血小板
S100A8型
血小板活化
化学
凝血酶
免疫学
细胞生物学
炎症
医学
生物
作者
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 O. Khan,Phillip L.R. Nicolson,Matthew Pugh,Paul Harrison,Asif Iqbal,G. Ed Rainger,Steve P. Watson,Mark R. Thomas,Nicola J. Mutch,Alice Assinger,Julie Rayes
出处
期刊:Blood
[American Society of Hematology]
日期:2022-08-26
卷期号:140 (24): 2626-2643
被引量:35
标识
DOI:10.1182/blood.2021014966
摘要
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.
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