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Monoclonal antibodies bound to subunits of the integrin GPIIb-IIIa are
internalized and interfere with filopodia formation and platelet
aggregation
WM Isenberg, DF Bainton and PJ Newman
Department of Pathology, University of California, San Francisco 94143-
0506.
The monoclonal antibodies Tab and AP3 are directed, respectively, against
GPIIb and GPIIIa, the subunits of the platelet fibrinogen receptor. When
added together to platelets, these antibodies prevent adenosine diphosphate
(ADP)-induced platelet aggregation, despite normal fibrinogen binding
(Newman et al, Blood 69:668, 1987). To explore the cellular requirements of
aggregation after fibrinogen binding, we used several techniques to study
platelets treated with Tab and AP3, then stimulated with ADP. We used
scanning and transmission electron microscopy to evaluate platelet
morphology, immunolabel- surface replication to determine whether
individual GPIIb-IIIa complexes clustered, immunocytochemistry on frozen
thin sections to study the subcellular distribution of the integrin
GPIIb-IIIa and fibrinogen, and biochemical methods to assess the activation
of the platelet cytoskeleton. We found that the treated cells had short,
blunted projections instead of normal filopodia. Other morphologic
abnormalities, apparent in thin section, were aberrantly placed alpha-
granules and microtubules, and a prominent, worm-like, fibrinogen- filled
surface-connected canalicular system. Biochemical analysis suggested that
such platelets undergo massive actomyosin-controlled membrane flow, which
serves to sequester GPIIb-IIIa and makes the platelets refractory to
aggregation. We conclude that aggregation requires the formation of long,
slender filopodia, probably directed by cytoskeletal rearrangements after
activation, and that the transmembrane GPIIb-IIIa complex may play a role
in signaling these events.
Volume 76,
Issue 8,
pp. 1564-1571,
10/15/1990
Copyright © 1990 by The American Society of Hematology
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