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678 Part VI: The Erythrocyte Chapter 46: Erythrocyte Membrane Disorders 679

In neonates the clinical severity of HE can be affected by the weak A few cases of hydrops fetalis accompanied by fetal or early
binding of BPG to fetal hemoglobin leading to an increase in free BPG, neonatal death as a result of unusually severe forms of HE have been
which, in turn, destabilizes the spectrin–actin–protein 4.1 interac- described. A severely affected hydropic infant salvaged by intrauterine
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tion. Finally, hemolytic anemia can be exacerbated by several acquired transfusions (Chap. 55) and early exchange transfusion has remained
conditions, including those that alter microcirculatory stress to the transfusion dependent for more than 2 years.
cells.
Laboratory Features
Inheritance The hallmark of HE is the presence of cigar-shaped elliptocytes on
HE is typically inherited as an autosomal dominant disorder. De novo blood films (Figs. 46–10D and 46–11F). These normochromic, normo-
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mutations are rare. The severity of clinical symptoms is highly vari- cytic elliptocytes may number from a few to 100 percent. The degree of
able reflecting heterogeneous molecular abnormalities, as well as the hemolysis does not correlate with the number of elliptocytes present.
coinheritance of other genetic defects or polymorphisms that modify Spherocytes, stomatocytes, and fragmented cells may be seen. Osmotic
disease expression. A strong genetic relationship exists between HE and fragility is abnormal in severe HE and in HPP. The reticulocyte count
HPP, and parents or siblings of patients with HPP often have typical HE. generally is less than 5 percent but may be higher when hemolysis is
severe. Other laboratory findings in HE are similar to those of other
hemolytic anemias and are nonspecific markers of increased erythro-
Clinical Features cyte production and destruction. For example, increased serum biliru-
The clinical presentation of HE is heterogeneous, ranging from asymp- bin, increased urinary urobilinogen, and decreased serum haptoglobin
tomatic carriers to patients with severe, life-threatening anemia. The reflect increased erythrocyte destruction.
overwhelming majority of patients with HE are asymptomatic and are HPP blood films exhibit similar features to severe HE, but in addi-
diagnosed incidentally during testing for unrelated conditions. HPP tion, they reveal extreme poikilocytosis, some bizarre-shaped cells with
patients present in infancy or early childhood with a very severe hemo- fragmentation or budding and often only very few or no elliptocytes
lytic anemia. (Fig. 46–13). Microspherocytosis is common and MCV is usually low,
Asymptomatic carriers who possess the same molecular defect ranging between 50 to 70 fL. Pyknocytes are prominent on blood films
as an affected HE relative but who have normal or near-normal blood of neonates with HPP. The thermal instability of erythrocytes, originally
films have been identified. The erythrocyte life span is normal, and the reported as diagnostic of HPP, is not unique to this disorder because it
patients are not anemic. Asymptomatic HE patients may experience is also commonly found in HE erythrocytes.
hemolysis in association with infections, hypersplenism, vitamin B Specialized testing has been used in difficult cases or cases requir-
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deficiency, or microangiopathic hemolysis, such as disseminated intra- ing a molecular diagnosis. Tests on isolated membrane proteins include
vascular coagulation or thrombotic thrombocytopenic purpura. In the analysis and quantitation of the proteins by SDS-PAGE; extraction
latter two conditions, increased hemolysis may result from microcircu- of spectrin from the membranes to evaluate the spectrin-dimer-to-
latory damage superimposed on the underlying mechanical instability tetramer ratio on nondenaturing gels, as well as limited tryptic digestion
of red cells. of spectrin followed by SDS-PAGE or two-dimensional gel electropho-
HE patients with chronic hemolysis experience moderate to severe resis to identify the defective domain. Ektacytometry may be used to
hemolytic anemia with elliptocytes and poikilocytes on the blood film. measure membrane stability and deformability. Genomic DNA and/or
Red cell life span is decreased and patients may develop complications complementary DNA analyses are used to determine the underlying
of chronic hemolysis, such as gallbladder disease. In some kindreds, mutation.
the hemolytic HE has been transmitted through several generations. In
other kindreds, not all HE subjects have chronic hemolysis; some have Differential Diagnosis
only mild hemolysis, presumably because another genetic factor mod- Elliptocytes may be seen in association with several disorders, includ-
ifies disease expression. The blood films of the most severe HE patients ing megaloblastic anemias, hypochromic microcytic anemias (iron-
with chronic hemolysis exhibit elliptocytes, poikilocytes, fragments and deficiency anemia and thalassemia), myelodysplastic syndromes, and
small microspherocytes, reminiscent of HPP. myelofibrosis. In these conditions, elliptocytosis is acquired and gener-
HPP represents a subtype of common HE, as evidenced by the ally represents less than one-quarter of red cells seen on the blood film.
coexistence of HE and HPP in the same family and the presence of the History and additional laboratory testing usually clarify the diagnosis of
same molecular defects of spectrin. HE relatives are heterozygous these disorders. Pseudoelliptocytosis is an artifact of blood film prepa-
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for an elliptocytogenic spectrin mutation, whereas HPP patients are ration and these cells are found only in certain areas of the film, usually
homozygous or doubly heterozygous and are also partially deficient in near its tail. The long axes of pseudoelliptocytes are parallel, whereas the
spectrin. 128,129 axes of true elliptocytes are distributed randomly.
Hereditary Elliptocytosis and Pyropoikilocytosis in Infancy
Clinical symptoms of elliptocytosis are uncommon in the neonatal Therapy and Prognosis
period. Typically, elliptocytes do not appear on the blood film until the Therapy is rarely needed in patients with HE. In rare cases, occasional
patient is 4 to 6 months old. Occasionally, severe forms of HE pres- red blood cell transfusions may be required. In cases of severe HE and
ent in the neonatal period with severe, hemolytic anemia with marked HPP, splenectomy has been palliative, as the spleen is the site of ery-
poikilocytosis and jaundice. These patients may require red cell trans- throcyte sequestration and destruction. The same indications for sple-
fusion, phototherapy, or exchange transfusion. Usually, even in severely nectomy in HS can be applied to patients with symptomatic HE or HPP.
affected patients, the hemolysis abates between 9 and 12 months of age, Postsplenectomy, patients with HE or HPP exhibit increased hematoc-
and the patient progresses to typical HE with mild anemia. Infrequently, rit, decreased reticulocyte counts, and improved clinical symptoms.
patients remain transfusion dependent beyond the first year of life and Patients should be followed for signs of decompensation during
require early splenectomy. In cases of suspected neonatal HE or HPP, acute illnesses, characterized by acute decrease of hematocrit from
review of family history and analysis of blood films from the parents nonspecific suppression of erythropoiesis by a concurrent acute event.
usually are of greater diagnostic benefit than other available studies. HE and particularly HPP patients are at increased risk for parvovirus

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