Wittig K, Rothe G, Schmitz G
Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany.
Thromb Haemost. 1998 Mar;79(3):625-30.
Conformational activation of platelet GpIIb/IIIa which is coupled to increased affinity for binding of soluble fibrinogen is an important step in platelet aggregation. Antibodies, peptides, and small molecules which antagonise fibrinogen binding, therefore, have been developed as a new class of potent anti-aggregatory compounds. The binding of these artificial ligands, however, similar to fibrinogen binding may also stimulate platelet adhesion and degranulation. Therefore, in this study effects of MK-852, a cyclic hexapeptide based on the RGD-template, on the platelet phenotype were analysed by whole blood flow cytometry. MK-852 already in the nanomolar range completely inhibited the surface binding of fibrinogen to ADP or TRAP-6 stimulated platelets. In the micromolar range, MK-852 induced an up to four-fold increase of GpIIb/IIIa surface expression in the absence of increased P-selectin expression. In conclusion our results suggest that the selective surface recruitment of GpIIb/IIIa may be a side effect of exposure to RGD-analogues which occurs at concentrations well above inhibition of fibrinogen binding.
血小板糖蛋白IIb/IIIa的构象激活与可溶性纤维蛋白原结合亲和力增加相关联，这是血小板聚集的重要步骤。因此，已开发出拮抗纤维蛋白原结合的抗体、肽和小分子作为一类新型强效抗聚集化合物。然而，这些人工配体的结合，与纤维蛋白原结合类似，也可能刺激血小板黏附和脱颗粒。因此，在本研究中，通过全血流式细胞术分析了基于RGD模板的环六肽MK-852对血小板表型的影响。纳摩尔范围内的MK-852就完全抑制了纤维蛋白原与ADP或TRAP-6刺激的血小板的表面结合。在微摩尔范围内，MK-852在未增加P-选择素表达的情况下使GpIIb/IIIa表面表达增加高达四倍。总之，我们的结果表明，GpIIb/IIIa的选择性表面募集可能是暴露于RGD类似物的副作用，这种副作用发生在远高于抑制纤维蛋白原结合的浓度下。
