Platelet-Fibrinogen Interactions



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    1. Hematology-Oncology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Address for correspondence: Joel S. Bennett, M.D., Room 914, BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA. Voice: 215-573-3280; fax: 215-573-7039;


Abstract: Binding of fibrinogen to GPIIb-IIIa on agonist-stimulated platelets results in platelet aggregation, presumably by crosslinking adjacent activated platelets. Although unactivated platelets express numerous copies of GPIIb-IIIa on their surface, spontaneous, and potentially deleterious, platelet aggregation is prevented by tightly regulating the fibrinogen binding activity of GPIIb-IIIa. Preliminary evidence suggests that it is the submembranous actin or actin-associated proteins that constrains GPIIb-IIIa in a low affinity state and that relief of this constraint by initiating actin filament turnover enables GPIIb-IIIa to bind fibrinogen. Two regions of the fibrinogen α chain that contain an RGD motif, as well as the carboxyl-terminus of the fibrinogen γ chain, represent potential binding sites for GPIIb-IIIa in the fibrinogen molecule. However, ultrastructural studies using purified fibrinogen and GPIIb-IIIa, and studies using recombinant fibrinogen in which the RGD and relevant γ chain motifs were mutated indicate that sequences located at the carboxyl-terminal end of the γ chain mediates fibrinogen binding to GPIIb-IIIa. There is evidence that fibrinogen itself binds to regions in the amino terminal portions of both GPIIb and GPIIIa and that the sites interacting with the fibrinogen γ chain and with RGD-containing peptides are spatially distinct. Nonetheless, there appears to be allosteric linkage between these sites, accounting for the ability of RGD-containing peptides to inhibit platelet aggregation and arterial thrombosis.