血酶时间，并可能通过干扰因子VIII的活化延长aPTT，从而降低因子IXa/VIIIa复合物的催化活性。
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 immunodepleted 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.