Diagnosis and clinical management of red cell membrane disorders.

Heterogeneous red blood cell (RBC) membrane disorders and hydration defects often present with the common clinical findings of hemolytic anemia, but they may require substantially different management, based on their pathophysiology. An accurate and timely diagnosis is essential to avoid inappropriate interventions and prevent complications. Advances in genetic testing availability within the last decade, combined with extensive foundational knowledge on RBC membrane structure and function, now facilitate the correct diagnosis in patients with a variety of hereditary hemolytic anemias (HHAs). Studies in patient cohorts with well-defined genetic diagnoses have revealed complications such as iron overload in hereditary xerocytosis, which is amenable to monitoring, prevention, and treatment, and demonstrated that splenectomy is not always an effective or safe treatment for any patient with HHA. However, a multitude of variants of unknown clinical significance have been discovered by genetic evaluation, requiring interpretation by thorough phenotypic assessment in clinical and/or research laboratories. Here we discuss genotype-phenotype correlations and corresponding clinical management in patients with RBC membranopathies and propose an algorithm for the laboratory workup of patients presenting with symptoms and signs of hemolytic anemia, with a clinical case that exemplifies such a workup.

Inherited hemolytic anemia: a possessive beginner's guide.

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.

Red cell membrane disorders.

Significant advances have been made in our understanding of the structural basis for altered cell function in various inherited red cell membrane disorders with reduced red cell survival and resulting hemolytic anemia. The current review summarizes these advances as they relate to defining the molecular and structural basis for disorders involving altered membrane structural organization (hereditary spherocytosis [HS] and hereditary elliptocytosis [HE]) and altered membrane transport function (hereditary overhydrated stomatocytosis and hereditary xerocytosis). Mutations in genes encoding membrane proteins that account for these distinct red cell phenotypes have been identified. These molecular insights have led to improved understanding of the structural basis for altered membrane function in these disorders. Weakening of vertical linkage between the lipid bilayer and spectrin-based membrane skeleton leads to membrane loss in HS. In contrast, weakening of lateral linkages among different skeletal proteins leads to membrane fragmentation and decreased surface area in HE. The degrees of membrane loss and resultant increases in cell sphericity determine the severity of anemia in these two disorders. Splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span of spherocytic red cells that are normally sequestered by the spleen. Disordered membrane cation permeability and resultant increase or decrease in red cell volume account for altered cellular deformability of hereditary overhydrated stomatocytosis and hereditary xerocytosis, respectively. Importantly, splenectomy is not beneficial in these two membrane transport disorders and in fact contraindicated due to severe postsplenectomy thrombotic complications.

Detection of erythrocytes in patient with elliptocytosis complicating ITP using atomic force microscopy.

The pathological changes of erythrocytes were detected at the nanometer scale, which was important for revealing the onset of diseases, early diagnosis, and effective therapies. Diseases may disturb the morphology and function of erythrocytes at molecular scale. There were dramatic surface deformations in topography of erythrocytes from a patient with elliptocytosis complicating idiopathic thrombocytopenic purpura (ITP). The overall shape and surface membrane of the healthy, pre- and post-therapeutic erythrocytes have been studied by high-resolution atomic force microscopy imaging. The results showed that we can detect healthy and pathological erythrocytes by the morphologic parameters of the length, width, ratio of length to width, peak, valley, valley-to-peak, surface fluctuation, and standard deviations of the erythrocytes. Therefore, the morphologic information of erythrocytes is very important indictor for diagnosing the healthy and disease, as well as evaluating therapeutic effect.

Update on the clinical spectrum and genetics of red blood cell membrane disorders.

Disorders of the red blood cell membrane, such as hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis, are characterized by heterogeneity in their clinical and laboratory manifestations. Advances in molecular biology have allowed determination of the precise genetic defect in many cases of membrane-associated anemia and have revealed significant genetic heterogeneity. Six genetic loci have been identified and many defects, including gene deletions and insertions, missense and nonsense mutations, and splicing mutations, have been found. Analysis of these defects has provided a better understanding of the pathogenesis of these disorders and allowed a better understanding of the structure/function relationships of the proteins of the erythrocyte membrane.

Defective spectrin dimer-dimer association in a family with transfusion dependent homozygous hereditary elliptocytosis.

Red cell membrane proteins have been examined in a family in which three children have severe transfusion-dependent homozygous hereditary elliptocytosis. The membranes in all three show a considerable excess of spectrin dimers over tetramers in spectrin extracts. The red cell membranes of their parents with heterozygous hereditary elliptocytosis show a lesser but significant increase in spectrin dimers. Some of the family members also have an alpha-globin gene deletion and haemoglobin D trait. The present results are the first demonstration of a defect of spectrin dimer-dimer association in homozygous elliptocytosis and provide strong support for the concept that this defect is the primary cause of the red cell abnormality in at least some families of hereditary elliptocytosis.

Therapeutic splenectomy.

An eight-year experience at Charity Hosptial and Touro Infirmary indicates that 10 percent of splenectomies were performed for reasons other than trauma or malignancy. Fifty-nine per cent of therapeutic splenectomies were done for congenital spherocytosis or idiopathic thromboytopenic purpura. All patients having spherocytosis and 57 per cent having ITP had favorable response following splenctomy. Seven surgical death occurred following 69 splenectomies (mortality 10%). Three deaths were from pulmonary emboli, three from hemorrhagic disorders and one from peritonitis. Eighteen postopertive complications occurred, the most frequent being thromboembolic disease. Prophylactic anticoagulants were not used in any patient.