People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80–102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.
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Moloegthyo:dTo.Glo.g,yJ.:DT..BG.,.,V J..BD..-BV..,, VJ..AB..,-VT..R, J..,AJ..B, .T,.MR..,MJ.B.,.M, M.P..M, K., .MM..,PR., .KD..M, S.,.DR..,DA.,.SS..;Din.,vAe.sSti.;g iantvioens:tigVa.Bti.o-Vn.:, JV.A.B..,-VJ.B., .J,.AD..,S J..,BL.,. VD.,.SM., .LE..V, .H, M.L..E, .K, H.P..,LC., .KC..P, .J,.NC..C, F.,. AJ.N.,.P, .FZ.A., .A, P.W.Z..,, MA..WM..,, MN..MB.;., wNr.iBti.;n wg–riotriniggi–noarligdirnaaftl pdrreapfta prarteipoanr:aTt.iGon.,:JT.D.G.B.,. ,J.VD.B.B.-.V, V., .TB.R.-V., .M, T.J..R, .G, M.J.K.J..,, GG..JH.K.;.,w Gr.iHtin.;gw–rreitviinegw–r&eveidewiti n&g:edT.iGtin.,gJ.:DT..BG..,,VJ..DB..-BV..,, JV.A.B.,.-TV.R., .J,.AJ.B.,.,TD.R.S.,. ,J.LB..V, D., M.S..,E L.,.VH..,L M.,.KE..,P .H, C.L.C., .K, J.P.N., .C, F.C.A.,. ,J.PN.Z.,. ,FA.A.W., .P, .MZ..,J .A, M.W.M., M., M.J..,P M., K.M.M., .M, R.P.D., .K, S.M.D..,, AR..DS..,, NS..DB..,, AE..HS..,, NA..BZ..,, EG.H.M.,. VA..,ZG.,. JG.K.M., G.V.H., G.; .vJ.iKsu.,a Gliz.Hat.i;o vnis: uTa.Gli.z,aVti.Bon.-:VT.,.GM..,M V..;Bs.u-Vp.e,rMvi.sMio.n; s:uTp.Ger.,vJi.sDio.Bn.:, T.G., J.D.B., E.H., A.Z., G.M.V., G.H. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by CSL Behring.
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- Sickle cell anaemia
- Vaso-occlusive crisis
PubMed: MeSH publication types
- Journal Article