Hereditary Elliptocytosis Workup

Updated: Nov 06, 2019
  • Author: Daniel J Kim, MD, MS; Chief Editor: Emmanuel C Besa, MD  more...
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Approach Considerations

The diagnosis of hereditary elliptocytosis (HE) and its more severe form, hereditary pyropoikilocytosis (HPP), relies on identifying abnormal red blood cell (RBC) morphology on peripheral blood smear (elliptocytes, poikilocytosis and fragmented RBCs), and identifying characteristic membrane biomechanical properties using osmotic gradient ektacytometry. [2, 7]

Targeted next-generation gene sequencing can be used to identify or confirm the diagnosis of HE and HPP, especially in severe, transfusion-dependent cases in which the RBC phenotype cannot be evaluated. In addition, identification of the molecular cause allows genotype-phenotype correlations and may assist in discussions of prognosis. [7, 11]  

The major drawback of current next-generation sequencing applications is the difficulty in determining the pathogenicity of the numerous identified variants. One of the ways to overcome this limitation is the simultaneous evaluation of all family members, allowing one to establish the inheritance pattern of the identified variants and thus to understand its pathogenetic role, although functional characterizations are often necessary. [7]


Laboratory Studies

Initial laboratory studies for the diagnosis of hereditary elliptocytosis (HE) include the following [12] :

  • Complete blood cell count (CBC)
  • Peripheral blood smear
  • Direct antiglobulin test (Coombs test)
  • Bilirubin
  • Haptoglobin
  • Reticulocyte count/immature reticulocyte fraction
  • Potassium
  • Lactate dehydrogenase (LDH)

Microscopic examination of peripheral smears in patients with HE reveals that about 25% (sometimes nearly 100%) of cells are characteristically elliptical and often described as cigar-shaped. Some cases have fewer than 25% elliptocytes. Fragmented cells may also be seen. See the image below.

Hereditary elliptocytosis: Peripheral blood smear Hereditary elliptocytosis: Peripheral blood smear reveals cigar-shaped erythrocytes (elliptocytes). Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.

While an overwhelming majority of HE cases are asymptomatic, 10% of patients present with moderate‐to‐severe anemia. Poikilocytes and fragmented red cells in addition to elliptocytes are a feature of red cell morphology in HE patients with moderate–to‐severe anemia. [13]  

Peripheral smear findings in subcategories of HE include the following:

  • Patients with hereditary pyropoikilocytosis (HPP) have an increased number of microspherocytes (see the image below)

  • Patients with stomatocytic elliptocytosis have both spherocytes and elliptocytes but no poikilocytes. RBCs are distinctive, rounded elliptocytes bisected by a bar of hemoglobin

  • Southeast Asian ovalocytosis is unique among elliptocytoses in that the membrane structure of the RBCs is characterized by rigid stability rather than instability. RBCs show a characteristic morphology with one or two transverse slits across the body of oval-shaped RBCs 

Bizarre RBC morphology seen in hereditary pyropoik Bizarre RBC morphology seen in hereditary pyropoikilocytosis. Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.

Elliptocytes can occur in many other conditions (eg, iron deficiency, leukemias, megaloblastic anemias, myeloproliferative diseases, myelodysplastic syndromes) but usually do not reach the proportions observed in patients with HE. Elliptocytes in patients with severe iron deficiency anemia are markedly hypochromic, a finding not associated with any of the HE disorders. Of most importance, patients with HE have a positive family history, whereas patients with other diseases associated with elliptocytes have underlying manifestations of their particular diseases.

Elliptocytosis must be differentiated from pseudoelliptocytosis, which is a common artifact of peripheral smear preparation. In pseudoelliptocytosis, the blood cells appear stretched and lined up in parallel, whereas in true elliptocytosis, the cells are oriented in different directions.

Results of osmotic fragility testing are within reference ranges in typical HE, but values are increased in spherocytic HE and HPP. [14]  When tested for thermal stability, normal RBCs can withstand temperatures up to 49°C, but RBCs associated with HPP denature at 45-46°C.

Laboratory studies may show evidence of hemolysis, such as low haptoglobin levels; a high reticulocyte count; and elevated concentrations of LDH and indirect bilirubin. It is important to emphasize that the percentage of elliptocytes observed does not correlate with the severity of hemolysis.

Although in most cases, the diagnosis of HE can be made without further studies, for further testing, International Council for Standardization in Haematology (ICSH) guidelines recommend sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) for quantitation of protein 4.1 and spectrin analysis (spectrin dimer content and spectrin variant), if those are available; or use of ektacytometry to obtain a deformability index (DI) profile, which shows a characteristic trapezoidal shape in patients with HE. [12, 15]

Imaging studies are not needed in the diagnosis of HE, but can reveal findings consistent with chronic hemolysis, such as splenomegaly and gallstones.


Osmotic gradient ektacytometry has been the reference technique for diagnosis of RBC membrane disorders, but its limited availability has severely restricted its use. [16]  Although not readily available, ektacytometry in combination with gene sequencing can help clarify unusual variants. [17]  

An ektacytometer is a laser-diffraction viscometer in which deformability is measured as a continuous function of the osmolality of the suspending medium. The Omin point is the osmolality at which the minimum deformability index is reached and is related to the surface area–to-volume ratio of the cell. The Hyper point is the osmolality at which the minimum deformability index reaches half of its maximum value. The Hyper point is related to the internal viscosity of the cell and to its mechanical properties. [2]

In HE, ektacytometry shows decreased maximum deformability characterized by a trapezoidal curve with normal Omin and Hyper points. In HPP, the maximum deformability is decreased and the Omin and Hyper points are shifted towards the left. [7] In Southeast Asian ovalocytosis, the key finding is lack of deformability of the erythrocytes. [16]