Gawaz M, Ruf A, Pogatsa-Murray G, Dickfeld T, Rüdiger S, Taubitz W, Fischer J, Müller I, Meier D, Patscheke H, Schömig A
Medizinische Klinik Klinikum rechts der Isar und Deutsches Herzzentrum, Technische Universität München, Germany.
Thromb Haemost. 2000 Jun;83(6):915-22.
Resting platelets contain a substantial internal pool of GPIIb-IIIa complexes that is exposed on the surface of activated platelets. Whether the exposure of internal GPIIb-IIIa complexes on the activated platelet surface affects therapy with GPIIb-IIIa antagonists is poorly understood. We addressed this issue in thirteen patients who underwent elective coronary stenting and received abciximab. Platelet aggregation, surface expression of GPIIb-IIIa and P-selectin, receptor blockade of GPIIb-IIIa, and platelet release in response to ADP and thrombin-receptor activating peptide (TRAP) were determined ex vivo by Lumi-aggregometry and flow cytometry before, during and after abciximab administration. We found that inhibition of aggregation and GPIIb-IIIa blockade of ADP-stimulated platelets was almost complete during abciximab administration. In contrast, when TRAP was used to stimulate platelets ex vivo aggregation was only partially inhibited, most likely due to release of internal pool of unblocked GPIIb-IIIa complexes. Using electron microscopy we found that 7E3-occupied GPIIb-IIIa complexes are internalized into the surface connected system (SCS) and the alpha-granules of washed platelets which was associated with a reduced degranulation of the alpha-granula membrane protein P-selectin. We conclude, that despite internalization of abciximab into the internal pool of GPIIb-IIIa, upon strong platelet activation with thrombin a significant amount of unblocked internal GPIIb-IIIa can be exposed on the platelet surface and mediate platelet aggregation. Incomplete blockade of the internal GPIIb-IIIa pool may limit clinical efficacy of abciximab.
静息血小板含有大量内部的糖蛋白IIb-IIIa复合物池，这些复合物在活化血小板表面暴露。活化血小板表面内部糖蛋白IIb-IIIa复合物的暴露是否会影响糖蛋白IIb-IIIa拮抗剂的治疗尚不清楚。我们在13例接受择期冠状动脉支架置入并接受阿昔单抗治疗的患者中解决了这个问题。在阿昔单抗给药前、给药期间和给药后，通过光聚集法和流式细胞术在体外测定血小板聚集、糖蛋白IIb-IIIa和P-选择素的表面表达、糖蛋白IIb-IIIa的受体阻断以及对ADP和凝血酶受体激活肽（TRAP）的血小板释放。我们发现，在阿昔单抗给药期间，ADP刺激的血小板聚集抑制和糖蛋白IIb-IIIa阻断几乎是完全的。相反，当使用TRAP在体外刺激血小板时，聚集仅被部分抑制，最可能的原因是未被阻断的糖蛋白IIb-IIIa复合物内部池的释放。通过电子显微镜我们发现，7E3占据的糖蛋白IIb-IIIa复合物被内化到洗涤血小板的表面连接系统（SCS）和α-颗粒中，这与α-颗粒膜蛋白P-选择素的脱颗粒减少有关。我们得出结论，尽管阿昔单抗内化到糖蛋白IIb-IIIa的内部池中，但在凝血酶强烈激活血小板时，大量未被阻断的内部糖蛋白IIb-IIIa可暴露于血小板表面并介导血小板聚集。内部糖蛋白IIb-IIIa池的不完全阻断可能会限制阿昔单抗的临床疗效。
