S100A8/A9 drives the formation of procoagulant platelets through GPIbα

Martina Colicchia, Waltraud C. Schrottmaier, Gina Perrella, Jasmeet S. Reyat, Jenefa Begum, Alexandre Slater, Joshua Price, Joanne C. Clark, Zhaogong Zhi, Megan J. Simpson, Joshua H. Bourne, Natalie S. Poulter, Abdullah O. Khan, Phillip L.R. Nicolson, Matthew Pugh, Paul Harrison, Asif J. Iqbal, George E. Rainger, Steve P. Watson, Mark R. ThomasNicola J. Mutch, Alice Assinger, Julie Rayes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

S100A8/A9, also known as “calprotectin” or “MRP8/14,” is an alarmin primarily secreted by activated myeloid cells with antimicrobial, proinflammatory, and prothrombotic properties. Increased plasma levels of S100A8/A9 in thrombo-inflammatory diseases are associated with thrombotic complications. We assessed the presence of S100A8/A9 in the plasma and lung autopsies from patients with COVID-19 and investigated the molecular mechanism by which S100A8/A9 affects platelet function and thrombosis. S100A8/A9 plasma levels were increased in patients with COVID-19 and sustained high levels during hospitalization correlated with poor outcomes. Heterodimeric S100A8/A9 was mainly detected in neutrophils and deposited on the vessel wall in COVID-19 lung autopsies. Immobilization of S100A8/A9 with collagen accelerated the formation of a fibrin-rich network after perfusion of recalcified blood at venous shear. In vitro, platelets adhered and partially spread on S100A8/A9, leading to the formation of distinct populations of either P-selectin or phosphatidylserine (PS)-positive platelets. By using washed platelets, soluble S100A8/A9 induced PS exposure but failed to induce platelet aggregation, despite GPIIb/IIIa activation and alpha-granule secretion. We identified GPIbα as the receptor for S100A8/A9 on platelets inducing the formation of procoagulant platelets with a supporting role for CD36. The effect of S100A8/A9 on platelets was abolished by recombinant GPIbα ectodomain, platelets from a patient with Bernard-Soulier syndrome with GPIb-IX-V deficiency, and platelets from mice deficient in the extracellular domain of GPIbα. We identified the S100A8/A9-GPIbα axis as a novel targetable prothrombotic pathway inducing procoagulant platelets and fibrin formation, in particular in diseases associated with high levels of S100A8/A9, such as COVID-19.

Original languageEnglish
Pages (from-to)2626-2643
Number of pages18
JournalBlood
Volume140
Issue number24
DOIs
Publication statusPublished - 15 Dec 2022

Bibliographical note

Funding Information:
J.R. holds a British Heart Foundation (BHF) Intermediate Fellowship (FS/IBSRF/20/25039). This research was partially supported by a BHF project grant (PG/21/10737), the BHF Accelerator Award (AA/18/2/34218), UK Spine Knowledge exchange (R78606/CN003), and the Medical Research Council (Grant Number MC_PC_19029) for J.R. M.C. is supported by the Wellcome Trust 4 Year PhD studentship program on Mechanisms of Inflammatory Disease (204951). A.A. is supported by the Austrian Science Fund (P32064 and P34783). G.P. is supported by a Birmingham-Maastricht studentship. S.P.W. holds a BHF Chair (CH03/003). A.O.K. is a Henry Wellcome fellow (218649/Z/19/Z). N.J.M. is supported by University of Aberdeen Development Trust and National Health Service Grampian Endowment funds (COV19-004 and 20/021). A.J.I. holds a Birmingham fellowship.

Acknowledgments:
The authors thank Beata Grygielska for genotyping mice and University of Birmingham Enterprise Ltd or the translational Research Team for their support. J.R. holds a British Heart Foundation (BHF) Intermediate Fellowship (FS/IBSRF/20/25039). This research was partially supported by a BHF project grant (PG/21/10737), the BHF Accelerator Award (AA/18/2/34218), UK Spine Knowledge exchange (R78606/CN003), and the Medical Research Council (Grant Number MC_PC_19029) for J.R. M.C. is supported by the Wellcome Trust 4 Year PhD studentship program on Mechanisms of Inflammatory Disease (204951). A.A. is supported by the Austrian Science Fund (P32064 and P34783). G.P. is supported by a Birmingham-Maastricht studentship. S.P.W. holds a BHF Chair (CH03/003). A.O.K. is a Henry Wellcome fellow (218649/Z/19/Z). N.J.M. is supported by University of Aberdeen Development Trust and National Health Service Grampian Endowment funds (COV19-004 and 20/021). A.J.I. holds a Birmingham fellowship. Contribution: M.C. designed and performed experiments, collected and analyzed data, and wrote the manuscript; W.C.S. G.P. M.J.S. J.P. J.C.C. J.B. J.S.R. Z.Z. and A.S. performed experiments and analyzed data; J.H.B. and A.O.K. analyzed data; M.P. N.S.P. P.L.R.N. P.H. A.J.I. G.E.R. S.P.W. and M.R.T. provided key reagents and contributed to data analysis; N.J.M. and A.A. provided key reagents and supported research analysis; J.R. designed research and experiments, performed experiments, collected and analyzed data, and wrote the manuscript; and all authors read and approved the paper.

Keywords

  • S100A8/A9
  • calprotectin
  • fibrin
  • procoagulant platelets
  • GPIbα
  • Calgranulin A/metabolism
  • Phosphatidylserines/metabolism
  • Fibrin/metabolism
  • Blood Platelets/metabolism
  • Platelet Aggregation
  • Animals
  • COVID-19/metabolism
  • Mice

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