Comparison of Thrombin Generation, Platelet Activation and Aggregation Profiles in Patients With Sickle Cell Disease Depending on Their SS or SC Genotype (DrepAgreg)

Sickle cell anemia is the most common genetic disease worldwide. It is due to a homozygous mutation in the beta globin gene leading to the production of abnormal hemoglobin S (HbS). This hemoglobin polymerizes and precipitates in the red blood cells (RBCs) under hypoxic conditions, leading to the rigidification of the red blood cells that obstruct the small vessels and are subsequently destroyed. The disease is thus characterized by chronic hemolytic anemia associated with painful vaso-occlusive crises (VOC) and chronic inflammation. The HbSC genotype is associated with anemia and less severe clinical manifestations than the HbSS genotype. However, the risk of venous thromboembolic events, particularly pulmonary embolism, is paradoxically higher. The pathophysiological mechanisms involved in the occurrence of VOC and venous thromboembolic events (VTE) have not been fully elucidated. They involve phenomena of ischemia-reperfusion and complex interactions between the RBC, the endothelium, the leucocytes and the platelets. The sickle RBCs express phosphatidylserine (PS) on their surface, which facilitates their adhesion to other blood cells and their interaction with the endothelium. The release of hemoglobin and free heme into the circulation, along with oxidative stress, induces endothelial activation and dysfunction, as well as vascular inflammation, platelet activation and clotting. Numerous studies have documented the existence of coagulation activation in sickle cell patients during the stable phase of the disease and during VOCs, decreased levels of physiological inhibitors of coagulation and resistance to activated protein C. One of the main mechanisms of coagulation activation in sickle cell patients is increased tissue factor expression on the surface of activated monocytes and endothelial cells. Free heme promotes NETs (neutrophil extracellular traps) formation, which activates the intrinsic coagulation pathway. Moreover, platelets probably play a pivotal role in the thrombo-inflammatory process, coagulation activation, and the occurrence of VOC and VTE. We hypothesize that sickle cell patients may exhibit a different thrombin generation profile as well as distinct platelet activation and reactivity profiles, depending on their SS or SC genotype.