Incomplete inhibition of platelet aggregation and glycoprotein IIb-IIIa receptor blockade by abciximab: Importance of internal pool of glycoprotein IIb-IIIa receptors

Resting platelets contain a substantial internal pool of GPIIb-IIIa complex es that is exposed on the surface of activated platelets. Whether the expos ure of internal GPIIb-IIIa complexes on the activated platelet surface affe cts therapy with GPIIb-IIIa antagonists is poorly understood. We addressed this issue in thirteen patients who underwent elective coronary stenting an d received abciximab. Platelet aggregation, surface expression of GPIIb-III a and P-selectin, receptor blockade of GPIIb-IIIa, and platelet release in response to ADP and thrombin-receptor activating peptide (TRAP) were determ ined ex vivo by Lumi-aggregometly and flow cytometry before, during and aft er abciximab administration. We found that inhibition of aggregation and GP IIb-IIIa blockade of ADP-stimulated platelets was almost complete during ab ciximab administration. rn contrast, when TRAP was used to stimulate platel ets ex vivo aggregation was only partially inhibited, most likely due to re lease of internal pool of unblocked GPIIb-IIIa complexes. Using electron mi croscopy we found that 7E3-occupied GPIIb-IIIa connplexes are internalized into the surface connected system (ISCS) and the alpha-granules of washed p latelets which was associated with;I reduced degranulation of the alpha-gra nula membrane protein P-selectin. We conclude, that despite internalization of abciximab into the internal pool of GPIIb-IIIa, upon strong platelet ac tivation with thrombin a significant amount of unblocked internal GPIIb-III a can be exposed on the platelet surface and mediate platelet aggregation. Incomplete blockade of the internal GPIIb-IIIa pool may limit clinical effi cacy of abciximab.