{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T06:44:39Z","timestamp":1764657879900,"version":"3.46.0"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T00:00:00Z","timestamp":1761350400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR\u201022\u2010CE140058"],"award-info":[{"award-number":["ANR\u201022\u2010CE140058"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008322","name":"CSL Behring","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The major anticoagulant Protein S (PROS1) also contributes to the phagocytosis of apoptotic cells by bridging exposed phosphatidylserine (PtdSer) to the MerTK receptor on macrophages (efferocytosis). Whether PROS1 is involved in the splenic clearance of PtdSer\u2010positive senescent and altered erythrocytes such as erythrocyte ghosts (eryghosts) is unknown. Here, we investigate the contribution of PROS1 and MerTK to the phagocytosis of intact RBC and eryghosts in healthy subjects and patients with sickle cell disease (SCD). We show that PROS1 enhances the phagocytosis of ionomycin\u2010treated PtdSer\u2010positive erythrocytes and of eryghosts generated in\u00a0vitro. We confirm that eryghosts circulate in patients with SCD at higher levels than in healthy subjects and observe increased hemolysis and decreased levels of plasmatic PROS1 in patients with the highest concentration of eryghosts. The proportion of circulating eryghosts is correlated with the intensity of hyposplenism, and eryghosts are less frequently observed in sections of SCD compared to control spleens. We demonstrate that circulating eryghosts are procoagulant and adhere to endothelial cells. In SCD, PROS1 enhances their phagocytosis in a MerTK\u2010dependent manner but has no such effect on intact erythrocytes. PROS1 is therefore involved in erythrophagocytosis, a physiological process insufficient in patients with SCD due to intense intravascular hemolysis and hyposplenism, leading to PROS1 consumption and the abnormal persistence of eryghosts in circulation. PROS1 deficiency may in turn initiate a pathogenic loop, enhancing unregulated activation of coagulation and defective clearance of procoagulant and adherent eryghosts. This deeper understanding of physiological and pathological erythrophagocytosis opens new therapeutic approaches targeting PROS1 in SCD.<\/jats:p>","DOI":"10.1002\/ajh.70117","type":"journal-article","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T10:26:03Z","timestamp":1761387963000},"page":"26-40","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein S Enhances the Phagocytosis of Phosphatidylserine\u2010Exposing Erythrocytes: Implications\u00a0in\u00a0Sickle Cell Disease"],"prefix":"10.1002","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8499-1862","authenticated-orcid":false,"given":"Claire","family":"Auditeau","sequence":"first","affiliation":[{"name":"H\u00e9mostase, Inflammation, Thrombose (HITh), UMR\u2010S1176, INSERM Universit\u00e9 Paris\u2010Saclay  Le Kremlin\u2010Bic\u00eatre France"},{"name":"Service D'h\u00e9matologie Biologique H\u00f4pital Necker Enfants Malades, Assistance Publique\u2010H\u00f4pitaux de Paris (AP\u2010HP)  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aur\u00e9lie","family":"Fricot","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rapha\u00ebl","family":"Gauthier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdoulaye","family":"Sissoko","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeynep","family":"Cacan","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9line","family":"Gounou","sequence":"additional","affiliation":[{"name":"UMR\u2010CBMN, CNRS\u2010Universit\u00e9 de Bordeaux\u2010IPB  Pessac France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laure","family":"Joseph","sequence":"additional","affiliation":[{"name":"Department of Biotherapy, French National Sickle Cell Disease Referral Center H\u00f4pital Necker, Assistance\u2010Publique H\u00f4pitaux de Paris, Gr Ex  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Manceau","sequence":"additional","affiliation":[{"name":"Department of Biotherapy, French National Sickle Cell Disease Referral Center H\u00f4pital Necker, Assistance\u2010Publique H\u00f4pitaux de Paris, Gr Ex  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7068-4530","authenticated-orcid":false,"given":"Slimane","family":"Allali","sequence":"additional","affiliation":[{"name":"Reference Centre for Sickle Cell Disease Necker\u2010Enfants Malades University Hospital, AP\u2010HP Centre  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Dussiot","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM, Institut Imagine Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4094-022X","authenticated-orcid":false,"given":"Mickael","family":"Marin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3471-6093","authenticated-orcid":false,"given":"Alexis","family":"Lavergne","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariem","family":"Khamari","sequence":"additional","affiliation":[{"name":"H\u00e9mostase, Inflammation, Thrombose (HITh), UMR\u2010S1176, INSERM Universit\u00e9 Paris\u2010Saclay  Le Kremlin\u2010Bic\u00eatre France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Moog","sequence":"additional","affiliation":[{"name":"H\u00e9mostase, Inflammation, Thrombose (HITh), UMR\u2010S1176, INSERM Universit\u00e9 Paris\u2010Saclay  Le Kremlin\u2010Bic\u00eatre France"},{"name":"Inovarion 251 Rue Saint Jacques  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsa","family":"Bianchini","sequence":"additional","affiliation":[{"name":"H\u00e9mostase, Inflammation, Thrombose (HITh), UMR\u2010S1176, INSERM Universit\u00e9 Paris\u2010Saclay  Le Kremlin\u2010Bic\u00eatre France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laetitia","family":"Claer","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Laurance","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentine","family":"Brousse","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"},{"name":"Centre de R\u00e9f\u00e9rence MCGRE, Service D'h\u00e9mato\u2010Immunologie H\u00f4pital Universitaire Robert Debr\u00e9, APHP  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-510X","authenticated-orcid":false,"given":"S\u00e9bastien","family":"Eymieux","sequence":"additional","affiliation":[{"name":"IBiSA Electron Microscopy Facility University Hospital Center of Tours  Tours France"},{"name":"Inserm U1259 MAVIVHe Universit\u00e9 de Tours and CHRU de Tours  Tours France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Roingeard","sequence":"additional","affiliation":[{"name":"IBiSA Electron Microscopy Facility University Hospital Center of Tours  Tours France"},{"name":"Inserm U1259 MAVIVHe Universit\u00e9 de Tours and CHRU de Tours  Tours France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"Amireault","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"},{"name":"Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM, Institut Imagine Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thiago","family":"Trovati Maciel","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM, Institut Imagine Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alain","family":"Brisson","sequence":"additional","affiliation":[{"name":"UMR\u2010CBMN, CNRS\u2010Universit\u00e9 de Bordeaux\u2010IPB  Pessac France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Buffet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"},{"name":"Service de Maladies Infectieuses et Tropicales H\u00f4pital Universitaire Necker Enfants Malades Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7ois","family":"Saller","sequence":"additional","affiliation":[{"name":"H\u00e9mostase, Inflammation, Thrombose (HITh), UMR\u2010S1176, INSERM Universit\u00e9 Paris\u2010Saclay  Le Kremlin\u2010Bic\u00eatre France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Delphine","family":"Borgel","sequence":"additional","affiliation":[{"name":"H\u00e9mostase, Inflammation, Thrombose (HITh), UMR\u2010S1176, INSERM Universit\u00e9 Paris\u2010Saclay  Le Kremlin\u2010Bic\u00eatre France"},{"name":"Service D'h\u00e9matologie Biologique H\u00f4pital Necker Enfants Malades, Assistance Publique\u2010H\u00f4pitaux de Paris (AP\u2010HP)  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille","family":"Roussel","sequence":"additional","affiliation":[{"name":"Service D'h\u00e9matologie Biologique H\u00f4pital Necker Enfants Malades, Assistance Publique\u2010H\u00f4pitaux de Paris (AP\u2010HP)  Paris France"},{"name":"Universit\u00e9 Paris Cit\u00e9, INSERM, BIGR  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)68566-2"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504240103"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk5836"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(95)90520\u20100"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni871"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/35075603"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400404"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.148.7.2207"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30375"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020005351"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-3030-5_1"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12554"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.24536"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201090477\u2010z"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13416"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20102143(99)90149\u2010x"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2011.04610.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003632"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22669"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3791\/60659"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.958098"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.05715\u201011"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.10.015"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196909042811002"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102008\u201003\u2010146779"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27481"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1055\/a\u20102373\u20102829"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpth.2024.102426"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.182303"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13267"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.960401"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/iai.55.9.2074\u20102080.1987"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2010.199"},{"issue":"2","key":"e_1_2_10_35_1","first-page":"107","article-title":"Innate Immune and Non\u2010Immune Mediators of Erythrocyte Clearance","volume":"50","author":"Lutz H. U.","year":"2004","journal-title":"Cellular and Molecular Biology (Noisy\u2010le\u2010Grand, France)"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1159\/000089839"},{"issue":"2","key":"e_1_2_10_37_1","first-page":"117","article-title":"Band 3 and Its Alterations in Health and Disease","volume":"50","author":"Kay M. M.","year":"2004","journal-title":"Cellular and Molecular Biology (Noisy\u2010le\u2010Grand, France)"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102011\u201010\u2010386805"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00073"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017013094"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023021611"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3233\/CH\u2010189013"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102015\u201004\u2010637702"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.5.1873.1873"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.3.1119"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102002\u201011\u20103416"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2522"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10051265"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20102141.1997.2663083.x"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102018\u201004\u2010841585"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019003543"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V128.22.162.162"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12336"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2013.092460"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102009\u201004\u2010210112"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15736"}],"container-title":["American Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.70117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T06:41:28Z","timestamp":1764657688000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajh.70117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,25]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/ajh.70117"],"URL":"https:\/\/doi.org\/10.1002\/ajh.70117","archive":["Portico"],"relation":{},"ISSN":["0361-8609","1096-8652"],"issn-type":[{"type":"print","value":"0361-8609"},{"type":"electronic","value":"1096-8652"}],"subject":[],"published":{"date-parts":[[2025,10,25]]},"assertion":[{"value":"2025-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}