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• W4291778406 abstract "Purpose: Endothelial cell (EC) activation and red blood cell (RBC) adhesion are central to both acute and chronic pathogenesis of sickle cell disease (SCD). Quantitatively, RBC-derived extracellular vesicles, REVs, are more abundant from SS RBCs compared with HbA-containing RBCs (AA RBCs). Sickle RBC-derived REVs (SS REVs) are known to transfer heme to endothelial cells and to promote endothelial activation through cell signaling and transcriptional regulation, triggering neutrophil adhesion to activated endothelium in vitro and vaso-occlusion in SS mice in vivo. Our objective is to test the hypothesis that SS REVs will trigger acute non-transcriptional regulation on human microvascular ECs. The adhesion characteristics of SS RBCs to ECs was used as a direct biomarker of endothelial activation. Materials and methods: We examined the impact of SS REVs on microvascular EC activation and RBC adhesion using in vitro microfluidic assays. For in vitro studies, SS REVs were collected from pooled SS RBCs activated using calcium ionophore. Human pulmonary microvascular endothelial cells (HPMECs) were cultured in microfluidic channels under controlled shear stress and exposed to REVs at 37 °C for 2 hours. Von Willebrand factor (vWF) display on REV-exposed HPMECs was quantified. Adhesion quantification was performed with and without the vWF protease ADAMTS13 at 1 dyne/cm2 shear stress, followed by a rinse step and quantification of adhered RBCs. In vivo, HbSS-Townes mice and a dorsal skin-fold chamber model was used to determine if ADAMTS13 would reduce microvascular stasis in response to hemin. Results: Compared with AA REVs, SS REVs promoted activation of human pulmonary microvascular endothelial cells (HPMEC) as reflected by increased vWF expression (Fig. 1A-C). Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs that had been exposed to SS REVs (Fig. 1D). SS RBC adhesion was reduced by vWF cleaving protease ADAMTS13 to a level similar to HPMECs exposed to AA REVs (Fig. 1D). The RBC adhesion induced by SS REVs was variable, and was higher in SS RBCs from patients with increased markers of hemolysis (Lactate Dehydrogenase, LDH and reticulocyte count) or with a history of deep vein thrombosis (DVT, Fig. 2). Consistent with these observations, studies in SS mice with implanted dorsal skin-fold chambers found hemin-induced stasis was inhibited by ADAMTS13 (Fig. 1E). Conclusion: Our results emphasize the critical contribution made by REVs to the pathophysiology of SCD by triggering microvascular EC activation and abnormal RBC adhesion mediated by vWF. Additionally, results from both in vitro microfluidic RBC adhesion tests using patient samples and in vivo stasis tests using SS mice indicated the effect of ADAMTS13 in mitigating SS RBC adhesion and vaso-occlusion. 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.Figure 1. SS RBCs generate higher levels of REVs which activate HPMECs, increase vWF expression and mediates enhanced adhesion of SS RBCs, which can be reduced by ADAMTS13. (A, B): HPMECs were treated with SS REVs (A) and AA REVs (B) for 2 hours in 37 °CFigure 2. RBC adhesion to REV-activated HPMECs correlates with subject clinical phenotype including hemolytic and inflammatory biomarkers. (A): A subpopulation (Group 1, N = 6) with distinct hemolysis markers of lactate dehydrogenase (LDH) levels and abso J. LITTLE declares a conflict of interest: Invitation to national or international congresses: ASH Patent or product inventor: Heme Chip SCD Biochip Research support/Scientific studies: Bluebird Bio" @default.
• W4291778406 created "2022-08-16" @default.
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• W4291778406 date "2022-08-01" @default.
• W4291778406 modified "2023-10-14" @default.
• W4291778406 title "P-006: SICKLE RED BLOOD CELL (RBC)-DERIVED EXTRACELLULAR VESICLES ACTIVATE ENDOTHELIAL CELLS AND ENHANCE SICKLE RBC ADHESION MEDIATED BY VON WILLEBRAND FACTOR" @default.
• W4291778406 doi "https://doi.org/10.1097/01.hs9.0000872928.68498.09" @default.
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