TY - JOUR
T1 - S100A8/A9 drives the formation of procoagulant platelets through GPIbα
AU - Colicchia, Martina
AU - Schrottmaier, Waltraud C.
AU - Perrella, Gina
AU - Reyat, Jasmeet S.
AU - Begum, Jenefa
AU - Slater, Alexandre
AU - Price, Joshua
AU - Clark, Joanne C
AU - Zhi, Zhaogong
AU - Simpson, Megan
AU - Bourne, Joshua
AU - Poulter, Natalie S.
AU - Khan, Abdullah Obaid
AU - Nicolson, Phillip Lindsay Ross
AU - Pugh, Matthew Richard
AU - Harrison, Paul
AU - Iqbal, Asif J
AU - Rainger, George E.
AU - Watson, Steve P
AU - Thomas, Mark R.
AU - Mutch, Nicola J
AU - Assinger, Alice
AU - Rayes, Julie
PY - 2022/8/26
Y1 - 2022/8/26
N2 - 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.
AB - 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.
U2 - 10.1182/blood.2021014966
DO - 10.1182/blood.2021014966
M3 - Article
SN - 0006-4971
JO - Blood
JF - Blood
ER -