Fibrin-glycoprotein VI interaction increases platelet procoagulant activity and impacts clot structure

Julia Gauer, Cedric Duval, Rui-Gang Xu, Fraser L Macrae, Helen McPherson, Christian Tiede, Darren Tomlinson, Steve Watson, Robert A. S. Ariëns*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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The glycoprotein VI (GPVI) signaling pathway was previously reported to direct procoagulant platelet activity through collagen binding. However, the impact of GPVI-fibrin interaction on procoagulant platelet development and how it modulates the clot structure are unknown.

To determine the effect of GPVI-fibrin interaction on the platelet phenotype and its impact on the clot structure.

Procoagulant platelets in platelet-rich plasma clots were determined by scanning electron microscopy (wild-type and GPVI-deficient murine samples) and confocal microscopy. Procoagulant platelet number, clot density, clot porosity, and clot retraction were determined in platelet-rich plasma or whole blood clots of healthy volunteers in the presence of tyrosine kinase inhibitors (PRT-060318, ibrutinib, and dasatinib) and eptifibatide.

GPVI-deficient clots showed a higher nonprocoagulant vs procoagulant platelet ratio than wild-type clots. The fiber density and the procoagulant platelet number decreased in the presence of Affimer proteins, inhibiting GPVI-fibrin(ogen) interaction and the tyrosine kinase inhibitors. The effect of GPVI signaling inhibitors on the procoagulant platelet number was exacerbated by eptifibatide. The tyrosine kinase inhibitors led to an increase in clot porosity; however, no differences were observed in the final clot weight, following clot retraction with the tyrosine kinase inhibitors, except for ibrutinib. In the presence of eptifibatide, clot retraction was impaired.

Our findings showed that GPVI-fibrin interaction significantly contributes to the development of procoagulant platelets and that inhibition of GPVI signaling increases clot porosity. Clot contractibility was impaired by the integrin αIIbβ3 and Btk pathway inhibition. Thus, inhibition of GPVI-fibrin interactions can alleviate structural characteristics that contribute to a prothrombotic clot phenotype, having potential important implications for novel antithrombotic interventions.
Original languageEnglish
Pages (from-to)667-681
Number of pages15
JournalJournal of Thrombosis and Haemostasis
Issue number3
Early online date22 Dec 2022
Publication statusPublished - 28 Feb 2023


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