Summary
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 α-granules of washed
platelets which was associated with a reduced degranulation of the α-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.
Keywords Platelets - GPIIb-IIIa - abciximab - internal pool - GPIIb-IIIa inhibitors
