iScience (Mar 2022)
Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19
- Jun Wang,
- Prasanti Kotagiri,
- Paul A. Lyons,
- Rafia S. Al-Lamki,
- Federica Mescia,
- Laura Bergamaschi,
- Lorinda Turner,
- Michael D. Morgan,
- Fernando J. Calero-Nieto,
- Karsten Bach,
- Nicole Mende,
- Nicola K. Wilson,
- Emily R. Watts,
- Patrick H. Maxwell,
- Patrick F. Chinnery,
- Nathalie Kingston,
- Sofia Papadia,
- Kathleen E. Stirrups,
- Neil Walker,
- Ravindra K. Gupta,
- David K. Menon,
- Kieren Allinson,
- Sarah J. Aitken,
- Mark Toshner,
- Michael P. Weekes,
- James A. Nathan,
- Sarah R. Walmsley,
- Willem H. Ouwehand,
- Mary Kasanicki,
- Berthold Göttgens,
- John C. Marioni,
- Kenneth G.C. Smith,
- Jordan S. Pober,
- John R. Bradley
Affiliations
- Jun Wang
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK
- Prasanti Kotagiri
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Paul A. Lyons
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Rafia S. Al-Lamki
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
- Federica Mescia
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Laura Bergamaschi
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Lorinda Turner
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Michael D. Morgan
- Cancer Research UK –Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK; Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- Fernando J. Calero-Nieto
- Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0AW, UK
- Karsten Bach
- Cancer Research UK –Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK; Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK
- Nicole Mende
- Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0AW, UK
- Nicola K. Wilson
- Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0AW, UK
- Emily R. Watts
- Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
- Patrick H. Maxwell
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK
- Patrick F. Chinnery
- NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK
- Nathalie Kingston
- NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- Sofia Papadia
- NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- Kathleen E. Stirrups
- NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- Neil Walker
- NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- Ravindra K. Gupta
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- David K. Menon
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
- Kieren Allinson
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
- Sarah J. Aitken
- Cancer Research UK –Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK; Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK; Medical Research Council Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
- Mark Toshner
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Royal Papworth Hospital NHS Foundation Trust, Papworth Road, Cambridge CB2 0AY, UK
- Michael P. Weekes
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK
- James A. Nathan
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Sarah R. Walmsley
- Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
- Willem H. Ouwehand
- Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0AW, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK
- Mary Kasanicki
- Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
- Berthold Göttgens
- Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, Cambridgeshire CB2 0AW, UK
- John C. Marioni
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; Cancer Research UK –Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK; EMBL-EBI, Wellcome Genome Campus, Hinxton, CB10 1SD, UK
- Kenneth G.C. Smith
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Jordan S. Pober
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
- John R. Bradley
- Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Rd, Cambridge CB2 0QQ, UK; Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 3
p. 103971
Abstract
Summary: Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.
