Function of Glycoprotein VI and Integrin α2β1 in the Procoagulant Response of Single, Collagen-Adherent Platelets

Johan W. M. Heemskerk; Pia Siljander; Wim M. J. Vuist; Githa Breikers; Chris P. M. Reutelingsperger; Michael J. Barnes; C. Graham Knight; Riitta Lassila; Richard W. Farndale

doi:10.1055/s-0037-1614571

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1999; 81(05): 782-792
DOI: 10.1055/s-0037-1614571

Rapid Communication

Schattauer GmbH

Function of Glycoprotein VI and Integrin α₂β₁ in the Procoagulant Response of Single, Collagen-Adherent Platelets

Johan W. M. Heemskerk

¹From the Departments of Biochemistry and Human Biology, University of Maastricht, Maastricht, The Netherlands; the

,

Pia Siljander

²Wihuri Research Institute, Helsinki, Finland; University of Cambridge, Cambridge, United Kingdom

,

Wim M. J. Vuist

¹From the Departments of Biochemistry and Human Biology, University of Maastricht, Maastricht, The Netherlands; the

,

Githa Breikers

¹From the Departments of Biochemistry and Human Biology, University of Maastricht, Maastricht, The Netherlands; the

,

Chris P. M. Reutelingsperger

¹From the Departments of Biochemistry and Human Biology, University of Maastricht, Maastricht, The Netherlands; the

,

Michael J. Barnes

³Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

,

C. Graham Knight

³Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

,

Riitta Lassila

²Wihuri Research Institute, Helsinki, Finland; University of Cambridge, Cambridge, United Kingdom

,

Richard W. Farndale

³Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

› Institutsangaben

Abstract

Summary

Various collagen-based materials were used to assess the structural requirements of collagen for inducing the procoagulant response of adhering platelets, as well as the collagen receptors involved. Cross-linked or monomeric collagen-related peptide (CRP), Gly-Cys-Hyp-(Gly-Pro-Hyp)₁₀-Gly-Cys-Hyp-Gly was highly adhesive for platelets in a glycoprotein VI- (GpVI-)dependent manner. Adhesion was followed by a prolonged increase in cytosolic [Ca²⁺]_i, formation of membrane blebs, exposure of phosphatidylserine (PS) and generation of prothrombinase-stimulating activity. Fibrils of type-I collagen were less adhesive but, once adhered, many of the platelets presented a full procoagulant response. Monomeric type-I collagen was unable to support adhesion, unless Mg²⁺-dependent integrin α₂β₁ interactions were facilitated by omission of Ca²⁺ ions. With all surfaces, however, post-addition of CaCl₂ to adhering platelets resulted in a potent Ca²⁺-influx signal, followed by PS exposure and bleb formation. The procoagulant response elicited by binding to CRP was inhibited by anti-GpVI Fab fragments, but not by impeding integrin α₂β₁-mediated events. With fibrillar collagen, it was inhibited by blocking either the GpVI- or integrin α₂β_1- mediated interactions. This suggests that the triple-helical Gly-Pro-Hyp repeat in CRP and analogous sequences in fibrillar collagen stimulate the procoagulant response of adherent platelets by acting as ligands for GpVI. Influx of Ca²⁺ is required for this response, and adhesion via integrin α₂β₁ serves to potentiate the signaling effects of GpVI.

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