Protein S Enhances the Phagocytosis of Phosphatidylserine‐Exposing Erythrocytes: Implications in Sickle Cell Disease

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-positive 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-treated PtdSer-positive erythrocytes and of eryghosts generated in vitro. 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-dependent 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.

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Publication Details

Journal
American Journal of Hematology
Published
2025-10-25
DOI
https://doi.org/10.1002/ajh.70117
Primary Topic
Phagocytosis and Immune Regulation
Type
article
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article

Protein S Enhances the Phagocytosis of Phosphatidylserine‐Exposing Erythrocytes: Implications in Sickle Cell Disease

Laetitia Claër, Elsa P. Bianchini, Abdoulaye Sissoko, Sophie Moog et al.
American Journal of Hematology
Phagocytosis and Immune Regulation
article

Protein S Enhances the Phagocytosis of Phosphatidylserine‐Exposing Erythrocytes: Implications in Sickle Cell Disease

Laetitia Claër, Elsa P. Bianchini, Abdoulaye Sissoko, Sophie Moog, Claire Auditeau, Slimane Allali, Pierre Buffet, Aurélie Fricot, Pascal Amireault, Mickaël Marin, Thiago Trovati Maciel, Alain Brisson, Sandra Manceau, Sandrine Laurance, Valentine Brousse, Alexis Lavergne, Céline Gounou, Michaël Dussiot, R Gauthier, Sébastien Eymieux, Delphine Borgel, Philippe Roingeard, François Saller, Zeynep Cacan, Camille Roussel, Laure Joseph, Mohamed Choukri Khamari
article en

Abstract

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-positive 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-treated PtdSer-positive erythrocytes and of eryghosts generated in vitro. 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-dependent 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.

American Journal of HematologyVol. 101(1)
Université de Tours (FR), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Université de Bordeaux (FR), Inserm (FR), Université Paris Cité (FR), Sorbonne Paris Cité (FR), Centre Hospitalier Universitaire de Tours (FR), Assistance Publique – Hôpitaux de Paris (FR), Hôpital Robert-Debré (FR), Hôpital Saint-Jacques (FR), Hemostase Inflammation Thrombosis (FR), Institut Polytechnique de Bordeaux (FR), Institut des Maladies Génétiques Imagine (FR)
CSL Behring, Agence Nationale de la Recherche
Openalex Percentile: Top 68%
Phagocytosis and Immune Regulation
DOIOpen Access PDFOpenAlex
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