Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis

  1. Helen McPherson
  2. Cedric Duval
  3. Stephen R Baker
  4. Matthew S Hindle
  5. Lih T Cheah
  6. Nathan L Asquith
  7. Marco M Domingues
  8. Victoria C Ridger
  9. Simon DA Connell
  10. Khalid Naseem
  11. Helen Philippou
  12. Ramzi A Ajjan
  13. Robert Ariens  Is a corresponding author
  1. University of Leeds, United Kingdom
  2. Wake Forest University, United States
  3. Harvard Medical School, United States
  4. Universidade de Lisboa, Portugal
  5. University of Sheffield, United Kingdom
  6. University of Leeds, United States

Abstract

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short, stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.

Data availability

The source data for Figures 1 B-F, figure 2 B and D, figure 3 B, figure 4, figure 5 B, C and D and figure 6 A-C and D-F and supplementary Figures 1 supplement 1, figures 4 supplement 1 and figures 5 supplement 1 and 2 and figures 6 supplement 1 are made available as separate source data files.

Article and author information

Author details

  1. Helen McPherson

    Discovery and Translational Science Department, Leeds Institute of Cariovasular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3519-498X
  2. Cedric Duval

    Discovery and Translational Science Department, Leeds Institute of Cariovasular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Stephen R Baker

    Department of Physics, Wake Forest University, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3147-4925
  4. Matthew S Hindle

    Discovery and Translational Science Department, Leeds Institute of Cariovasular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Lih T Cheah

    Discovery and Translational Science Department, Leeds Institute of Cariovasular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Nathan L Asquith

    Division of Hematology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Marco M Domingues

    Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
    Competing interests
    The authors declare that no competing interests exist.
  8. Victoria C Ridger

    Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Simon DA Connell

    Molecular and Nanoscale Physics Group, University of Leeds, Leeds, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Khalid Naseem

    Discovery and Translational Science Department, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Helen Philippou

    Discovery and Translational Science Department, Leeds Institute of Cariovasular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Ramzi A Ajjan

    Discovery and Translational Science Department, Leeds Institute of Cariovasular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1636-3725
  13. Robert Ariens

    Discovery anTranslational Science Department, University of Leeds, Leeds, United Kingdom
    For correspondence
    R.A.S.Ariens@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6310-5745

Funding

British Heart Foundation (RG/13/3/30104)

  • Helen McPherson
  • Cedric Duval
  • Stephen R Baker
  • Marco M Domingues
  • Victoria C Ridger
  • Simon DA Connell
  • Helen Philippou
  • Ramzi A Ajjan
  • Robert Ariens

British Heart Foundation (RG/18/11/34036)

  • Helen McPherson
  • Cedric Duval
  • Stephen R Baker
  • Victoria C Ridger
  • Simon DA Connell
  • Helen Philippou
  • Ramzi A Ajjan
  • Robert Ariens

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jameel Iqbal, Icahn School of Medicine at Mount Sinai, United States

Ethics

Animal experimentation: Procedures were performed according to accepted standards of humane animal care, approved by the ethical review committee at the University of Leeds, and conducted under license (P144DD0D6) from the United Kingdom Home Office.

Version history

  1. Received: March 24, 2021
  2. Preprint posted: May 8, 2021 (view preprint)
  3. Accepted: October 4, 2021
  4. Accepted Manuscript published: October 11, 2021 (version 1)
  5. Accepted Manuscript updated: October 15, 2021 (version 2)
  6. Version of Record published: October 28, 2021 (version 3)
  7. Version of Record updated: January 7, 2022 (version 4)

Copyright

© 2021, McPherson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Helen McPherson
  2. Cedric Duval
  3. Stephen R Baker
  4. Matthew S Hindle
  5. Lih T Cheah
  6. Nathan L Asquith
  7. Marco M Domingues
  8. Victoria C Ridger
  9. Simon DA Connell
  10. Khalid Naseem
  11. Helen Philippou
  12. Ramzi A Ajjan
  13. Robert Ariens
(2021)
Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis
eLife 10:e68761.
https://doi.org/10.7554/eLife.68761

Share this article

https://doi.org/10.7554/eLife.68761

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