Inherited hemolytic anemia: a possessive beginner's guide

Abstract

Significant advances have been made in diagnosis and clinical management of inherited red cell membrane disorders that result in hemolytic anemia. Membrane structural defects lead to hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), whereas altered membrane transport function accounts for hereditary xerocytosis (HX) and hereditary overhydrated stomatocytosis (OHS). The degrees of membrane loss and resultant increases in cell sphericity determine the severity of anemia in HS and HE, and splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span. Alterations in cell volume as a result of disordered membrane cation permeability account for reduced life span red cells in HX and OHS. Importantly, splenectomy is not beneficial in these 2 membrane transport disorders and is not recommended because it is ineffective and may lead to an increased risk of life-threatening thrombosis. Rational approaches are now available for the diagnosis and management of these inherited red cell disorders, and these will be discussed in this review.

Figure 1.

A schematic representation of the human red cell membrane. The membrane is a composite structure of a lipid bilayer anchored to a two-dimensional elastic network of skeletal proteins through ankyrin- and protein 4.1–based transmembrane protein complexes embedded in the lipid bilayer. Deficiency in any of the proteins involved in the vertical linkages involving the ankyrin complex leads to loss of cohesion between the lipid bilayer and membrane skeleton and the resultant loss of membrane surface area. The horizontal linkages between spectrin-spectrin dimers and between spectrin-actin-protein 4.1R in the junctional complex determine red cell membrane mechanical integrity. Defective horizontal linkages lead to decreased integrity of the membrane mechanics and cell fragmentation. Reproduced with permission from Mohandas and Gallagher.

Figure 2.

Peripheral blood smears in red cell membrane disorders. HS with marked spherocytic red cells (top left). HE with marked red cell fragmentation (top right). Hereditary OHS with stomatocytic red cells (bottom left). HX with a few target cells and variable number of stomatocytes (bottom right). Images adapted from ASH Image Bank.

Figure 3.

(A) Osmotic deformability profile of normal human red blood cells showing deformability index (DI) as a continuous function of suspending medium osmolality. The maximum DI, which is attained in near isotonic osmolality, is a measure of membrane surface area. Omin in the hypotonic arm corresponds to osmolality in which 50% of the red cells lyse in an osmotic fragility test, and O′ in the hypertonic arm corresponds to the state of cell hydration and hence MCHC. (B) Osmotic deformability profile of 3 patients with HS. Decreased maximum DI is the consequence of decreased membrane surface area, increase in Omin is the result of increased osmotic fragility, and decreased O′ reflects cell dehydration.