Sandrin Gauer, J orcid.org/0000-0002-0835-639X, Duval, C orcid.org/0000-0002-4870-6542, Xu, RG orcid.org/0000-0003-0774-112X et al. (6 more authors) (2023) Fibrin-glycoprotein VI interaction increases platelet procoagulant activity and impacts clot structure. Journal of Thrombosis and Haemostasis, 21 (3). pp. 667-681. ISSN 1538-7933
Abstract
Background
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.
Objectives
To determine the effect of GPVI-fibrin interaction on the platelet phenotype and its impact on the clot structure.
Methods
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.
Results
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.
Conclusion
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | clot structure; fibrin; GPVI; procoagulant platelets; tyrosine kinase inhibitors |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Synthetic Biology (Leed) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 204951/B/16/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 05 Oct 2022 11:53 |
Last Modified: | 26 Jun 2023 16:10 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jtha.2022.09.004 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:191635 |
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