Membrane Phospholipid Asymmetry in Human Thalassemia

Abstract

Phospholipid asymmetry in the red blood cell (RBC) lipid bilayer is well maintained during the life of the cell, with phosphatidylserine (PS) virtually exclusively located in the inner monolayer. Loss of phospholipid asymmetry, and consequently exposure of PS, is thought to play an important role in red cell pathology. The anemia in the human thalassemias is caused by a combination of ineffective erythropoiesis (intramedullary hemolysis) and a decreased survival of adult RBCs in the peripheral blood. This premature destruction of the thalassemic RBC could in part be due to a loss of phospholipid asymmetry, because cells that expose PS are recognized and removed by macrophages. In addition, PS exposure can play a role in the hypercoagulable state reported to exist in severe β-thalassemia intermedia. We describe PS exposure in RBCs of 56 comparably anemic patients with different genetic backgrounds of the α- or β-thalassemia phenotype. The use of fluorescently labeled annexin V allowed us to determine loss of phospholipid asymmetry in individual cells. Our data indicate that in a number of thalassemic patients, subpopulations of red cells circulate that expose PS on their outer surface. The number of such cells can vary dramatically from patient to patient, from as low as that found in normal controls (less than 0.2%) up to 20%. Analysis by fluorescent microscopy of β-thalassemic RBCs indicates that PS on the outer leaflet is distributed either over the entire membrane or localized in areas possibly related to regions rich in membrane-bound α-globin chains. We hypothesize that these membrane sites in which iron carrying globin chains accumulate and cause oxidative damage, could be important in the loss of membrane lipid organization. In conclusion, we report the presence of PS-exposing subpopulations of thalassemic RBC that are most likely physiologically important, because they could provide a surface for enhancing hemostasis as recently reported, and because such exposure may mediate the rapid removal of these RBCs from the circulation, thereby contributing to the anemia.

Endothelin B receptor stimulation inhibits suicidal erythrocyte death

“…Several anemic conditions are paralleled by accelerated suicidal erythrocyte death, such as iron deficiency (13), phosphate depletion (14), hemolytic uremic syndrome (15), sepsis (16), malaria (17,18), Wilson's disease (19), sickle cell disease (20 -27), thalassemia (20,24,25,28,29), and glucose-phosphate dehydrogenase deficiency (25,30). Moreover, suicidal erythrocyte death is stimulated by a wide variety of endogenous mediators and xenobiotics (31)(32)(33)(34)(35)(36)(37).…”

Activated platelet‐derived microparticles in thalassaemia

“…For example, the RBC membrane undergoes vesiculation under a variety of conditions, which include increased cytoplasmic calcium concentration, reduced ATP content and disruption of the membrane lipid-protein organization (Wagner et al, 1986)all of which are features characteristic of thalassaemic RBCs. It has been shown that vesicles and MPs from platelets and RBC strongly bind annexin V, a protein known for its interaction with negatively charged phospholipids such as phosphatidylserine (PS) (Shinar et al, 1987;Borenstain-Ben Yashar et al, 1993;Zwaal & Schroit, 1997;Kuypers et al, 1998). PS is one of the key membrane phospholipids that is normally located along the inner side of the membrane bilayer.…”

“…PS is one of the key membrane phospholipids that is normally located along the inner side of the membrane bilayer. It is known to activate the alternative complement pathway and to support the formation of activated clotting enzymes when expressed on the outer lipid bilayer (Borenstain-Ben Yashar et al, 1993;Zwaal & Schroit, 1997;Kuypers et al, 1998;Freyssinet, 2003). An important insight into this procoagulant potential was corroborated by clinical studies showing elevated levels of circulating MPs in patients with an increased risk for thromboembolic events (i.e.…”

Complement‐induced procoagulant alteration of red blood cell membranes with microvesicle formation in paroxysmal nocturnal haemoglobinuria (PNH): implication for thrombogenesis in PNH

“…In the congenital haemolytic anaemias, sickle cell disease and thalassaemia, an enhanced exposure of PS on the abnormal RBC surfaces has recently been found (Chiu et al, 1979(Chiu et al, , 1981Yashar et al, 1993;Kuypers et al, 1998). The addition of sickle or thalassaemic RBC with a PS-rich surface q 1999 Blackwell Science Ltd Correspondence: Dr Haruhiko Ninomiya, Division of Haematology, Institute of Clinical Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan.…”