Clinical Information

The functional red cell membrane is composed of a cholesterol and phospholipid bilayer anchored by integral proteins to an elastic cytoskeletal network. These interactions form the shape, deformability, and proper ion balance of the cell. Abnormalities in these moieties result in red cell membrane disorders.

Hereditary spherocytosis (HS) is a common membrane disorder, which can be present in many ethnic groups. Its prevalence has been estimated at approximately 1 in 3000 persons of Northern European ancestry. It is usually associated with visible spherocytes on the peripheral blood smear and can be associated with variable clinical features of hemolysis ranging from completely compensated to mild to severe.

Hereditary elliptocytosis (HE) is another fairly common and clinically variable disorder that can range from normal red blood cell indices in the large majority of cases to rare patients with moderate to severe anemia.

Common hereditary elliptocytosis is characterized by the presence of elliptocytes on the peripheral blood smear. Genetic variants associated with HE have been reported in widely variable ethnicities, with greater prevalence in populations overlapping the malaria belt.

Hereditary pyropoikilocytosis is best classified as a severe form of hereditary elliptocytosis. It is uncommon and presents in early childhood as a severe hemolytic anemia. These disorders are associated with marked poikilocytosis on the peripheral blood smear.(1,2) Red cell membrane disorders can result from abnormalities involving several red cell membrane proteins, such as band 3, alpha and beta spectrin, protein 4.1, protein 4.2, glycophorin C, and ankyrin.

Most often, red cell membrane disorders are diagnosed in childhood, adolescence, or early adult life. The diagnosis of HS is usually made by a combination of patient and family history, laboratory evidence of hemolysis, and review of a peripheral blood smear. The osmotic fragility (OF) test is usually markedly abnormal in HS cases. However, factors such as age, iron status, and medications can affect the OF test. OF is nonspecific and can be increased in acquired disorders, such as autoimmune hemolytic anemia. Coombs testing should be negative prior to ordering this test.

The addition of eosin-5-maleimide (EMA) binding (band 3) flow cytometry to this profile increases specificity if a typical moderately decreased pattern is present. Hereditary pyropoikilocytosis can have normal or only mildly increased OF results and often displays a very dim and sometimes dual peak pattern with EMA-binding testing. Common hereditary elliptocytosis cases are not discriminated from normal patients in either OF and EMA binding testing, and this profile does not add confirmatory information for HE.