Protein S (PROS1), best known as a major vitamin K–dependent anticoagulant, has a second, less-studied function: it promotes the clearance of apoptotic cells by acting as a molecular bridge between the phosphatidylserine (PtdSer) exposed on their surface and the macrophage receptor MerTK, a process termed efferocytosis. Until now, it was unknown whether this mechanism was involved in the splenic clearance of senescent or damaged PtdSer-exposing red blood cells, and in particular of "erythrocyte ghosts" (eryghosts), the membrane remnants arising from the lysis of red cells. This work specifically investigates the contribution of the PROS1/MerTK axis to the phagocytosis of intact red blood cells and eryghosts, in healthy subjects and in patients with sickle cell disease.
The authors show that PROS1 enhances the phagocytosis of erythrocytes rendered PtdSer-positive by ionomycin treatment, as well as that of eryghosts generated in vitro. They confirm that eryghosts circulate at higher levels in sickle cell patients than in healthy subjects, with marked interindividual heterogeneity. Patients with the highest eryghost concentrations display increased hemolysis and lower plasma PROS1 levels. The proportion of circulating eryghosts is moreover correlated with the degree of hyposplenism, and these particles are less frequently found in sickle cell spleens than in control spleens. The team further establishes that these circulating eryghosts are procoagulant—increasing thrombin generation and fibrin formation—and adhere to endothelial cells, a feature reported here for the first time and central to the pathophysiology of the disease. In sickle cell disease, PROS1 stimulates the phagocytosis of eryghosts in a MerTK-dependent manner, but has no effect on intact red blood cells; indeed, no increased PtdSer exposure was detected on the latter.
The authors thus propose a model in which PROS1-mediated erythrophagocytosis, physiologically effective, becomes insufficient in sickle cell patients. Intense intravascular hemolysis, functional hyposplenism, and PROS1 consumption—both by erythrophagocytosis itself and by chronic coagulation activation—together contribute to the abnormal persistence of eryghosts in the circulation. The acquired PROS1 deficiency could thereby initiate a pathogenic loop, aggravating the uncontrolled activation of coagulation and the defective clearance of these procoagulant, adherent remnants. According to the authors, this finer understanding of erythrophagocytosis, both physiological and pathological, opens up new therapeutic avenues targeting PROS1 in sickle cell disease.