Red Blood Cell Membrane Disorders

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Chapter 15 Red Blood Cell Membrane Disorders

Patrick G. Gallagher

Figure 15-1 A SIMPLIFIED CROSS-SECTION OF THE ERYTHROCYTE MEMBRANE.

The lipid bilayer forms the equator of the cross-section with its polar heads (small circles) turned outward. 4.1R, Protein 4.1R; 4.2, protein 4.2; Rh, Rhesus polypeptide; RhAG, Rh-associated glycoprotein; LW, Landsteiner-Wiener glycoprotein.

(From Perrotta S, Gallagher PG, Mohandas N: Hereditary spherocytosis. Lancet 372:1411, 2008.)

Table 15-1 Erythrocyte Membrane Abnormalities in Hereditary Spherocytosis, Hereditary Elliptocytosis, and Related Disorders

Gene	Disorder	Comment
α-Spectrin	HS, HE, HPP, NIHF	Location of mutation determines clinical phenotype. α-Spectrin mutations are most common cause of typical HE.
Ankyrin	HS	Most common cause of typical dominant HS.
Band 3	HS, SAO, NIHF	In HS “pincer-like” spherocytes on smear presplenectomy. SAO erythrocytes have transverse ridge or longitudinal slit.
β-Spectrin	HS, HE, HPP, NIHF	Location of mutation determines clinical phenotype. In HS, acanthrocytic spherocytes on smear presplenectomy.
Protein 4.2	HS	Common in Japanese HS.
Protein 4.1	HE
Glycophorin C	HE	Concomitant protein 4.1 deficiency is basis of HE in glycophorin C defects.

HE, Hereditary elliptocytosis; HPP, hereditary pyropoikilocytosis; HS, hereditary spherocytosis; NIHF, nonimmune hydrops fetalis; SAO, Southeast Asian ovalocytosis.

Table 15-2 Peripheral Blood Film Evaluation in a Patient With Red Cell Membrane Disorder

Shape	Pathobiology	Diagnosis
Microspherocytes	Loss of membrane lipids leading to a reduction of surface area resulting from deficiencies of spectrin, ankyrin, or band 3 and protein 4.2 Removal of membrane material from antibody-coated red cells by macrophages Removal of membrane-associated Heinz bodies, with the adjacent membrane lipids, by the spleen	HS Immunohemolytic anemias Heinz body hemolytic anemias
Elliptocytes	Permanent red cell deformation resulting from a weakening of skeletal protein interactions (such as the spectrin dimer-dimer contact). This facilitates disruption of existing protein contacts during shear stress–induced elliptical deformation. Subsequently, new protein contacts are formed that stabilize elliptical shape Unknown	Mild common HE Iron deficiency, megaloblastic anemias, myelofibrosis, myelophthisic anemias, myelodysplastic syndrome, thalassemias
Poikilocytes/Fragments	Weakening of skeletal protein contacts resulting from skeletal protein mutations Unknown	Hemolytic HE/HPP Iron deficiency, megaloblastic anemias, myelofibrosis, myelophthisic anemias, myelodysplastic syndrome, thalassemias
Schistocytes, fragmented red cells	Red cells “torn” by mechanical trauma (fibrin strands, turbulent flow)	“Microangiopathic” hemolytic anemia associated with disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, vasculitis, heart valve prostheses
Acanthocytes	Uptake of cholesterol and its preferential accumulation in the outer leaflet of the lipid bilayer Selective accumulation of sphingomyelin in the outer lipid leaflet Unknown	Spur cell hemolytic anemia in severe liver disease Abetalipoproteinemia Chorea-acanthocytosis syndrome, malnutrition, hypothyroidism McLeod phenotype
Echinocytes	Expansion of the surface area of the outer hemileaflet of lipid bilayer relative to the inner hemileaflet Unknown	Hemolytic anemia associated with hypomagnesemia and hypophosphatemia in malnourished patients, pyruvate kinase deficiency; in vitro artifact of low blood storage (ATP depletion), contact with glass or elevated pH Hemolysis in long-distance runners, renal failure
Stomatocytes	Expansion of the surface area of the inner hemileaflet of the bilayer relative to the outer leaflet Unknown	Exposure of red cells to cationic anesthetics in vitro; in vivo the drug concentrations may not be sufficient to produce similar effect Alcoholism, inherited disorders of membrane permeability (hereditary stomatocytosis)
Target cells	Absolute excess of membrane lipids (both cholesterol and phospholipids: “symmetric” lipid gain), followed by an increase of cell surface area Relative excess of surface area because of a decrease in cell volume	Obstructive jaundice, liver disease with intrahepatic cholestasis Thalassemias and some hemoglobinopathies (C, D, E)

ATP, Adenosine triphosphate; HE, hereditary elliptocytosis; HPP, hereditary pyropoikilocytosis; HS, hereditary spherocytosis.

Splenectomy for Hereditary Spherocytosis

Splenectomy is a permanently curative treatment in most cases of hereditary spherocytosis (HS). Thus for years splenectomy was recommended for all HS patients regardless of the severity of anemia, gallbladder disease, or other symptoms. However, increasing concerns regarding overwhelming postsplenectomy infection (OPSI), the emergence of penicillin-resistant pneumococci, and increased risk for cardiovascular diseases have tempered these recommendations. When considering splenectomy, health care providers, the patient, and the patient’s family should review and consider the risks and benefits. Individual factors that may pose additional risk, such as distance from medical care in case of febrile illness and residence in or travel to areas where parasitic diseases such as malaria or babesiosis occur, should be considered. Expert opinions vary on indications for splenectomy. There are no studies to guide practice. However, because the risk for OPSI is highest in infancy and childhood, most agree it is best to avoid total splenectomy in early childhood.

Benefits

Anemia ameliorated

Risk for hemolysis-associated gallbladder disease eliminated

Risk for aplastic crisis eliminated

Risks

OPSI—especially with encapsulated organisms (Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae)

Increased risk for thrombotic complications

Increased risk for vascular complications (pulmonary hypertension, cardiovascular disease)

Indications for Splenectomy

Expert opinions vary

Severe, symptomatic spherocytosis

Growth failure, skeletal changes, leg ulcers, and extramedullary hematopoietic tumors (signs of severe anemia)

Older patients with vascular compromise of vital organs

Moderate HS with compensated, asymptomatic anemia: controversial; decision should be individualized

Figure 15-2 BLOOD FILMS OF SUBJECTS WITH VARIOUS FORMS OF HEREDITARY ELLIPTOCYTOSIS (HE).

A, Simple heterozygote with mild common HE. Note the predominant elliptocytosis with some rod-shaped cells (arrow) and virtual absence of poikilocytes. B, Simple heterozygote with severe common hemolytic elliptocytosis. Note the numerous small fragments and poikilocytes. C, “Homozygous” common HE because of doubly heterozygous state for two mutant α-spectrins. Both parents have mild HE. Note the many elliptocytes as well as numerous fragments and poikilocytes. D, Hereditary pyropoikilocytosis. The patient is a double heterozygote for a structural α-spectrin mutant and a presumed α-spectrin synthetic defect. Note the prominent microspherocytosis, micropoikilocytosis, and fragmentation. Only few elliptocytes are present. Some poikilocytes are in the process of budding (arrow). E, Spherocytic HE (hereditary ovalocytosis). Most red blood cells are oval rather than truly elliptical. Many oval cells are “fat,” lacking a central concavity, the feature distinguishing spherocytic HE from common HE. F, Southeast Asian ovalocytosis. Most cells are oval, some containing either a longitudinal slit or a transverse ridge (arrow).

Figure 15-3 BLOOD FILM OF A PATIENT WITH LIVER CIRRHOSIS AND SPUR CELL ANEMIA BEFORE (A) AND AFTER (B) SPLENECTOMY.

The latter smear demonstrates the effect of cholesterol acquisition leading to targeting (indicating increase in surface area) and irregularities in cell contour. The conditioning effect of the spleen (A) is demonstrated by the spheroidal shape of the cells and the remodeling of the spicules.

(From Cooper RA, Kimball DB, Durocher JR: The role of the spleen in membrane conditioning and hemolysis of spur cells in liver disease. N Engl J Med 290:1279, 1974.)