Protein S in Sickle cell disease – PROSICK

Protein S (PS) is a physiological anticoagulant which has also been implicated in phagocytosis of phosphatidylserine-exposing cells through the activation of TAM receptors. As such, PS appears to be at the crossroads of major pathophysiological mechanisms of sickle cell disease (SCD). SCD is caused by the presence of abnormal haemoglobin leading to the formation of dysfunctional sickle RBCs under hypoxic conditions. Sickle RBCs expose phosphatidylserine on their surface, which participates in promoting their phagocytosis/removal, but also their adhesion to the endothelium and activation of coagulation. These processes contribute to the occurrence of the vaso-occlusive crisis (VOC) that are the hallmark of this disease. Interestingly, patients with SCD often present with PS deficiency which is exacerbated during VOC. The ambition of PROSICK is to study in depth the involvement of PS in SCD and to develop a treatment aiming at increasing the activity of this PS. Thus, the study of a mouse model of PS deficiency in sickle mice will constitute a model of choice to better understand the involvement of PS in the pathophysiology of SCD, but also to evaluate the effectiveness of potential treatments. The strength of this project lies in the complementary nature of the consortium which involves teams recognized in the fields of RBCs, SCD and PS, but also in the novelty of the approaches envisaged. Moreover, promising results using an original nanobody potentiating the anticoagulant activity of PS have already been obtained and have shown that this nanobody could limit hypoxia/reoxygenation-induced VOC in mice. Human models of RBC adhesion to the endothelium and phagocytosis by macrophages will be implemented and will provide essential elements for more clearly understanding the role of PS in SCD. They will also constitute interesting models to explore the molecular bases underlying the protective effects of our anti-PS nanobody on VOC.