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Quantitatively, RBC\u2010derived extracellular vesicles (REVs) are more abundant from SS RBCs compared with healthy RBCs (AA RBCs). Sickle RBC\u2010derived REVs (SS REVs) are known to promote endothelial cell (EC) activation through cell signalling and transcriptional regulation at longer terms. However, the SS REV\u2010mediated short\u2010term non\u2010transcriptional response of EC is unclear. Here, we examined the impact of SS REVs on acute microvascular EC activation and RBC adhesion at 2\u2009h. Compared with AA REVs, SS REVs promoted human pulmonary microvascular ECs (HPMEC) activation indicated by increased von Willebrand factor (VWF) expression. Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs exposed to SS REVs. This enhanced SS RBC adhesion was reduced by haeme binding protein haemopexin or VWF cleaving protease ADAMTS13 to a level similar to HPMECs treated with AA REVs. Consistent with these observations, haemin\u2010 or SS REV\u2010induced microvascular stasis in SS mice with implanted dorsal skin\u2010fold chambers that was inhibited by ADAMTS13. The adhesion induced by SS REVs was variable and was higher with SS RBCs from patients with increased markers of haemolysis (lactate dehydrogenase and reticulocyte count) or a concomitant clinical diagnosis of deep vein thrombosis. Our results emphasise the critical contribution made by REVs to the pathophysiology of SCD by triggering acute microvascular EC activation and abnormal RBC adhesion. These findings may help to better understand acute pathophysiological mechanism of SCD and thereby the development of new treatment strategies using VWF as a potential target.<\/jats:p>","DOI":"10.1111\/bjh.18616","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T00:45:32Z","timestamp":1672965932000},"page":"552-563","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Sickle red blood cell\u2010derived extracellular vesicles activate endothelial cells and enhance sickle red cell adhesion mediated by von Willebrand factor"],"prefix":"10.1111","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-0120","authenticated-orcid":false,"given":"Ran","family":"An","sequence":"first","affiliation":[{"name":"Mechanical and Aerospace Engineering Department Case Western Reserve University Cleveland Ohio USA"},{"name":"Department of Biomedical Engineering University of Houston 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunsheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Hematology, Oncology and Transplantation, Vascular Biology Center University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Mechanical and Aerospace Engineering Department Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuad","family":"Abdulla","sequence":"additional","affiliation":[{"name":"Division of Hematology, Oncology and Transplantation, Vascular Biology Center University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erdem","family":"Kucukal","sequence":"additional","affiliation":[{"name":"Mechanical and Aerospace Engineering Department Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0708-3876","authenticated-orcid":false,"given":"William J.","family":"Wulftange","sequence":"additional","affiliation":[{"name":"Biomedical Engineering Department Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utku","family":"Goreke","sequence":"additional","affiliation":[{"name":"Mechanical and Aerospace Engineering Department Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Bode","sequence":"additional","affiliation":[{"name":"Mechanical and Aerospace Engineering Department Case Western Reserve University Cleveland Ohio USA"},{"name":"Department of Hematology and Oncology, School of Medicine Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalitha V.","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, School of Medicine Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Vercellotti","sequence":"additional","affiliation":[{"name":"Division of Hematology, Oncology and Transplantation, Vascular Biology Center University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Belcher","sequence":"additional","affiliation":[{"name":"Division of Hematology, Oncology and Transplantation, Vascular Biology Center University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"Little","sequence":"additional","affiliation":[{"name":"Divison of Hematology &amp; UNC Blood Research Center, Department of Medicine University of North Carolina Chapel Hill North Carolina 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