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 Bourne, Natalie S. Poulter, Abdullah Obaid Khan, Phillip Lindsay Ross Nicolson, Matthew Richard 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

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Abstract

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 pro-thrombotic 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 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
JournalBlood
Early online date26 Aug 2022
DOIs
Publication statusE-pub ahead of print - 26 Aug 2022

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