Immobilized fibrinogen activates human platelets through glycoprotein VI

Pierre H Mangin; Marie Blanche Onselaer; Nicolas Receveur; Nicolas Le Lay; Alexander Hardy; Clare Wilson; Ximena Sanchez; Stephane  Loyau; Arnaud Dupuis; Amir K. Babar; Jeanette L C Miller; Helen Philippou; Craig Hughes; Andrew B Herr; Robert A. S. Ariëns; Diego Mezzano; Martine Jandrot-Perrus; Christian Gachet; Steve Watson

doi:10.3324/haematol.2017.182972

Immobilized fibrinogen activates human platelets through glycoprotein VI

Pierre H Mangin, Marie Blanche Onselaer, Nicolas Receveur, Nicolas Le Lay, Alexander Hardy, Clare Wilson, Ximena Sanchez, Stephane Loyau, Arnaud Dupuis, Amir K. Babar, Jeanette L C Miller, Helen Philippou, Craig Hughes, Andrew B Herr, Robert A. S. Ariëns, Diego Mezzano, Martine Jandrot-Perrus, Christian Gachet, Steve Watson

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Abstract

GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI is a receptor for fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinogen activates GPVI. While mouse platelets fail to spread on fibrinogen, human-GPVI-transgenic mouse platelets show full spreading and increased Ca²⁺ signalling through the tyrosine kinase Syk. Direct binding of fibrinogen to human GPVI was shown by surface plasmon resonance and by increased adhesion of human GPVI-transfected Rbl-2H3 cells to fibrinogen relative to mock-transfected cells. Blockade of human GPVI with Fab 9O12 impairs platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human GPVI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow.

Original language	English
Pages (from-to)	898-907
Number of pages	10
Journal	Haematologica
Volume	103
Issue number	5
Early online date	22 Feb 2018
DOIs	https://doi.org/10.3324/haematol.2017.182972
Publication status	Published - May 2018

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10.3324/haematol.2017.182972Licence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

ManginP2018Immobilized
Pierre H Mangin, Marie-Blanche Onselaer, Nicolas Receveur, Nicolas Le Lay, Alexander T Hardy, Clare Wilson, Ximena Sanchez, Stéphane Loyau, Arnaud Dupuis, Amir K Babar, Jeanette LC Miller, Helen Philippou, Craig E Hughes, Andrew B Herr, Robert AS Ariëns, Diego Mezzano, Martine Jandrot-Perrus, Christian Gachet, Steve P. Watson, Immobilized fibrinogen activates human platelets through glycoprotein VI, Haematologica May 2018 103: 898-907; doi:10.3324/haematol.2017.182972. Copyright © 2018 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation.
Final published version, 1.3 MBLicence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

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Mangin, P. H., Onselaer, M. B., Receveur, N., Le Lay, N., Hardy, A., Wilson, C., Sanchez, X., Loyau, S., Dupuis, A., Babar, A. K., Miller, J. L. C., Philippou, H., Hughes, C., Herr, A. B., Ariëns, R. A. S., Mezzano, D., Jandrot-Perrus, M., Gachet, C., & Watson, S. (2018). Immobilized fibrinogen activates human platelets through glycoprotein VI. Haematologica, 103(5), 898-907. Advance online publication. https://doi.org/10.3324/haematol.2017.182972

@article{b1e7d52a572c470897afb7aac7e25454,

title = "Immobilized fibrinogen activates human platelets through glycoprotein VI",

abstract = "GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI is a receptor for fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinogen activates GPVI. While mouse platelets fail to spread on fibrinogen, human-GPVI-transgenic mouse platelets show full spreading and increased Ca2+ signalling through the tyrosine kinase Syk. Direct binding of fibrinogen to human GPVI was shown by surface plasmon resonance and by increased adhesion of human GPVI-transfected Rbl-2H3 cells to fibrinogen relative to mock-transfected cells. Blockade of human GPVI with Fab 9O12 impairs platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human GPVI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow.",

author = "Mangin, {Pierre H} and Onselaer, {Marie Blanche} and Nicolas Receveur and {Le Lay}, Nicolas and Alexander Hardy and Clare Wilson and Ximena Sanchez and Stephane Loyau and Arnaud Dupuis and Babar, {Amir K.} and Miller, {Jeanette L C} and Helen Philippou and Craig Hughes and Herr, {Andrew B} and Ari{\"e}ns, {Robert A. S.} and Diego Mezzano and Martine Jandrot-Perrus and Christian Gachet and Steve Watson",

year = "2018",

month = may,

doi = "10.3324/haematol.2017.182972",

language = "English",

volume = "103",

pages = "898--907",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "5",

}

Mangin, PH, Onselaer, MB, Receveur, N, Le Lay, N, Hardy, A, Wilson, C, Sanchez, X, Loyau, S, Dupuis, A, Babar, AK, Miller, JLC, Philippou, H, Hughes, C, Herr, AB, Ariëns, RAS, Mezzano, D, Jandrot-Perrus, M, Gachet, C & Watson, S 2018, 'Immobilized fibrinogen activates human platelets through glycoprotein VI', Haematologica, vol. 103, no. 5, pp. 898-907. https://doi.org/10.3324/haematol.2017.182972

TY - JOUR

T1 - Immobilized fibrinogen activates human platelets through glycoprotein VI

AU - Mangin, Pierre H

AU - Onselaer, Marie Blanche

AU - Receveur, Nicolas

AU - Le Lay, Nicolas

AU - Hardy, Alexander

AU - Wilson, Clare

AU - Sanchez, Ximena

AU - Loyau, Stephane

AU - Dupuis, Arnaud

AU - Babar, Amir K.

AU - Miller, Jeanette L C

AU - Philippou, Helen

AU - Hughes, Craig

AU - Herr, Andrew B

AU - Ariëns, Robert A. S.

AU - Mezzano, Diego

AU - Jandrot-Perrus, Martine

AU - Gachet, Christian

AU - Watson, Steve

PY - 2018/5

Y1 - 2018/5

N2 - GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI is a receptor for fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinogen activates GPVI. While mouse platelets fail to spread on fibrinogen, human-GPVI-transgenic mouse platelets show full spreading and increased Ca2+ signalling through the tyrosine kinase Syk. Direct binding of fibrinogen to human GPVI was shown by surface plasmon resonance and by increased adhesion of human GPVI-transfected Rbl-2H3 cells to fibrinogen relative to mock-transfected cells. Blockade of human GPVI with Fab 9O12 impairs platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human GPVI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow.

AB - GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI is a receptor for fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinogen activates GPVI. While mouse platelets fail to spread on fibrinogen, human-GPVI-transgenic mouse platelets show full spreading and increased Ca2+ signalling through the tyrosine kinase Syk. Direct binding of fibrinogen to human GPVI was shown by surface plasmon resonance and by increased adhesion of human GPVI-transfected Rbl-2H3 cells to fibrinogen relative to mock-transfected cells. Blockade of human GPVI with Fab 9O12 impairs platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human GPVI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow.

U2 - 10.3324/haematol.2017.182972

DO - 10.3324/haematol.2017.182972

M3 - Article

SN - 0390-6078

VL - 103

SP - 898

EP - 907

JO - Haematologica

JF - Haematologica

IS - 5

ER -

Immobilized fibrinogen activates human platelets through glycoprotein VI

Abstract

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