Konstantopoulos K, Kamat S G, Schafer A I, Bañez E I, Jordan R, Kleiman N S, Hellums J D
Cox Laboratory for Biomedical Engineering, Rice University, Houston, Tex 77251-1892.
Circulation. 1995 Mar 1;91(5):1427-31. doi: 10.1161/01.cir.91.5.1427.
Elevated levels of shear stress such as those that occur in stenotic arterial vessels can directly activate and aggregate platelets and thus contribute to the pathogenesis of acute arterial thrombosis. This shear-induced platelet aggregation (SIPA) is mediated by von Willebrand factor binding to platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa. The chimeric Fab fragment of the monoclonal antibody 7E3 (c7E3 Fab) that binds selectively to GPIIb/IIIa is under clinical evaluation in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). This study was undertaken to investigate the effects on ex vivo SIPA of c7E3 Fab administered to patients undergoing PTCA.
Six patients received aspirin (325 mg) and boluses of heparin (12,00o U) followed by c7E3 Fab 0.25 mg/kg. Blood collected from each patient before and after heparin treatment and at various time points after c7E3 Fab administration was subjected to laminar shear stress in a cone-and-plate viscometer. Flow cytometry was used to quantify the extents of platelet aggregation and of antibody binding to GPIIb/IIIa. Results indicate that c7E3 Fab injection resulted in a rapid, extensive blockade of GPIIb/IIIa receptors (98.6 +/- 0.2%) and a 50% inhibition of ex vivo platelet aggregation induced by shear stress. c7E3 Fab also completely abolished the formation of large platelet aggregates ("large" refers to particles > 10 microns in equivalent sphere diameter), which are presumably the aggregates of greatest clinical significance. Partial reversibility of the inhibition was noted within 2 days after drug administration, but even after 1 week, platelet function had not been fully restored.
This study demonstrates that c7E3 Fab is a potent inhibitor of SIPA, which may be an important mechanism of its beneficial effect in the treatment of arterial occlusive diseases and in the prevention of thrombotic complications of coronary artery disease after angioplasty.
诸如在狭窄动脉血管中出现的高水平剪切应力可直接激活并聚集血小板，从而促使急性动脉血栓形成。这种剪切诱导的血小板聚集（SIPA）是由血管性血友病因子与血小板膜糖蛋白（GP）Ib和GPIIb/IIIa结合介导的。选择性结合GPIIb/IIIa的单克隆抗体7E3的嵌合Fab片段（c7E3 Fab）正在接受经皮腔内冠状动脉成形术（PTCA）患者的临床评估。本研究旨在调查给予接受PTCA患者c7E3 Fab对体外SIPA的影响。
6例患者接受阿司匹林（325 mg）和大剂量肝素（12000 U），随后给予0.25 mg/kg的c7E3 Fab。在肝素治疗前后以及给予c7E3 Fab后的不同时间点采集每位患者的血液，在锥板粘度计中施加层流剪切应力。流式细胞术用于量化血小板聚集程度以及抗体与GPIIb/IIIa的结合程度。结果表明，注射c7E3 Fab导致GPIIb/IIIa受体迅速、广泛被阻断（98.6±0.2%），并使体外剪切应力诱导的血小板聚集受到50%的抑制。c7E3 Fab还完全消除了大血小板聚集体的形成（“大”指等效球体直径>10微米的颗粒），这些聚集体可能具有最大的临床意义。给药后2天内观察到抑制作用有部分可逆性，但即使在1周后，血小板功能仍未完全恢复。
本研究表明c7E3 Fab是SIPA的有效抑制剂，这可能是其在治疗动脉闭塞性疾病以及预防血管成形术后冠状动脉疾病血栓并发症中发挥有益作用的重要机制。
