eMedicine Specialties > Hematology > Uncommon RBC Membrane Disorders

Spur Cell Anemia

Author: Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences
Coauthor(s): Mansoor Javeed, MD, FACP, Clinical Assistant Professor of Medicine, University of California Davis; Consultant, Sierra Hematology-Oncology Medical Center; James O Ballard, MD, Kienle Chair for Humane Medicine, Professor, Departments of Humanities, Medicine, and Pathology, Division of Hematology/Oncology, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine
Contributor Information and Disclosures

Updated: Nov 10, 2009

Introduction

Background

Spur cells or acanthocytes are large erythrocytes covered with spikelike projections that vary in width, length, and distribution. Spur cells can be encountered in acquired or inherited disorders.

Pathophysiology

The red blood cell membrane is composed of a lipid bilayer and proteins assembled in a complex manner, which allows the erythrocyte to function as an interface between the cell and its environment, protecting the red blood cell integrity and allowing a bidirectional flux of electrolytes, energy, and information.³ To preserve the red blood cell shape and regulate its deformability and mechanical stability, the plasma membrane is tethered to a filamentous network of proteins known as the membrane skeleton.

The lipid bilayer contains nearly equal quantities (molar ratio 0.9-1) of unesterified cholesterol and phospholipids that are asymmetrically distributed between the outer and inner leaflets. Phosphatidylcholine (30% of phospholipids) and sphingomyelin (30%) are found mainly in the outer layer, whereas phosphatidylethanolamine (28%) and phosphatidylserine (14%) reside in the inner layer. 

Although the cholesterol contents of the membrane are in equilibrium with the plasma-free cholesterol, the uneven distribution of phospholipids is maintained by both passive and active processes. Most acanthocytic disorders are associated with acquired abnormalities of the outer leaflet of the lipid bilayer. However, some rare conditions have normal lipids and abnormal membrane proteins.

In severe liver disease, free cholesterol in red blood cells equilibrates with abnormal lipoproteins containing a high free cholesterol-to-phospholipid ratio, resulting in the preferential expansion of the outer leaflet and the development of the spur cell shape.^4,5,6,7 A decrease occurs in polyunsaturated versus saturated and monounsaturated fatty acid content in red blood cells of patients with cirrhosis. This abnormality is more pronounced in patients with spur cell anemia, resulting in the alteration of the red blood cell shape and a decrease of their fluidity. An increase in the proteolytic activity of the erythrocyte membrane is also reported in spur cell anemia. The significance and role of this abnormality in changing the shape of the red blood cell shape and in hemolysis are unknown.

The plasma of some of these patients exhibits decreased activity of lecithin cholesterol acyltransferase, resulting in increased free cholesterol in the outer layer of the red blood cell membrane as a direct consequence of its increased concentration in the plasma. After acquiring these abnormalities in the plasma, the red blood cells undergo a remodeling process in the spleen, which gives them the spheroidal shape with longer and more irregular projections.

Spur cells are characterized by diminished deformability, which is responsible for their entrapment and destruction in the spleen. Alteration of band 3, the anion exchange protein, is thought to play role in the formation of acanthocytes in chorea-acanthocytosis.⁸ According to this hypothesis the red blood cell shape is controlled by the ratio of the outward-facing (band 3o) and inward-facing (band 3i) conformations of band 3. Depending on this ratio, there will be contraction (leading to echinocytosis) or relaxation (leading to either stomatocytosis) of the membrane skeleton.⁸

In abetalipoproteinemia, B-apoprotein–containing lipoproteins (chylomicrons, very low-density lipoproteins [VLDL], low-density lipoproteins [LDL]) are nearly absent in the plasma. Plasma cholesterol and phospholipids are decreased, with a relative increase of sphingomyelin at the expanse of lecithin. At equilibrium, the sphingomyelin concentration in the outer leaflet increases, resulting in its expansion and acanthocytosis.

The expression of the Kell antigen (the product of a single gene on band 7q23) on red blood cells, white blood cells, and monocytes is under the control of the Kx antigen encoded for by the XK gene on band Xp21.⁹ Both antigens are transmembrane proteins bound by a single disulfide bond. In the McLeod phenotype, the XK gene is deleted and the Kell antigen cannot be expressed, whereas in the Kell null phenotype, the Kell antigen is missing and the Kx antigen is present at a normal level. The Kell null phenotype is not associated with hematologic disorders.⁹

The close proximity on the short arm of band Xp21 of the genes responsible for chronic granulomatous disease (CGD) of childhood, retinitis pigmentosa (RP), and Duchenne muscular dystrophy (DMD) explains the variable association of the McLeod phenotype in these diseases. Red blood cells from patients with chorea-acanthocytosis syndrome and McLeod phenotype do not show measurable abnormalities of the lipid bilayer.¹⁰ Focal membrane skeleton heterogeneity has been described as characterized by decreased compactness of the filamentous meshwork in the areas underlying the spikes. This focal weakness allows limited detachment of the lipid bilayer that does not result in membrane loss. The nature of the membrane skeleton abnormality is not known.

Frequency

United States

Five percent of all patients with severe hepatocellular disease develop spur cell anemia. Abetalipoproteinemia is an uncommon disorder. Chorea-acanthocytosis syndrome and McLeod phenotypes are rare; only a few dozen cases have been published in the literature.

Age

• Acanthocytosis in abetalipoproteinemia is an autosomal-recessive disease that manifests in the first months of life.
• Neurologic symptoms appear in patients aged 5-10 years and may progress to death in the second or third decade of life.
• In chorea-acanthocytosis syndrome, the median age at onset of symptoms is 32 years.

Clinical

History

The symptoms of spur cell anemia are related to the anemia and to the underlying disease.

• Spur cell anemia in severe liver disease
  • In spur cell anemia, the hemoglobin level usually falls to less than 10 g/dL and, occasionally, to levels as low as 5 g/dL. This fall may be associated with severe jaundice and rapid deterioration of liver function, coagulopathy, and hepatic encephalopathy.
  • In its chronic presentation, the anemia accompanying the alcoholic cirrhosis is mild, whereas in the acute presentation, the anemia develops weeks to months before death and as liver function deteriorates.
  • The course of spur cell anemia correlates with the liver function. Cases of reversal of the hemolytic anemia have been reported after improvement of liver disease.
  • Spur cell anemia has been reported in cases of pediatric cholestatic liver disease.⁵ In most cases, the condition is transient and resolves with the improvement of underlying liver disease.
  • Hemosiderosis is reported in 20% of patients undergoing orthotopic liver transplantation for alcoholic liver disease. Spur cell hemolytic anemia is present in 75% of these patients. In the absence of the C282Y/HFE hemochromatosis gene mutation, spur cell hemolytic anemia is postulated to be responsible for the hemosiderosis related to repeated blood transfusions and increasing intestinal iron absorption.
• Acanthocytosis in abetalipoproteinemia
  • The clinical presentation of acanthocytosis in cases of abetalipoproteinemia includes ataxia, retinitis pigmentosa that may lead to blindness, and fat malabsorption.
  • Symptoms related to the deficiency of lipid-soluble vitamins (ie, A, K, E, D) may be seen.
  • Spur cells (50-90%) are present on the peripheral smear, and the hemolysis and anemia are mild.
  • This is an autosomal-recessive disease that manifests in the first months of life, with steatorrhea, abdominal distention, and growth retardation. Neurologic symptoms appear in patients aged 5-10 years and may progress to death in the second or third decade.
• Chorea-acanthocytosis syndrome
  • The median age at onset of symptoms is 32 years. Median survival is 8-14 years.
  • Limb chorea is the initial symptom in many cases, but, because it may be mild, patients may be able to suppress it for long periods before the other symptoms are evident.
  • Orofacial tics, buccolingual dyskinesia, and tongue biting that causes major problems with eating and swallowing occur early in the disease course.
  • Neurogenic muscle hypotonia, atrophy, and areflexia are common.
  • Dysarthria develops during the course of the disease and, occasionally, may be the presenting feature.
  • Dementia and seizures are relatively common.
  • Organic personality changes with impulsive, easily distracted behavior occur. Apathy and loss of insight are the most consistent symptoms.
  • Other psychiatric symptoms that are encountered include depression, anxiety, paranoid delusions, and obsessive-compulsive features.
  • The percentage of acanthocytes in the peripheral blood varies from 20-50%. Patients do not have anemia.
• McLeod phenotype
  • This condition is characterized by a mild compensated hemolytic anemia and, occasionally, late-onset myopathy or chorea.
  • The acanthocyte number varies between 25% and 85%, and serum creatine kinase (CK) is elevated. This disorder is also described in association with CGD, RP, and DMD. The deletion of band Xp21 affects all or some of the genetic loci of these disorders because of their close proximity on the short arm of chromosome X.

Physical

Signs are related to the associated disease entity:

• In advanced liver disease, jaundice, hepatosplenomegaly, ascites, altered mental status, and bleeding diathesis may be present.
• In abetalipoproteinemia, ataxia and decreased visual acuity are the main findings.
• Chorea-acanthocytosis syndrome is characterized by limb chorea, orofacial dyskinesia, muscle atonia, and atrophy.

Causes

• Acquired acanthocytosis is associated with advanced liver disease regardless of the primary cause. Although alcohol abuse is the most common cause of chronic liver disease in Western societies, other entities have recently been recognized including nonalcoholic steatohepatitis (NASH) that may progress to cirrhosis.² Anorexia nervosa, hypothyroidism, and myelodysplasia are rare causes of this disorder.
• Inherited disorders are regrouped under the name of neuroacanthocytosis. They include autosomal-recessive disorders, abetalipoproteinemia/aprebetalipoproteinemia (chromosome 2), chorea-acanthocytosis syndrome (band 9q21), and the X-linked McLeod phenotype.

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