Spur cells, or acanthocytes (from the Greek word acantha, "thorn"), are erythrocytes covered with spikelike projections that vary in width, length, and distribution[1] (see image below). They are characterized by diminished deformability, which is responsible for their entrapment and destruction in the spleen. Spur cells are often confused with burr cells, or echinocytes (from the Greek word echinos, "sea urchin); however, the latter have multiple smaller projections that are uniformly distributed throughout the cell surface. A freshly prepared peripheral blood smear is essential in distinguishing between the two types of cells.
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Acanthocytes with target cells in a patient with advanced liver disease.
The presence of spur cells in peripheral blood (acanthocytosis) is a common feature of a heterogeneous variety of acquired and inherited disorders. Historically, spur cell anemia has been associated with advanced alcoholic liver cirrhosis, but it is also seen in other types of severe liver disease.[2] Acanthocytosis has also been associated with inherited neurologic disorders, aptly named neuroacanthocytosis syndromes, which include the X-linked disorder McLeod syndrome and the autosomal recessive disorder chorea-acanthocytosis.[3] Other conditions associated with acanthocytosis include the autosomal recessive disorder abetalipoproteinemia and treatment with alectinib, a tyrosine kinase inhibitor used for ALK-positive non–small cell lung cancer.[4, 5]
The diagnosis should be suspected when severe anemia requiring frequent red blood cell (RBC) transfusions occurs together with progressive liver failure, jaundice, coagulopathy, and encephalopathy. Rapid resolution of spur cell anemia has been observed after liver transplantation; therefore, early diagnosis is crucial.[2]
For discussion of this finding in pediatric patients, see Acanthocytosis. For patient education information, see Liver Disease.
The red blood cell membrane is composed of a lipid bilayer and proteins assembled in a complex manner that protects the red blood cell’s integrity and allows a bidirectional flux of electrolytes, energy, and information between the cell and its environment.[6] To preserve the red blood cell’s shape and regulate the cell’s 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 of 0.9-1) of unesterified cholesterol and phospholipids 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 passive and active processes.
Acanthocytes can result from abnormalities in membrane lipids and proteins. Lipid alterations impact the deposition of cholesterols and phospholipids in the red cell membrane.
Acanthocytosis in severe liver disease
The formation of spur cells in severe liver disease is a two-step process. First, free cholesterol in red blood cells equilibrates with abnormal lipoproteins containing a high ratio of free cholesterol to phospholipid, resulting in the preferential expansion of the outer leaflet and the development of the spur cell shape. Subsequently, remodeling by the spleen leads to the formation of acanthocytes with irregular bizarre projections.[7, 8, 9, 10, 11, 12]
Cirrhosis results in a decrease in polyunsaturated versus saturated and monounsaturated fatty acid content in red blood cells. This abnormality is more pronounced in individuals with spur cell anemia, resulting in altered red blood cell shape and decreased cell 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 and in hemolysis are unknown.[13]
The plasma of some patients with spur cell anemia 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.
Chorea-acanthocytosis
Chorea-acanthocytosis is an autosomal recessive disorder that results from pathogenic mutations of the VPS13A gene.[3, 14] Alteration of band 3, the anion exchange protein, is thought to play a role in forming acanthocytes in chorea-acanthocytosis.[15] 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 stomatocytosis) of the membrane skeleton.[15] Most acanthocytic disorders are associated with acquired abnormalities of the outer leaflet of the lipid bilayer. However, some rare conditions feature normal lipids and abnormal membrane proteins.
Abetalipoproteinemia
Abetalipoproteinemia is a rare autosomal recessive disorder that manifests with inability to absorb dietary fat, spinocerebellar degeneration, and retinitis pigmentosa, along with acanthocytosis.[16] In abetalipoproteinemia, beta-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 expense of lecithin. At equilibrium, the sphingomyelin concentration in the outer leaflet increases, resulting in its expansion and acanthocytosis.
McLeod syndrome
Acanthocytosis is an almost universal feature of McLeod syndrome, an extremely rare X-linked disorder caused by loss-of-function mutations in the XK gene, located on band Xp21. Nonhematologic signs and symptoms include a wide range of central nervous system, neuromuscular, and cardiac manifestations. Red blood cells are marked by absence of the Kx antigen and an associated reduced expression of antigens of the Kell blood group system.[3]
The close proximity on the short arm of band Xp21 of the genes responsible for chronic granulomatous disease (CGD) of childhood, retinitis pigmentosa, and Duchenne muscular dystrophy (DMD) explains the variable association of the McLeod phenotype with these diseases. Red blood cells from patients with chorea-acanthocytosis syndrome and McLeod phenotype do not show measurable abnormalities of the lipid bilayer.[17]
Focal membrane skeleton heterogeneity has been described, 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.
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 been recognized, including nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis.[18] Anorexia nervosa, hypothyroidism, and myelodysplasia are rare causes of this disorder.
Acanthocytosis is also a feature of certain inherited disorders. These include the autosomal recessive disorders abetalipoproteinemia/aprebetalipoproteinemia (chromosome 2) and chorea-acanthocytosis syndrome (band 9q21), and the X-linked McLeod syndrome.
More recently, alectinib, an anaplastic lymphokinase (ALK) inhibitor used for the treatment of non–small cell lung cancer, has been associated with spheroacanthocytosis without causing significant hemolytic anemia.[5] A notable increase in the membrane cholesterol content was observed, but no significant abnormalities were present on liver function tests. The specific abnormality induced by alectinib is unknown; it is suggested that the drug affects the cytoskeleton during erythropoiesis.[19]
Spur cell anemia develops in 5% of all patients with severe liver disease. In a study of 119 individuals with liver cirrhosis, Bevilacqua and colleagues reported that 9.2% were diagnosed with spur cell anemia.[20]
Abetalipoproteinemia is an uncommon disorder, inherited in autosomal-recessive pattern, that manifests in the first few months of life. Chorea-acanthocytosis syndrome and McLeod syndrome are rare; only a few dozen cases have been published in the literature. 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.
Spur cell hemolytic anemia in advanced liver disease indicates a poor prognosis; frequently, the condition precedes death by a few weeks to months.[21] Most patients die of gastrointestinal bleeding, hepatic encephalopathy, or sepsis.
Patients with abetalipoproteinemia develop functional deterioration early in life and do not survive beyond the third decade.
The course of chorea-acanthocytosis syndrome is slowly progressive, irreversible and, unrelenting. Death occurs within 8-14 years of symptom onset.
The signs and symptoms of spur cell anemia are related to the anemia and the underlying 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 over weeks to months as liver function deteriorates.The course of spur cell anemia correlates with liver function.
Spur cell anemia has been reported in cases of pediatric cholestatic liver disease.[8] 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, vitamins A, K, E, and D) may be seen. Spur cells (50-90%) are present on the peripheral smear, and the hemolysis and anemia are mild.
Abetalipoproteinemia is an autosomal recessive disease that manifests in the first months of life, with steatorrhea, abdominal distention, and growth retardation. Neurologic signs and symptoms appear at age 5-10 years and may progress to death in the second or third decade.
Chorea-acanthocytosis syndrome
The median age at onset of symptoms in chorea-acanthocytosis syndrome 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 cause 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.
Seizures have been described as a late manifestation in well‐established cases, but only rarely as the presenting symptom.[22] Dementia is 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.
An increased number of acanthocytes in peripheral blood is characteristic but not pathognomonic and may appear only late in the course.[22] The percentage of acanthocytes in the peripheral blood varies from 20-50%. Patients do not have anemia.
McLeod syndrome
This condition is characterized by a mild, compensated hemolytic anemia and, occasionally, late-onset myopathy or chorea.[23] The acanthocyte percentage varies between 25% and 85%, and serum creatine kinase (CK) levels are elevated. This phenotype is also described in association with chronic granulomatous disease, retinitis pigmentosa, and Duchenne muscular dystrophy; like McLeod syndrome, those disorders involve deletions in the Xp21 region of chromosome X.[3]
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.
Findings on the workup for spur cell anemia include the following:
Complete blood cell count - Variable degrees of anemia are present, with the hematocrit commonly between 15% and 20%. White blood cell and platelet counts may be normal; however, they are decreased in most cases due to advanced liver disease.
Reticulocyte count - An increase in the reticulocyte count depends on the degree of the anemia, but the count is usually greater than 5%. In certain cases, the reticulocyte count may be decreased as a result of concomitant folate deficiency.
Liver function tests - Hyperbilirubinemia, predominantly indirect bilirubin, is present, and its increase parallels the hemolysis. Synthetic liver function is decreased, as evidenced by low levels of albumin and fibrinogen and prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT).
Plasma lipids - This study helps screen suspected cases of abetalipoproteinemia. These patients have very low levels of serum cholesterol, phospholipid, and triglyceride. Lipoprotein electrophoresis reveals the absence of beta-lipoproteins.
Blood typing - Kell antisera react poorly with red blood cells, white blood cells, or both in the McLeod phenotype.
Serum creatine kinase - In McLeod syndrome, the creatine kinase levels are increased.
Erythrocyte sedimentation rate (ESR) - In patients with neuroacanthocytosis, particularly McLeod syndrome and chorea acanthocytosis, the ESR tends to be low. It decreases as the fraction of acanthocytes increases.[25]
Intestinal biopsy in abetalipoproteinemia - This procedure reveals the presence of fat droplets within the mucosal cells.
This study is the mainstay for the diagnosis of spur cell anemia. It reveals the presence of red blood cells with thornlike surface projections that are variable in size.
Characteristically, a high percentage of acanthocytes is present, equal to or greater than 20% of the erythrocytes observed. In cases of liver disease, particularly if obstructive jaundice is present, the smear may also reveal target cells (ie, erythrocytes in which hemoglobin is concentrated in the center and on the periphery, with a colorless zone in between, creating a "bullseye" appearance; see the image below)
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Acanthocytes with target cells in a patient with advanced liver disease.
Treatment in cases of acanthocytosis is directed at the underlying disease.
Complete resolution of spur cell anemia has been reported after liver transplantation.[26] This phenomenon might be attributed to the normalization of lipid metabolism or a decrease in portal hypertension and hypersplenism following transplantation.[2]
Patients with acanthocytosis should abstain from alcohol use. Abstinence from alcohol may result in the nearly complete disappearance of acanthocytes in the peripheral blood in patients with mild to moderate alcoholic liver cirrhosis. Abstinence from alcohol is also the best preventive measure for spur cell anemia.
Anemia can be improved by red blood cell transfusion. However, the transfused cells become acanthocytic, with shortened life span in the circulation.
The poor general status of acanthocytic patients limits the use of splenectomy. Although splenectomy can potentially improve hemolytic anemia, most of these patients are severely ill and cannot undergo surgery.
Patients with abetalipoproteinemia may benefit from dietary measures that include triglyceride restriction and lipid-soluble vitamin supplementation.Because these patients cannot absorb triglycerides, a diet restricted in these nutrients may significantly improve symptoms. Vitamin E can prevent the progression of the disease in these patients, and supplementation of the diet with lipid-soluble vitamins A, K, E, and D results in further improvement of neurologic and retinal symptoms.
Genetic counseling is offered to families of patients with abetalipoproteinemia and chorea-acanthocytosis syndromes.
Experimental therapies including corticosteroids, pentoxifylline, flunarizine and plasmapheresis lack evidence of efficacy.[27, 28]
In patients with acanthocytosis due to abetalipoproteinemia, who cannot absorb triglycerides, vitamin E supplementation can prevent the progression of the disease, and supplementation of the diet with lipid-soluble vitamins A, K, E, and D results in further improvement of neurologic and retinal symptoms.
Clinical Context:
Vitamin E protects polyunsaturated fatty acids in membranes from attack by free radicals and protects red blood cells from hemolysis.
Clinical Context:
Vitamin K is a fat-soluble vitamin absorbed by the gut and stored in the liver. It is necessary for the function of clotting factors in the coagulation cascade. Phytonadione is used to replace the essential vitamin K forms not obtained in sufficient quantities in the diet or to further supplement levels.
Clinical Context:
This agent stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood. Use for treatment of vitamin D deficiency or prophylaxis of vitamin D deficiency.
Maham Bakhtyar, MBBS, Rawalpindi Medical College, Pakistan
Disclosure: Nothing to disclose.
Coauthor(s)
Issam Makhoul, MD, Laura F Hutchins, MD, Distinguished Chair of Hematology and Oncology, Professor of Medicine, Co-Chair, Breast Cancer Disease Oriented Committee, Director of Hematology/Oncology Division, Department of Internal Medicine, University of Arkansas for Medical Sciences College of Medicine
Disclosure: Nothing to disclose.
Mansoor Javeed, MD, FACP, Clinical Assistant Professor of Medicine, University of California, Davis, School of Medicine; Consultant, Sierra Hematology-Oncology Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Disclosure: Nothing to disclose.
Additional Contributors
Christopher D Braden, DO, Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee
Disclosure: Nothing to disclose.
Acknowledgements
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
James O Ballard, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American Society of Hematology
Disclosure: Nothing to disclose.
Marcel E Conrad, MD (Retired) Distinguished Professor of Medicine, University of South Alabama
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group
Disclosure: Nothing to disclose.
Koyamangalath Krishnan, MD, FRCP, FACP Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University
Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Gullapalli V, Wen Xu W, Lewis CR, Anazodo A, Kidson Gerber G. A multi-centre case series of alectinib-related erythrocyte membrane changes and associated haemolysis. J Hematop. 2021. 14:131-136.
Ronald Hoffman, Edward J. Benz, Jr., Leslie E. Silberstein, et al. Hereditary Elliptocytosis and Related Disorders. Hematology: Basic Principles and Practice. 7th ed. Elsevier; 640-643.
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