Synergistic action of two murine monoclonal antibodies that inhibit ADP-induced platelet aggregation without blocking fibrinogen binding.
Synergistic action of two murine monoclonal antibodies that inhibit ADP-induced platelet aggregation without blocking fibrinogen binding.
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DOI：
10.1182/blood.v69.2.668.bloodjournal692668
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发表时间：
1987-02
期刊：
影响因子：
20.3
通讯作者：
P. Newman;R. McEver;M. Doers;T. Kunicki
中科院分区：
文献类型：
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作者：
P. Newman;R. McEver;M. Doers;T. Kunicki
我们使用了两种鼠单克隆抗体，每种都针对人血小板膜糖蛋白 (GP) IIb-IIIa 复合物的一种成分，以进一步检查纤维蛋白原与血小板表面结合以及随后的血小板-血小板凝聚（聚集）的分子要求。虽然针对 GPIIIa 的 AP3 和针对 GPIIb 的 Tab 特异性均不能单独抑制二磷酸腺苷 (ADP) 诱导的纤维蛋白原结合、血小板聚集或分泌，但 AP3 和 Tab 的组合完全消除了血小板聚集和释放反应。出乎意料的是，这种对血小板-血小板凝聚力的协同抑制发生在明显正常的纤维蛋白原结合存在的情况下。在这两种抗体存在的情况下，结合的纤维蛋白原分子的数量和纤维蛋白原结合的解离常数基本上保持不变。聚集的抑制取决于 AP3 和 Tab 的二价性，因为用任一抗体的 Fab 片段替换完整的 IgG 都会导致聚集和分泌的完全恢复。与 ADP 诱导相反，在 AP3 加 Tab 存在的情况下，凝血酶激活的血小板既不聚集也不结合纤维蛋白原，而是完全能够分泌，这说明了血小板表面可以对不同激动剂做出反应的多种机制。这些数据表明，纤维蛋白原单独与血小板表面结合不足以支持血小板-血小板凝聚，并且可能需要可被这两种单克隆抗体抑制的额外纤维蛋白原结合后事件。
We have used two murine monoclonal antibodies, each directed against one component of the human platelet membrane glycoprotein (GP) IIb-IIIa complex, to examine further the molecular requirements for fibrinogen binding to the platelet surface and subsequent platelet-platelet cohesion (aggregation). Although neither AP3, which is directed against GPIIIa, nor Tab, which is specific for GPIIb, were individually able to inhibit adenosine diphosphate (ADP)-induced fibrinogen binding, platelet aggregation, or secretion, the combination of AP3 and Tab completely abolished platelet aggregation and the release reaction. Unexpectedly, this synergistic inhibition of platelet-platelet cohesion occurred in the presence of apparently normal fibrinogen binding. Both the number of fibrinogen molecules bound and the dissociation constant for fibrinogen binding remained essentially unchanged in the presence of these two antibodies. Inhibition of aggregation was dependent upon the divalency of both AP3 and Tab because substitution of Fab fragments of either antibody for the intact IgG resulted in a complete restoration of both aggregation and secretion. In contrast to ADP induction, thrombin-activated platelets neither aggregated nor bound fibrinogen in the presence of AP3 plus Tab but were fully capable of secretion, which illustrated the multiple mechanisms by which the platelet surface can respond to different agonists. These data demonstrate that fibrinogen binding to the platelet surface alone is not sufficient to support platelet-platelet cohesion and that an additional post-fibrinogen-binding event(s) that is inhibitable by these two monoclonal antibodies may be required.