Elliptocytosis and Ovalocytosis in Stained Blood Smears

Angela M. Ehinger, DVM; Kenneth S. Latimer, DVM, PhD; Bruce E. LeRoy, DVM, Dipl. ACVP; Perry J. Bain, DVM, PhD

Class of 2003 (Ehinger) and Department of Pathology (Latimer, LeRoy, Bain), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Elliptocytes (ovalocytes) are non-nucleated erythrocytes that are ovoid to elliptical in shape and are usually flat instead of the standard biconcave shape. This oval shape is a normal finding for animals in the Camelidae family (camels, llamas, alpacas, etc.; Fig. 1)¹ Circulating, mature erythrocytes of birds, reptiles, amphibians, and fish also are elliptical; however, the nucleus is normally retained (Fig. 2).^2,3 Elliptocytes can be present in the blood of healthy animals, but usually comprise <1% of erythrocyte population. Larger numbers of elliptocytes in the stained blood film usually indicate the presence of acquired or congenital disease.

Figure 1. Elliptical, anucleate erythrocytes from a llama. A lymphocyte also is present. Llama, blood smear, Wright-Leishman stain.	Figure 2. Elliptical, nucleated erythrocytes are a normal hematological finding in certain vertebrates such as birds. A monocyte also is present. Amazon parrot, blood smear, Wright-Leishman stain.

Acquired diseases (see below) usually result in <10% elliptocytes; however, up to 50% of the erythrocytes may be elliptocytes in dyserythropoises. In hereditary elliptocytosis the percentage of elliptocytes may vary from 0% to 98%.⁴ Elliptocytosis was first described in blood smears from humans in 1904 and was later demonstrated to be hereditary.⁴ The first reported case of hereditary elliptocytosis (HE) was described by Smith in 1983.⁵ Since the original description in human beings, HE has also been reported in mice.⁶

Figure 3. Elliptocytes or ovalocytes (arrow) in the blood smear of a cat following doxorubicin treatment. A macroplatelet is present in the upper lefthand corner. Cat, blood smear, Wright-Leishman stain.

Elliptocytosis is the term generally used to describe conditions in which the erythrocytes are ovoid to elliptical in shape. Ovalocytosis is a term usually reserved for a rarer condition in which erythrocytes appear more oval and lack a central concavity. Spherocytes also may be present in the blood film.⁷ In humans, this condition has been designated Southeast Asian ovalocytosis, Melanesian ovalocytosis, or stomatocytic HE. Affected erythrocytes typically are more round than elliptical and have a longitudinal or transverse slit.⁴

Erythrocyte Structure

The erythrocyte is a relatively simple cell, composed of only a membrane and cytoplasm. Energy is provided via glycolysis and mature mammalian erythrocytes are anucleate. Membrane structure is important in the formation of elliptocytes and ovalocytes. The cell membrane is composed of lipid and the cytoskeleton (Fig. 4). The "lipid portion" of the membrane actually consists of cholesterol, phospholipids, and protein. The cytoskeleton is formed by several proteins (spectrin, ankyrin, actin, and protein 4.1) that are arranged beneath and interact with the lipid layer. This cytoskeleton is vital to the integrity and stability of the erythrocyte. Deficiencies of any of the proteins may result in an altered erythrocyte cytoskeletal structure. This change is reflected by an inability of the erythrocyte to alter shape when passing through capillary beds.⁸ In HE, the membrane change is due to an abnormality of the cytoskeletal protein spectrin (protein 4.1). This results in decreased deformability of affected erythrocytes as they traverse the capillary beds of the body.

Figure 4. Schematic diagram of the erythrocyte cell membrane (courtesy of Dr. Guillaume Lenormand, Harvard School of Public Health, Boston, MA, 02115-6021).

Causes of Elliptocytosis and Ovalocytosis

Elliptocytosis may be associated with inherited or acquired diseases. These conditions are listed in Table 1.

Table 1. Causes of elliptocytosis^{4,8,9,10,11,12,13,14,15}

Hereditary Elliptocytosis

Hereditary elliptocytosis (HE) has been described in humans, dogs, and a mouse. In both humans and dogs, HE is inherited as an autosomal recessive trait. In humans, the HE may have different degrees of effect as presented in Table 2.

Table 2. Types of human hereditary elliptocytosis^4,17,18

In dogs, HE is primarily a result of protein 4.1 deficiency. However, previous mutations in protein 4.1 coupled with a deficiency of protein 4.1 also causes HE.¹⁶ HE has been documented in mixed breed dogs and in a Silky Terrier. ^7,19

In mice (as in humans), deficiency of spectrin results in an inherited spherocytic hemolytic anemia. Affected erythrocytes appear more round than oval. One case of HE has been documented in a mouse. HE in mice is caused by a mutation spectrin or protein 4.1 rather than a deficiency of the protein.⁹

Clinical Signs and Laboratory Findings

The clinical signs of elliptocytosis are highly variable, depending on the cause of the red blood cell defect and the species affected. Human carriers of HE may lack signs of disease. In individuals affected with HE, the degree of anemia may be variable. People with mild HE may have a mild but fully compensated anemia. Patients with HE of moderate severity may present with a moderate, incompletely compensated hemolytic anemia with splenomegaly. Patients with incompletely compensated anemia also are susceptible to more severe, acute, anemic crises that can be triggered by stress and other disease processes. In severe cases of chronic hemolytic anemia, treatment may include blood transfusions and splenectomy. There also are variants of HE where the disease is severe in newborns and gradually decreases in severity with age.^4,18 A specific variant of HE, Southeast Asian ovalocytosis, is seen in humans in southeast Asia where the red blood cell is more rigid than normal and resists invasion by malaria parasites.¹⁷

The clinical signs of hereditary elliptocytosis in the dog are minimal to nil, and the disease usually is diagnosed incidentally.^5,19 Theoretically, dogs with HE could present with episodes of severe hemolytic anemia, but this has not been documented yet.

Diagnosis of Elliptocytosis and Ovalocytosis

Elliptocytosis and ovalocytosis are diagnosed by microscopic examination of the stained blood smear. These abnormally shaped erythrocytes generally are not detected by automated hematology analyzers. As a result, diagnosis of elliptocytosis in people and animals is incidental.

Treatment

In humans, severe cases of HE are often treated by splenectomy. Blood transfusions may be necessary in cases of noncompensated hemolytic anemia.^4,18 Treatment of elliptocytosis in dogs is not well documented. Elliptocytosis usually is an incidental finding on blood smear examination. Clinical signs of disease are rare and usually do not require treatment.⁵

Summary

Elliptocytes are erythrocytes that are oval to elliptical in shape. They are a normal finding in birds, reptiles, amphibians, fish, and members of the Camelidae family (camels, llamas, alpacas). In other mammals, elliptocytosis (ovalocytosis) is an uncommon morphologic change of erythrocytes due to inherited or acquired disease. HE has been documented in humans, dogs, and mice as a result of erythrocyte membrane protein mutation or deficiency. In humans, Southeastern Asian ovalocytosis is a specific form of HE in which the erythrocyte are more malaria-resistant. Acquired elliptocytosis is not as well documented, but often is associated with hemolytic anemia in humans. In dogs and cats, elliptocytosis usually is an incidental finding related to systemic disease. Treatment of HE in humans is variable depending on the severity of the disease and associated hemolytic anemia. Blood transfusions and splenectomy sometimes are required in severe hemolytic anemia. In contrast, treatment in animals is poorly documented. Because most cases of elliptocytosis to date are diagnosed as incidental findings, this condition is not necessarily treated per se. However, therapy may be recommended for the underlying cause of the disease.

References

1. Harvey J: Atlas of Veterinary Hematology: Blood and Bone Marrow of Domestic Animals. W.B. Saunders Company, Philadelphia, 2001, pp. 33.

2. Fudge AM (ed): Laboratory Medicine- Avian and Exotic Pets. W.B. Saunders Company, Philadelphia, 2000, pp. 15, 194.

3. Stoskopf MK: Clinical Pathology, In: Stoskopf MK (ed): Fish Medicine. W. B. Saunders Company, Philadelphia, 1993, pp. 113-125.

4. Beutler E, Lichtman MA, Coller BS, Kipps TJ (eds): Williams Hematology, 5^th ed. McGraw-Hill, Inc., New York, 1995, pp. 361, 543, 550.

5. Smith JE, Moore K, Arens M, Rinderknecht GA, Ledet A: Hereditary elliptocytosis with protein band 4.1 deficiency in the dog. Blood 61:373-377, 1983.

6. Muro AF, Marro ML, Gajovic S, Porro F, Luzzatto L, Baralle FE: Mild spherocytic hereditary elliptocytosis and altered levels of alpha- and gamma-adducins in beta-adducin-deficient mice. Blood 95:3978-3985, 2000.

7. Feldman BF, Zinkl JG, Jain NC (eds): Schalm’s Veterinary Hematology, 5^th ed. Lippincott Williams and Wilkins, Baltimore, 2000, pp. 956, 1014-1015.

8. Smith JE: Erythrocyte membrane: structure, function, and pathophysiology. Vet Pathol 24:471-476, 1987.

9. Wandersee NJ, Roesch AN, Hamblen NR, de Moes J, van der Valk MA, Bronson RT, Gimm JA, Mohandas N, Demant P, Barker JE: Defective spectrin integrity and neonatal thrombosis in the first mouse model for severe hereditary elliptocytosis. Blood 97:543-550, 2001.

10. Hoff B, Lumsden, JH, Valli VEO: An appraisal of bone marrow biopsy in assessment of sick dogs. Can J Comp Med 49:34-42, 1985.

11. Shelly SM: Causes of canine pancytopenia. Comp Cont Educ Pract Vet 10:9-16, 1988.

12. O’Keefe DA, Schaeffer DJ: Hematologic Toxicosis associated with doxorubicin administration in cats. J Vet Intern Med 6:276-283, 1992.

13. Scavelli TD, Hornbuckle WE, Roth L, Rendano Jr. VT, de Lahunta A, Center SA, French TW, Zimmer JF: Portosystemic shunts in cats: seven cases (1976-1984). J Am Vet Med Assoc 189:317-325, 1986.

14. Christopher MM, Lee SE: Red cell morphologic alterations in cats with hepatic disease. Vet Clin Pathol 23:7-12, 1994.

15. Weiss DJ, Lulich J: Myelodysplastic syndrome with sideroblastic differentiation in a dog. Vet Clin Pathol 28:59-63, 1999.

16. Conboy JG, Shitamoto R, Parra M, Winardi R, Kabra A, Smith J, Mohandas N: Hereditary elliptocytosis due to both qualitative and quantitative defects in membrane skeletal protein 4.1. Blood 78:2438-2443, 1991.

17. Liu SC, Zhai S, Palek J, Golan DE, Amato D, Hassan K, Nurse GT, Babona D, Coetzer T, Jarolim P, and et al.: Molecular defect of the band 3 protein in southeast Asian ovalocytosis. New Engl J Med 323:1530-1538, 1990.

18. Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN: Wintrobe’s Clinical Hematology, 9^th ed. Lea & Febiger, Philadelphia, 1993, pp. 972-976.

19. Mills JN, Marsden CA: Presumed hereditary elliptocytosis in a dog. Aust Vet J 77:651-652, 1999.

Acknowledgement

"Peruvian Woman with Alpaca" is from Angela Cater's Pet Portraits and Animal Art and is used with permission of the artist.

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