Erythrocyte Phosphatidylserine Exposure in β-Thalassemia

Abstract

[ABS]Phospholipid asymmetry is well maintained in erythrocyte (RBC) membranes with phosphatidylserine (PS) exclusively present in the inner leaflet. Eryptosis, the suicidal death of RBCs, is characterized by cell shrinkage, membrane blebbing, and cell membrane phospholipids scrambling with PS exposure at the cell surface. Erythrocytes exposing PS are recognized, bound, engulfed, and degraded by macrophages. Eryptosis thus fosters clearance of affected RBCs from circulating blood, which may aggravate anemia in pathological conditions. Thalassemia patients are more sensitive to the eryptotic depletion and osmotic shock which may affect RBC membrane phospholipid asymmetry. We aimed in this work to determine the RBC PS exposure in splenectomized and nonsplenectomized β-thalassemia major (β-TM) patients and correlate it with the clinical presentation and laboratory data. RBCs were stained for annexin V to detect phosphatidylserine (PS) exposure in 46 β-TM patients (27 splenectomized and 19 nonsplenectomized) compared to 17 healthy subjects as a control group. We observed a significant increase in RBC PS exposure in β-TM patients compared to control group (P = .0001). Erythrocyte PS exposure was significantly higher in splenectomized β-TM patients compared with nonsplenectomized β-TM patients (P = .001). No correlation was found between RBC PS exposure and clinical or hematological data of β-TM patients, but there was a positive correlation between RBC PS exposure and ferritin level in β-TM patients have higher levels of RBC PS exposure, and splenectomy was shown to aggravate RBC PS exposure without aggravation of anemia.

Oxidative stress in β-thalassaemia and sickle cell disease

“…Unpaired α-globins have the tendency to precipitate and autoxidise producing high amounts of ROS, free haeme and iron [169] . As previously mentioned, these molecules can promote oxidation of membrane lipids and proteins resulting in band-3 clusterisation and PS exposure [116,76] . These are signs of senescence and eryptosis of RBCs, which are then removed by macrophages.…”

“…Additionally, the resulting disruption of the physiological asymmetry of phospholipids causes phosphatidylserine (PS) exposure to the outer membrane ( Fig. 1 A) [76] . PS is a signal for cell removal recognised by scavenging receptors in macrophages, which engulf and degrade the PS-exposed RBCs [88] .…”

“…PS is a signal for cell removal recognised by scavenging receptors in macrophages, which engulf and degrade the PS-exposed RBCs [88] . PS-exposed RBCs have been observed in both SCD and β-thalassaemia [46,76] . Another factor that leads to abnormal PS exposure in SCD is the repeated cycles of sickling and unsickling, which disturb the membrane phospholipid asymmetry and result in microvesicle formation [8] .…”

Role of red blood cells in haemostasis and thrombosis

“…The abnormal phosphatidylserine exposure in sickle cell disease is thought to result from the repeated cell sickling and unsickling that are linked to polymerization and depolymerization of mutated hemoglobin [48]. An increase in RBC phosphatidylserine exposure in β-thalassemia patients has been shown to be connected with eryptosis, the suicidal death of RBCs [49]. …”

Stimulation of Suicidal Erythrocyte Death by Artesunate

“…Accordingly, phosphatidylserine exposing erythrocytes may impair microcirculation [35,107,110,111,112,113]. The proeryptotic effect of artesunate may be particularly strong in clinical disorders with accelerated eryptosis, such as sepsis [114], fever [115], malaria [103,104,116], sickle cell disease [117], thalassemia [118,119], Wilson's disease [120], iron deficiency [121] hepatic failure [122], malignancy [123], metabolic syndrome [124], diabetes [40,125], dehydration [70], renal insufficiency [126], hemolytic uremic syndrome [127], hyperphosphatemia [79] and phosphate depletion [128]. Under those conditions the use of artesunate may be contraindicated.…”