|
A Brief Review of Acanthocytosis
Angela M. Gunter, DVM; Kenneth S. Latimer, DVM, PhD; Perry J. Bain, DVM, PhD; Paula M. Krimer, DVM, DVSc
Class of 2003 (Gunter) and Department of Pathology (Latimer, Bain, Krimer), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388
Acanthocytes
There are numerous red blood cell abnormalities in shape that may occur in an animal once erythrocyte structure is compromised. Acanthocytes, also known as spur cells, occur when erythrocyte membranes contain excess cholesterol compared to phospholipid content. This can occur from an increase in blood cholesterol content or from the presence of abnormal plasma lipoprotein composition.1
The term acanthocyte is derived from the Greek word "acantha" meaning "thorn." Acanthocytes are cells with five to ten irregular, blunt, finger-like projections (Fig. 1). The projections vary in width, length, and surface distribution (Fig. 2). They are not to be confused with echinocytes, another morphologic variation of the erythrocyte that occurs in an alkaline pH or with certain diseases or disorders (please see clerkship manuscript titled "Significance of Echinocytosis in Blood Smears").4 Echinocytes have multiple, small, delicate regular-shaped spines distributed evenly around the cell membrane and are indistinguishable from artifactually crenated cells (Fig. 3).2, 8
 |
|
Figure 1. Acanthocytes with prominent, irregularly shaped, blunt, finger-like projections in the blood of a dog with hemangiosarcoma. Polychromatophilic erythrocytes also are present (blood, dog, Wright-Leishman stain). |
 |
 |
 |
 |
| Figure 2. Scanning electron micrographs demonstrating successive stages of acanthocyte formation in the blood. Membrane spicules are irregular in number, length, and spacing (modified from Bessis M: Blood Smears Reinterpreted, Springer-Verlag, 1977, p. 67). |
 |
| Figure 3. Echinocytes with evenly spaced, short projections from the cell membrane that have formed as an artifact of blood smear preparation (blood, cat, Wright-Leishman stain). |
Review of Erythrocyte Membrane Structure
To understand the pathophysiology of acanthocyte formation, basic knowledge of erythrocyte membrane structure is essential (Fig. 4). The erythrocyte membrane consists of two domains, the lipid bilayer and the cytoskeleton.3
 |
| Figure 4. Schematic diagram of the erythrocyte cell membrane (courtesy of Dr. Guillaume Lenormand, Harvard School of Public Health, Boston, MA, 02115-6021). |
Phospholipids and cholesterol compose most of the lipid bilayer. The membrane phospholipids are aphipathic; each leaflet has a hydrophilic domain (on the exterior cytoplasmic and extracellular surfaces) and a hydrophobic domain (between the two leaflets of the bilayer). The phospholipids are asymmetrically dispersed in the bilayer. The outer half of the bilayer contains sphingomyelin, glycolipids, and phosphatidylcholine, while the inner half (facing the cytoplasm) is composed of phosphatidylinositols, phospatidylserine, and phosphatidylethanolamine.3,7 Cholesterol is distributed evenly throughout the lipid domain.3 The cholesterol allows flexibility and provides stability to the membrane.8 The cell membrane also contains proteins and glycoproteins embedded in or attached to the lipid bilayer.
Proteins in the lipid domain are asymmetrically organized and usually extend through the entire bilayer, forming integral proteins. Carbohydrates are located on the hydrophilic, external portion of these proteins, forming red cell antigens and receptors or transport proteins.3,7
The cytoskeleton is the other domain of the erythrocyte membrane. It is composed of several proteins including spectrin, ankyrin, actin, and protein 4.1, forming a meshwork under the lipid bilayer. The aforementioned proteins interact with the integral proteins and lipid of the bilayer to preserve membrane integrity. The cytoskeleton is essential for maintaining shape, allowing flexibility, and organizing lipids in the erythrocyte.3,7
Pathophysiology of Acanthocyte Formation
Most research describing the pathophysiology of acanthocyte formation has been performed in human medicine. In humans, acanthocytes result from abnormalities of the lipid region in the red blood cell membrane. When observed in human blood smears, acanthocytosis is a serious finding that often is associated with severe liver disease, anorexia nervosa, cystic fibrosis, hypothyroidism, post-splenectomy, and myelodysplasia.4,5,6 It also is linked with at least three hereditary neurological disorders that are generally referred to as neuroacanthocytosis. These associated neurological diseases in humans are abetalipoproteinemia, chorea-acanthocytosis, and McLeod syndrome.5
Although the pathophysiology of acanthocytosis in domestic animals has not been studied extensively, it is believed to be similar to the acanthocytosis associated with severe liver disease in humans. With hepatocellular injury in humans, acanthocyte formation is due to a marked increase in cholesterol concentration and, subsequently, the cholesterol to phospholipid ratio of the erythrocyte cell membranes. In cirrhotic liver disease, the liver produces abnormal lipoproteins with a high cholesterol content. This excess cholesterol is readily transferred to the outer hemileaflet of the erythrocyte cell membrane, resulting in formation of flat scalloped cells.4,7 This occurs because there is a dramatic increase in the surface area of the outer portion of the lipid bilayer in comparison to the inner portion of the bilayer.4 Once in the spleen, these abnormal red cells are structurally modified, resulting in membrane fragmentation. The surface projections are remodeled and become longer and less regular, resembling spurs.4,7 The surface area is decreased, and these cholesterol-enriched erythrocytes become less deformable.4,7,8 Deformability is essential for erythrocyte passage through small capillary beds. It also is beneficial to prevent phagocytosis by macrophages, to allow exit from bone marrow, and to reduce bulk viscosity in larger vessels.3 This decrease in cellular deformability ultimately leads to destruction of acanthocytes by the spleen and, consequently, an extravascular hemolytic anemia.
Acanthocytosis in Domestic Animals
In veterinary medicine, acanthocytes appear to be associated with certain disease states and high fat diets, but may be observed in some young, healthy animals. Their presence in peripheral blood may not be as serious as it is in human medicine, but the veterinarian should consider the following conditions if acanthocytes are found on a blood smear:
Marked poikilocytosis of young ruminants: Marked poikilocytosis with the presence of acanthocytes is reported to occur in young goats and some young cattle. Acanthocytosis of young goats occurs as a result of the presence of hemoglobin C in erythrocytes during early stage of development.1
Hepatic disease: Acanthocytes also have been reported in animals with severe hepatic disease. These cells have been reported in the blood of a 2½ -year-old, mixed breed dog with chronic active necrotizing hepatitis.8 The pathogenesis of acanthocyte formation in this dog could not be determined definitively, but was believed to be similar to acanthocyte formation in humans with severe hepatic disease. The end result was an excess of cholesterol in the red cell membrane; however, it is unknown how the cholesterol accumulated in the membrane. Hypercholesterolemia did not appear to be a prerequisite for spur cell formation because the total serum cholesterol in this patient was within the reference interval. However, this patient did have an absence of high-density lipoproteins that would reduce the capability for cholesterol transport in the blood, favoring free cholesterol transfer to red cell membranes.8,9
Hemangiosarcoma: Another serious condition associated with acanthocytosis in dogs is hemangiosarcoma.9,10,12 The mechanism of acanthocyte formation is unclear. The end result is a 20-25% increase in the cholesterol to phospholipid ratio which increases membrane rigidity, resulting in poorly deformable erythrocytes.9 Gelberg and Stackhouse reported acanthocytosis in three dogs with hemangiosarcoma.10 In a larger study of hemangiosarcoma in dogs, Hirsch, Jacobsen, and Mills reported acanthocytosis in 6 of 12 dogs with hemangisarcomas of the liver and spleen.9 More recently, Ng and Mills also reported the presence of acanthocytes in the blood of dogs with hemangiosarcomas of the liver and spleen.12 Neoplastic involvement of the liver may cause severe liver disease or an unusual fragmentation due to the tortuosity of neoplastic vasculature, resulting in increased acanthocyte formation with hemangiosarcoma.2
Cholesterol-rich diet: A cholesterol-rich, atherogenic diet in dogs will induce cholesterol enrichment of red cell membranes with subsequent formation of acanthocytes. Similar effects also have been observed when guinea pigs and rabbits are fed a high cholesterol diet. Acanthocytosis may resolve once a normal diet is reinstated. The mechanism governing acanthocyte formation is once again believed to be similar to that of severe liver disease in humans, where the atherogenic diet due has a profound and injurious effect on both hepatic architecture and function.11
Miscellaneous conditions: Other conditions reported to have potential acanthocytosis include disseminated intravascular coagulopathy and renal disease-induced lipid abnormalities.1,2 A pathophysiologic mechanism for acanthocyte formation has not been proposed in these conditions.
Conclusion
Acanthocytosis does not appear to be a sensitive indicator of disease in domestic animal species as it is in humans. Further research regarding acanthocyte pathogenesis in veterinary medicine and the relationship of acanthocytosis to certain disease states needs further investigation before definitive associations can be proven. However, the presence of acanthocytosis in stained blood smears may be found in healthy, young ruminant as well as in animals with liver disease, hemangiosarcoma, or being fed a cholesterol-rich diet.
References
1. Harvey JW: Erythrocytes. In: Atlas of Veterinary Hematology. W.B. Saunders, Philadelphia, 2001, p. 29.
2. Reagan WJ, Sanders TG, DeNicola DB: Variations in red blood cell morphology. In: Veterinary Hematology, Atlas of Common Domestic Species. Iowa State University Press, Ames, 1998, pp. 21-22.
3. Smith JE: Erythrocyte membrane: Structure, function, and pathophysiology. Vet Pathol 24:471-76, 1987.
4. Palek J: Ancanthocytosis, stomatocytosis, and related disorders. In: Beutler E, Lichtman M, Coller B, Kipps T (eds.): William’s Hematology 5th ed. McGraw-Hill Inc., New York, 1995, pp. 557-560.
5. Rampoldi L, Danek A, Monaco AP: Clinical features and molecular bases of neuroacanthocytosis. J Mol Med80:475-491, 2002.
6. Kay J, Stricker R: Hematologic and immunologic abnormalities in anorexia nerovsa. Southern Med J76:1008-1010, 1983.
7. Glader B, Lukens J: Hereditary spherocytosis and other anemias due to abnormalities of the red cell membrane. In: Lee GR, Forester J, Lukens J, Paraskevas F, Greer J, Rodgers G (eds.): Wintrobe’s Clinical Hematology, 10th ed, vol 1. Lippincott Williams & Wilkins, Baltimore, 1999, pp. 1132-1134, 1150-1151.
8. Shull RM, Bunch SE, Maribei J, Spaulding GL: Spur cell anemia in a dog. J Am Vet Med Assoc 173:978-982, 1978.
9. Hirsch VM, Jacobsen J, Mills, JHL: A retrospective study of canine hemangiosarcoma and its association with acanthocytosis. Can Vet J 22: 152-155, 1981.
10. Gelberg H, Stackhouse LL: Three cases of canine acanthocytosis associated with splenic neoplasia. Vet Med Small Anim Clin72:1183-1184, 1977.
11. Cooper RA, Leslie MH, Knight D, Detweiler D: Red cell cholesterol enrichment and spur cell anemia in dogs fed a cholesterol-enriched atherogenic diet. J Lipid Res 21:1082-1089, 1980.
12. Ng CY, Mills JN: Clinical and haematological features of haemangiosarcoma in dogs. Aus Vet J62:1-4, 1985.
Photograph of Rosa sericea ptericantha by Paul Barden is from the website Old Garden Roses and Beyond.
Quotation added to the watercolor "Elvis Presley - 1960" by John Marston. The watercolor is from About Face Portraits.
|