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 Simpson, Joshua H. Bourne, Natalie S. Poulter, Abdullah Khan, Phillip L.R. Nicolson, Matthew Pugh, Paul Harrison, Asif J. Iqbal, George E. Rainger, Steve P. Watson, Mark R. ThomasNicola Mutch, Alice Assinger, Julie Rayes* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


S100A8/A9, also known as calprotectin or MRP8/14, is an alarmin primarily secreted by activated myeloid cells and platelets with anti-microbial, pro-inflammatory 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 fibrinrich network following 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-positive platelets. Using washed platelets,
soluble S100A8/A9 induced phosphatidylserine 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 Bernard-Soulier Syndrome patient with GPIb-IX-V deficiency and platelets from mice deficient in the extracellular domain of GPIbα.
In conclusion, we identified the S100A8/A9-GPIbα interaction 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
Publication statusAccepted/In press - 10 Aug 2022


  • S100A8/A9
  • calprotectin
  • fibrin
  • procoagulant platelets
  • GPIbα


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