Hemoglobinopathy

The patient, with a 1-year history of idiopathic thrombocytopenic purpura, was admitted to the hospital because of a severely decreased platelet count (9000/µL) found during follow-up complete blood count testing. She did not have any significant complaints. There was no history of bleeding from any source. However, on questioning, she mentioned a few spontaneous ecchymoses on the arms. No other significant findings were obtained on physical examination. Her complete blood count was remarkable for moderate anemia (hemoglobin, 8.5-9.6 g/dL), microcytosis (mean corpuscular volume of 60.8 fl, mean corpuscular hemoglobin of 19.7 pg, and mean corpuscular hemoglobin concentration of 32.4 g/dL), and elevated red cell distribution width (19.1%). Her red blood cell count was within the normal range. The platelet count was 11000/µL. Mild neutrophilia with a mild left shift was also present. The patient was admitted with a diagnosis of a relapse of idiopathic thrombocytopenic purpura, and treatment with steroids and intravenous immunoglobulin was initiated. Because of the microcytic anemia, further workup was performed, and hemoglobin studies were ordered. Hemoglobin electrophoresis was performed at alkaline (8.6) and acidic (6.2) pH. The corresponding gels are presented in Figure 1, A and B, respectively. Arrows indicate the index case in lane 3 of both gels. Lanes 1 and 5 are markers (hemoglobin A, S, C and hemoglobin A, F). Figure 2 represents the scan of the alkaline gel, and Figure 3 the high-performance liquid chromatography results.

What is your diagnosis?

Pathologic Diagnosis: Compound Heterozygosity for Hemoglobin S and E

S/E hemoglobinopathy occurs in a double-heterozygous individual with 2 different mutations in the beta-chain genes located on the p arm of chromosome 11. It is quite a rare entity.1,2 The prevalence of S/E carriers among all individuals with major hemoglobinopathies is not defined, because only a few cases have been reported so far. As is well known, the S mutation causes substitution of valine for glutamic acid in the 6 position, and the E mutation causes substitution of lysine for glutamic acid in the 26 position in the hemoglobin beta chain. As a result of mutations in both beta chains, the patient does not have any hemoglobin A. Approximately 30% to 35% of the total hemoglobin is hemoglobin E, and about 60% to 65% is hemoglobin S. The hemoglobin F level is usually normal or might be slightly elevated. The hemoglobin A^sub 2^ level cannot be assessed from the high-performance liquid chromatography data, because hemoglobin E has the same retention time as hemoglobin A^sub 2^ and overlaps the A^sub 2^ pick (Figure 3, the shaded area). Isoelectric focusing and its modification could be used for separation of these hemoglobins.3-5

S/E hemoglobinopathy is usually associated with mild anemia, microcytosis, and the presence of few target cells. As a rule, it does not cause sickle cell formation, and there are no complications associated with sickling. In general, these are healthy individuals with no significant pathologic changes related to the hemoglobinopathy. However, there are some reports that describe manifestations of a sickling disorder in affected individuals.6 To the best of our knowledge, there is no information suggesting higher incidence of idiopathic thrombocytopenic purpura in individuals with S/E or any other hemoglobinopathy. Most likely, in our case, these conditions occurred coincidentally.

The S mutation is the most common hemoglobin mutation in the African American population as well as in black populations worldwide. The E mutation is most common in Southeast Asia. This implies a higher probability of appearance of such double-heterozygous individuals from interracial relationships between individuals belonging to these ethnic groups. Nevertheless, S/E individuals have been reported in families where both biologic parents belong to the same ethnic group. These are cases of Saudi Arabian, Indian, Pakistani, Turkish, and African American origin. Our patient is of African American background.

References

1. Steinberg MH. Compound heterozygous and other sickle hemoglobinopathies. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge, United Kingdom: Cambridge University Press; 2001:786-810.

2. Hoyer JD, Kroft SH, eds. Color Atlas of Hemoglobin Disorders: A Compendium Based on Proficiency Testing. Northfield, Ill: College of American Pathologists; 2003.

3. Bossisio AB, Rochette J, Wajcman H, Gianazza E, Righetti PG. Electrophoretic and chromatographic techniques for the differential diagnosis of haemoglobin abnormality: hemoglobin E heterozygosity. J Chromatogr. 1985;330:299-306.

4. Molteni S, Frischknecht H, Thormann W. Application of dynamic capillary isoelectric focusing to the analysis of human hemoglobin variants. Electrophoresis. 1994;15:22-30.

5. Hempe JM, Craver RD. Separation of hemoglobin variants with similar charge by capillary isoelectric focusing: value of isoelectric point for identification of common and uncommon hemoglobin variants. Electrophoresis. 2000;21:743-748.

6. Eichhorn RF, Buurke EJ, Blok P, Berends MJH, Jansen CL. Sickle cell-like crisis and bone marrow necrosis associated with parvovirus B19 infection and heterozygosity for haemoglobins S and E. J Intern Med. 1999;245:103-106.

Lizmarie Andino, MD; Semyon A. Risin, MD, PhD

Accepted for publication August 24, 2004.

From the Department of Pathology & Laboratory Medicine, University of Texas Health Science Center-Houston Medical School, Houston.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Semyon A. Risin, MD, PhD, University of Texas Health Science Center-Houston Medical School, 6431 Fannin St, MSB, 2.290, Houston, TX 77030 (e-mail: semyon.a.risin@uth.tmc.edu).

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