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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1622-1633
Labeling of the Internal Pool of GP IIb-IIIa in Platelets by c7E3
Fab Fragments (abciximab): Flow and Endocytic Mechanisms
Contribute to the Transport
Paquita Nurden,
Christel Poujol,
Catherine Durrieu-Jais,
Joëlle Winckler,
Robert Combrié,
Laurent Macchi,
Claude Bihour,
Carrie Wagner,
Robert Jordan, and
Alan T. Nurden
From UMR 5533 CNRS, IFR Coeur-Vaisseaux-Thrombose and Unité des
Soins Intensifs, Hôpital Cardiologique, Pessac, France; and
Centocor, Malvern, PA.
Abciximab is a new antiplatelet therapeutic in ischemic
cardiovascular disease. The drug, chimeric Fab fragments of a murine monoclonal antibody (MoAb) (c7E3), blocks GP IIb-IIIa function. However, its capacity to reach all receptor pools in platelets is
unknown. Electron microscopy and immunogold labeling were used to
localize abciximab in platelets of patients receiving the drug for up
to 24 hours. Studies on frozen-thin sections showed that c7E3 Fab, in
addition to the surface pool, also labeled the surface-connected canalicular system (SCCS) and  -granules. Analysis of gold particle distribution showed that intraplatelet labeling was not accumulative and in equilibrium with the surface pool. After short-term incubations of platelets with c7E3 Fab in vitro, gold particles were often seen in
lines within thin elements of the SCCS, some of which appeared in
contact with -granules. Little labeling was associated with
Glanzmann's thrombasthenia platelets, confirming that the channels
contained bound and not free c7E3 Fab. Endocytosis of abciximab in
clathrin-containing vesicles was visualized by double staining and
constitutes an alternative mechanism of transport. The remaining free
pool of GP IIb-IIIa was evaluated with the MoAb AP-2; flow cytometry
showed it to be about 9% on the surface of nonstimulated platelets but
33% on thrombin-activated platelets. The ability of drugs to block all
pools of GP IIb-IIIa and then to be associated with secretion-dependent
residual aggregation must be considered when evaluating their
efficiency in a clinical context.
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