Abulencia J P, Tien N, McCarty O J, Plymire D, Mousa S A, Konstantopoulos K
Department of Chemical Engineering, Johns Hopkins University, Baltimore, Md, USA.
Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):149-56. doi: 10.1161/01.atv.21.1.149.
Glycoprotein (GP) IIb/IIIa is pivotal in homotypic platelet aggregation and may also be involved in the heterotypic adhesion of leukocytes and tumor cells to platelets. This study was primarily undertaken to compare the antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist, XV454, to that of abciximab in 2 flow models of platelet thrombus formation: (1) direct shear-induced platelet aggregation imposed by a cone-and-plate rheometer and (2) platelet adhesion onto von Willebrand factor (vWF)/collagen I followed by aggregation in a perfusion system. XV454 inhibited platelet aggregation in a concentration-dependent manner in both experimental models. Maximal inhibition of aggregation was achieved by XV454 at approximately 70% receptor occupancy, which is lower than the >/=85% previously reported for abciximab. At similar levels of receptor blockade (approximately 45%), XV454 appeared to be relatively more effective than abciximab in suppressing platelet aggregation. Neither XV454 nor abciximab inhibited platelet adhesion to collagen. Pretreatment of surface-adherent platelets with either XV454 or abciximab inhibited the attachment of monocytic THP-1 cells under flow. In contrast, the rapidly reversible GPIIb/IIIa inhibitor orbofiban failed to suppress these heterotypic interactions. These findings demonstrate that XV454 is a potent GPIIb/IIIa antagonist with a long receptor-bound lifetime like abciximab and may be beneficial for the treatment/prevention of thrombotic complications.
糖蛋白（GP）IIb/IIIa在血小板同型聚集过程中起关键作用，也可能参与白细胞和肿瘤细胞与血小板的异型黏附。本研究主要比较新型非肽类GPIIb/IIIa拮抗剂XV454与阿昔单抗在两种血小板血栓形成流动模型中的抗血小板疗效：（1）由锥板流变仪施加的直接剪切诱导的血小板聚集，以及（2）血小板黏附于血管性血友病因子（vWF）/I型胶原后在灌注系统中发生的聚集。在两个实验模型中，XV454均以浓度依赖方式抑制血小板聚集。XV454在受体占有率约为70%时实现了对聚集的最大抑制，这低于先前报道的阿昔单抗的≥85%。在相似的受体阻断水平（约45%）下，XV454在抑制血小板聚集方面似乎比阿昔单抗相对更有效。XV454和阿昔单抗均未抑制血小板与胶原的黏附。用XV454或阿昔单抗对表面黏附的血小板进行预处理可抑制流动状态下单核细胞THP-1细胞的附着。相比之下，快速可逆的GPIIb/IIIa抑制剂奥扎格雷未能抑制这些异型相互作用。这些发现表明，XV454是一种强效的GPIIb/IIIa拮抗剂，与阿昔单抗一样具有较长的受体结合寿命，可能对血栓形成并发症的治疗/预防有益。
