Anemias due to hereditary red cell membrane defects

Haema 2013; 4(1):58-65

by Εvangelos Premetis, Alexandra Stamoulakatou

Hematology Laboratory, Children’s Hospital «Agia Sophia», Athens, Greece

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The human erythrocyte membrane is the most thoroughly studied biologic membrane. It is composed of three major structural elements: a lipid bilayer mainly composed of phospholipids and cholesterol; integral proteins incorporated in the lipid bilayer; and a protein cytoskeleton on the internal side of the red cell membrane. The erythrocyte membrane provides the erythrocyte with its unique deformability, durability, and tensile strength to undergo large deformations during repeated passages through narrow microcirculatory channels. Red cell membrane disorders can be divided according to red cell morphology into four groups: hereditary spherocytosis (HS), hereditary elliptocytosis (HE), hereditary ovalocytosis and hereditary stomatocytosis. Hereditary spherocytosis is the most common red cell membranopathy with a prevalence of one in 3,000 in people of northern European origin and characterized by spherically shaped erythrocytes on the blood film, reticulocytosis, and splenomegaly. Autosomal dominant mutations predominate (75%), with recessive forms leading to more severe phenotypes. The clinical severity of hereditary spherocytosis is heterogeneous, from extremely mild to severe haemolysis. The principal cellular defect is the propensity to lose membrane surface area during passage through the splenic circulation, leading to spherical shape and decreased deformability. Splenic destruction of nondeformable spherocytes leads to anemia. Membrane loss results from defects in several membrane proteins, including ankyrin, band 3, α-spectrin, β-spectrin, and protein 4.2. Hereditary elliptocytosis is an autosomal-dominant disorder characterized by the presence of elliptical (cigar-shaped) erythrocytes on the blood film. Its distribution mirrors that of malaria, indicating that elliptocytes confer a survival advantage in the form of malarial resistance. Patients with hereditary elliptocytosis are generally asymptomatic, but approximately 10% have moderate to severe anemia including a few reported cases of hydrops foetalis and the severe variant hereditary pyropoikilocytosis, characterized by important membrane fragmentation and reduced membrane surface area. Hereditary elliptocytosis is caused by weakened “horizontal” linkages in membrane skeleton due either to a defective spectrin dimer-dimer interaction or a defective spectrin-actin-protein 4.1R junctional complex. Splenectomy reduces the severity of anemia by increasing the circulatory life span of fragmented red cells. Hereditary ovalocytosis is an autosomal dominant disease very common in Southeast Asia. It is characterized by the pres- ence of oval-shaped red cells with one or two transverse ridges or a longitudinal slit on a blood smear. A genomic deletion of 27 bp encoding amino acids 400 to 408 of band 3 has been identified, however the mechanism that leads to a marked increase in membrane rigidity has yet to be established.Overhydrat- ed hereditary stomatocytosis (OHS) and dehydrated hereditary stomatocytosis (xerocytosis) (DHS) are autosomal dominant disorders characterized by the presence of stomatocytes on blood smears. While anemia is mild in DHS, it is severe in OHS. Molecular analysis showed two mutations associated with OHS in RHAG (Ile61Arg and Ser65Phe). Recent studies showed mutations in the mechanosensitive ion channel, PIEZO1 in dehydrated hereditary stomatocytosis. While splenectomy is highly beneficial in the management of HS ad HE, it is contraindicated in hereditary stomatocytosis since venous thromboembolic complications occur following splenectomy.