A thorny matter: Spur cell anemia.

Spur cell anemia (SCA) is an acquired form of non-autoimmune hemolytic anemia that occurs in advanced liver disease. It is characterized by the presence of acanthocytes or spur cells, spiculated erythrocytes whose shortened life span causes anemia that is unresponsive to transfusion. SCA has been regarded as a rare condition with an ominous prognosis for which the only known cure is liver transplantation, but recent prospective studies have demonstrated the existence of a milder form of SCA in which there are smaller numbers of acanthocytes, but which is nevertheless associated with hemolysis and poor outcomes. This form of SCA appears to be considerably more common than the severe classical variant. The conventional understanding of the pathogenesis of SCA is that abnormalities of lipid metabolism are the primary event driving the formation of spur cells. However, the studies that underpin this theory are based on small numbers of patients with heterogeneous clinical features and inconsistent use of nomenclature for dysmorphic red blood cells. In this review, we discuss the evolution of the current understanding of SCA and therapeutic strategies that have been employed based on this understanding. Our goal is to raise awareness of this understudied condition that has significant implications for patient outcomes. Furthermore, we highlight the need for rigorous, contemporary research into the underlying cause or causes of SCA in order to develop an effective therapy for this disorder.

Glomerular Hematuria and the Utility of Urine Microscopy: A Review.

Evaluation of hematuria and microscopic examination of urine sediment are commonly used tools by nephrologists in their assessment of glomerular diseases. Certain morphological aspects of urine red blood cells (RBCs) seen by microscopy may help in identifying the source of hematuria as glomerular or not. Recognized signs of glomerular injury are RBC casts or dysmorphic RBCs, in particular acanthocytes (ring-shaped RBCs with protruding blebs). Despite being a highly operator-dependent test, urine sediment examination revealing these signs of glomerular hematuria has demonstrated specificities and positive predictive values ranging between 90%-100% for diagnosing glomerular disease, although sensitivity can be quite variable. Hematuria is a commonly used tool for diagnosing patients with proliferative glomerulonephritis such as IgA nephropathy, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and lupus nephritis, sometimes even as a surrogate for kidney involvement. Studies examining the role for hematuria in monitoring and predicting adverse outcomes in these diseases have shown inconsistent results, possibly due to inconsistent definitions that often fail to consider specific markers of glomerular hematuria such as dysmorphic RBCs, acanthocytes, or RBC casts. A consensus definition of what constitutes glomerular hematuria would help standardize use in future studies and likely improve the diagnostic and prognostic value of hematuria as a marker of glomerulonephritis.

[Diagnosis of anemia associated with alcoholic cirrhosis]. / Diagnostic différentiel de l'anémie dans la cirrhose éthylique.

We report here the case of a 62-year-old patient with Child-Pugh stage C ethylic cirrhosis associated with severe macrocytic anaemia, refractory to iterative transfusions and withdrawal. After a haemorrhagic, deficiency-related, or sideroblastic etiology was ruled out, haemolytic anaemia was suspected. A blood smear allowed diagnosis of haemolytic anaemia with acanthocytes. This offers the opportunity to discuss anaemia in patients with alcoholic cirrhosis, a frequent complication spanning a broad severity range and having the potential to be life-threatening. Its origin can be multifactorial : acute haemorrhage, dilution, haemolysis (here due to acanthocytosis), marrow insufficiency caused by direct alcohol toxicity, malnutrition, iron deficiency, vitamin B9 or B12 deficiency, chronic inflammation, splenic sequestration induced by portal hypertension...

Nous rapportons le cas d'une patiente de 62 ans atteinte d'une cirrhose éthylique de stade Child-Pugh C associée à une anémie macrocytaire sévère, réfractaire aux transfusions itératives et au sevrage. Après avoir exclu les étiologies hémorragiques, carentielles et sidéroblastiques, une anémie hémolytique (AH) est suspectée. La réalisation d'un frottis sanguin a permis le diagnostic d'une anémie hémolytique à acanthocytes. L'opportunité nous est donnée de discuter de l'anémie chez le patient cirrhotique alcoolique, complication fréquente recouvrant un large spectre de gravité et pouvant menacer la survie. Elle peut être multifactorielle : hémorragie aiguë, dilution, hémolyse (dans le cas particulier, liée à une acanthocytose), insuffisance médullaire par toxicité directe de l'alcool, malnutrition, carence martiale, déficit en vitamine B9 ou B12, inflammation chronique, séquestration splénique induite par l'hypertension portale….

Osmotic gradient ektacytometry - a novel diagnostic approach for neuroacanthocytosis syndromes.

Introduction: The unique red blood cell (RBC) properties that characterize the rare neuroacanthocytosis syndromes (NAS) have prompted the exploration of osmotic gradient ektacytometry (Osmoscan) as a diagnostic tool for these disorders. In this exploratory study, we assessed if Osmoscans can discriminate NAS from other neurodegenerative diseases. Methods: A comprehensive assessment was conducted using Osmoscan on a diverse group of patients, including healthy controls (n = 9), neuroacanthocytosis syndrome patients (n = 6, 2 VPS13A and 4 XK disease), Parkinson's disease patients (n = 6), Huntington's disease patients (n = 5), and amyotrophic lateral sclerosis patients (n = 4). Concurrently, we collected and analyzed RBC indices and patients' characteristics. Results: Statistically significant changes were observed in NAS patients compared to healthy controls and other conditions, specifically in osmolality at minimal elongation index (Omin), maximal elongation index (EImax), the osmolality at half maximal elongation index in the hyperosmotic part of the curve (Ohyper), and the width of the curve close to the osmolality at maximal elongation index (Omax-width). Discussion: This study represents an initial exploration of RBC properties from NAS patients using osmotic gradient ektacytometry. While specific parameters exhibited differences, only Ohyper and Omax-width yielded 100% specificity for other neurodegenerative diseases. Moreover, unique correlations between Osmoscan parameters and RBC indices in NAS versus controls were identified, such as osmolality at maximal elongation index (Omax) vs. mean cellular hemoglobin content (MCH) and minimal elongation index (EImin) vs. red blood cell distribution width (RDW). Given the limited sample size, further studies are essential to establish diagnostic guidelines based on these findings.

Acanthocytes Identified in Huntington's Disease.

Background: Neuroacanthocytosis (NA) and Huntington's disease (HD) are neurodegenerative conditions that share clinical symptoms and imaging findings, despite their distinct genetic etiologies. Usually, the presence of acanthocytes can help narrow the differential diagnosis of a familial choreiform disorder, as the diagnosis of NA syndrome is supported by the presence of acanthocytes in peripheral blood. In this study, we demonstrate four patients who present with HD and acanthocytosis. Methods: We retrieved the data of 40 HD patients with fresh peripheral blood screened for erythrocytes in our hospital from 2014 to 2022. Of these 40 patients, four patients with acanthocytes were recruited for this study. Patients' investigations included clinical and laboratory studies, HTT gene sequencing, and whole-exome sequencing. Fresh peripheral blood was screened for erythrocytes by scanning electron microscopy. Results: The four adult patients were Han Chinese and unrelated. The age ranged from 45 to 61 years, with a disease duration of 4-10 years. The main neurological features at diagnosis included progressive involuntary movements, psychiatric changes, and dementia. Genetic analysis showed an expansion at the HTT gene. The mean proportion of acanthocytes was mild (6-10%) elevated in patient one and high (>20%) elevated in patients 2-4 by scanning electron microscopy examination. Conclusion: Our study illustrates that HD can combine with acanthocytosis, which may expand the clinical phenotype. Even though the primary gene defect appears to be predominately directed at the brain, a peripheral defect can be seen in HD. Our study highlights the complexity and diversity of HD.

A Potential Citrate Shunt in Erythrocytes of PKAN Patients Caused by Mutations in Pantothenate Kinase 2.

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive neurodegenerative disease caused by mutations in the pantothenate kinase 2 (PANK2) gene and associated with iron deposition in basal ganglia. Pantothenate kinase isoforms catalyze the first step in coenzyme A (CoA) biosynthesis. Since PANK2 is the only isoform in erythrocytes, these cells are an excellent ex vivo model to study the effect of PANK2 point mutations on expression/stability and activity of the protein as well as on the downstream molecular consequences. PKAN erythrocytes containing the T528M PANK2 mutant had residual enzyme activities but variable PANK2 abundances indicating an impaired regulation of the protein. Patients with G521R/G521R, G521R/G262R, and R264N/L275fs PANK2 mutants had no residual enzyme activity and strongly reduced PANK2 abundance. G521R inactivates the catalytic activity of the enzyme, whereas G262R and the R264N point mutations impair the switch from the inactive to the active conformation of the PANK2 dimer. Metabolites in cytosolic extracts were analyzed by gas chromatography-mass spectrometry and multivariate analytic methods revealing changes in the carboxylate metabolism of erythrocytes from PKAN patients as compared to that of the carrier and healthy control. Assuming low/absent CoA levels in PKAN erythrocytes, changes are consistent with a model of altered citrate channeling where citrate is preferentially converted to α-ketoglutarate and α-hydroxyglutarate instead of being used for de novo acetyl-CoA generation. This finding hints at the importance of carboxylate metabolism in PKAN pathology with potential links to reduced cytoplasmic acetyl-CoA levels in neurons and to aberrant brain iron regulation.

Movement Disorders and Hematologic Diseases.

BACKGROUND: Movement disorders can be associated with or caused by hematological abnormalities. The objective of this review is to highlight features that will aid in the clinician's recognition and treatment of these disorders. METHODS: MESH terms relevant to movement disorders and hematologic diseases were searched to identify conditions included in this narrative, educational review. RESULTS: Several conditions were identified, and they were organized by hematologic categories to include red blood cell abnormalities, white blood cell abnormalities, disorders of clotting and bleeding, hematologic malignancies, and others. CONCLUSIONS: This review will increase providers' understanding of disorders that include movement disorders and hematologic abnormalities. Basic hematologic laboratories can aid in assessment of these disorders, to include complete blood count/hemogram and peripheral blood smear. Recognition is key, especially in the setting of underlying malignancy, vitamin deficiency, or other disorder in which treatment is available.

The Erythrocyte Sedimentation Rate and Its Relation to Cell Shape and Rigidity of Red Blood Cells from Chorea-Acanthocytosis Patients in an Off-Label Treatment with Dasatinib.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disease with deformed red blood cells (RBCs), so-called acanthocytes, as a typical marker of the disease. Erythrocyte sedimentation rate (ESR) was recently proposed as a diagnostic biomarker. To date, there is no treatment option for affected patients, but promising therapy candidates, such as dasatinib, a Lyn-kinase inhibitor, have been identified. METHODS: RBCs of two ChAc patients during and after dasatinib treatment were characterized by the ESR, clinical hematology parameters and the 3D shape classification in stasis based on an artificial neural network. Furthermore, mathematical modeling was performed to understand the contribution of cell morphology and cell rigidity to the ESR. Microfluidic measurements were used to compare the RBC rigidity between ChAc patients and healthy controls. RESULTS: The mechano-morphological characterization of RBCs from two ChAc patients in an off-label treatment with dasatinib revealed differences in the ESR and the acanthocyte count during and after the treatment period, which could not directly be related to each other. Clinical hematology parameters were in the normal range. Mathematical modeling indicated that RBC rigidity is more important for delayed ESR than cell shape. Microfluidic experiments confirmed a higher rigidity in the normocytes of ChAc patients compared to healthy controls. CONCLUSIONS: The results increase our understanding of the role of acanthocytes and their associated properties in the ESR, but the data are too sparse to answer the question of whether the ESR is a suitable biomarker for treatment success, whereas a correlation between hematological and neuronal phenotype is still subject to verification.

Spur Cells Causing Severe and Transfusion-Refractory Anemia in Patients With Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of chronic liver disease associated with organ failures. Anemia of diverse etiology is common in patients with ACLF. Spur cell anemia (SCA) is a form of acquired hemolytic anemia that occurs rarely in such patients due to dysregulated lipids metabolism. Spur cells are large erythrocytes with spike-like projections, which predispose them for sequestration and destruction in splenic canaliculi. There is a paucity of data on SCA in patients with ACLF. Here we report a series of five ACLF patients who had severe (hemoglobin level < 8 g/dL) and transfusion-refractory SCA with aggressive clinical course and high mortality rate.

Poikilocytosis and tissue damage as negative impacts of tramadol on juvenile of Tilapia (Oreochromis niloticus).

Pharmaceuticals residue was detected in the water bodies as a consequence of the incomplete treatment. Recently, the side impacts of that residue on aquatic creatures have received a considerable attention. However, there is insufficient information about the effect of the most consumed narcotic drug (tramadol) on fish as an aquatic model. Thus, this study aims at investigating the poikilocytosis and tissue damage in Oreochromis niloticus after the exposure to 100 and 200 mg/L of tramadol hydrochloride. Three groups of fish were used; one as a control group, and the other two groups were exposed to 100 mg/L and 200 mg/L of tramadol hydrochloride respectively for 25 days. Exposure to tramadol caused a significant increase in the percentage of poikilocytosis compared to the control group. Poikilocytosis included tear-drop cell, spindle-shaped cell, sickle cell, schistocyte, blebbed cell, acanthocyte, eccentric nucleus, amoebocyte, dividing cell, and crenated cell. Moreover, liver tissue in fish exposed to tramadol showed degeneration and vacuolization of hepatocytes and atrophy of pancreatic acini as signs of histopathological alterations. Histopathological changes of brain showed severe gliosis, dark neurons, and vacuolization in fish exposed to tramadol compared to control fish. Gills tissue showed erosion, epithelial lifting, and secondary lamellae shrinking in fish exposed to tramadol compared to control fish. In conclusion, tramadol induced histopathological changes in liver, brain, and gills of Oreochromis niloticus as well as poikilocytosis were indicated clearly. Therefore, tramadol leakage to waters should be avoided to preserve aquatic creatures.

Protective role of Spirulina platensis against UVA-induced haemato-biochemical and cellular alterations in Clarias gariepinus.

Recently, it has become widely recognized that ultraviolet A (UVA) exposure is harmful for both aquatic and terrestrial organisms. Many studies have reported the effects of UVA on aquatic animals, especially fish, but little is known about the antioxidant role of microalgae in ameliorating the negative effects of UVA exposure. Recently, there has been great interest in using Spirulina platensis (SP) as a dietary antioxidant agent. Therefore, this study aimed to investigate the protective role of SP against UVA-induced effects by analysing haemato-biochemical alterations and erythrocyte cytotoxic and genotoxic biomarkers in African catfish (Clarias gariepinus). Fish were exposed to UVA, UVA + 100 mg/L SP extract, UVA + 200 mg/L SP extract for 3 days (UVA exposure: 1 h/day), and were not subjected to treatment (control group). The results showed the presence of some morphological malformations in red blood cells (RBCs) after UVA exposure. Additionally, nuclear abnormalities, including micronuclei, were observed. UVA induced alterations in most of the haemato-biochemical indices. Adding SP to the fish aquaria restored the haemato-biochemical parameters to their control values. In addition, SP repaired cellular damage in a dose-dependent manner. We conclude that SP plays a modulatory role in preventing and/or repairing the haemotoxic effects induced by UVA.

Sensitivity of medaka (Oryzias latipes) to 4-nonylphenol subacute exposure; erythrocyte alterations and apoptosis.

The present study was undertaken to assess the effects of the endocrine-disrupting compound; 4-nonylphenol (4-NP) in medaka (Oryzias latipes). The frequencies of erythrocyte alterations, apoptosis, and micronuclei were used as biological indicators of damage. Medaka were exposed 15 days to 4-NP at three sublethal concentrations (50, 80, and 100 µg/l 4-NP) and results compared with those of a previous study using catfish as an animal model. Exposure of medaka resulted in a dose-dependent increase in the frequency of erythrocyte alterations, apoptosis and micronucleus (MN). Many morphological alterations and nuclear abnormalities were observed, including acanthocytes, lobed nucleus, eccentric nucleus, fragmented nucleus, blebbed nucleus, binuclei, deformed nucleus, notched nucleus, hemolysed cells, crenated cells, teardrop-like cells, and schistocytes. Mortality was recorded after treatment with 80 and 100 µg/l 4-NP, indicating that medaka are more sensitive than catfish to 4-NP exposure. We concluded that, 4-NP causes several malformations in the shape and number of erythrocytes in medaka, indicating its genotoxicity.

Absence of Acanthocytosis in Huntington's Disease-like 2: A Prospective Comparison with Huntington's Disease.

Background: Huntington's Disease-like 2 (HDL2) is classified as a neuroacanthocytosis; however, this remains unverified. We aim to determine if acanthocytes are present in HDL2 and whether acanthocytes can differentiate HDL2 from Huntington's disease (HD). Methods: We prospectively compared 13 HD and 12 HDL2 cases against 21 unaffected controls in Johannesburg. Blood smears were prepared using international standards and reviewed by at least two blinded reviewers. An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. Flow cytometry was performed on all but four of the cases. Red cell membrane protein analysis was performed on all participants. Results: There were 12 HDL2, 13 HD, and 21 controls enrolled. None of the HD or HDL2 participants had defined acanthocytosis or other morphological abnormalities. None of the HD or HDL2 cases had evidence of an abnormal band 3. Discussion: Acanthocytosis was not identified in either HDL2 or HD in our patient population. Our results, based on the first prospective study of acanthocytes in HDL2 or HD, suggest that screening for acanthocytes will not help establish the diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question if HDL2 should be placed within the neuroacanthocytosis syndromes.

Clinical variability of neuroacanthocytosis syndromes-a series of six patients with long follow-up.

OBJECTIVE: To provide clinical clues to differential diagnosis in patients with chorea and other movement disorders with blood acanthocytes. METHODS: We present a long-term video accompanied follow-up of six Caucasian patients with neuroacanthocytosis from several centers, three diagnosed with chorea-acanthocytosis (ChAc): 34-y.o.(no.1), 36-y.o.(no.2), 43-y.o.(no.3), two diagnosed with McLeod Syndrome (MLS): 52-y.o.(no.4), 61-y.o.(no.5) and one 63-y.o.(no.6), a brother of no.5, with clinical suspicion of MLS. Additionally we report pathological findings of the mother of two brothers with MLS reported in our series with acanthocytes on peripheral blood smear RESULTS: The patients had an unremarkable family history and were asymptomatic until adulthood. Patients no. 1,2,4,5,6 developed generalized chorea and patient no. 3 had predominant bradykinesia. Patients no. 1,2,3 had phonic and motor tics, additionally patients no. 1 and 2 exhibited peculiar oromandibular dystonia with tongue thrusting. In patients no. 2 and 3 dystonic supination of feet was observed, patient no. 3 subsequently developed bilateral foot drop. Patients no. 2 and 4 had signs of muscle atrophy. Tendon reflexes were decreased or absent and electroneurography demonstrated sensorimotor neuropathy in patients no. 1,2,3,4,5, except no. 6. Generalized seizures were seen in patients no. 2,3,5,6 and myoclonic jerks in patient no. 1. Cognitive deterioration was reported in patients no. 1,2,3,5,6. Serum creatine kinase levels were elevated in all six patients. CONCLUSION: We highlight the variability of clinical presentation of neuroacanthocytosis syndromes and the long time from the onset to diagnosis with the need to screen the blood smears in uncertain cases, however, as in one of our cases acanthocytes may even be not found. Based on our observations and data from the literature we propose several red flags that should raise the suspicion of an NA syndrome in a patient with a movement disorder: severe orofacial dyskinesia with tongue and lip-biting (typical of ChAc), feeding dystonia, psychiatric and cognitive disturbances, seizures, peripheral neuropathy, elevation of creatine kinase, elevation of transaminases, hepatosplenomegaly, cardiomyopathy and arrhythmias, and an X-linked pattern of inheritance (McLeod Syndrome, MLS).

Chorea-acanthocytosis: a case report.

Neuroacanthocytosis is a group of rare disorders. We report a 36-year-old right-handed female who presented with gradually progressive abnormal facial movements, generalized weakness, and lower-lip biting starting 4 years ago. On examination, she had lower-lip ulcer, orofacial dyskinesias, and peripheral neuropathy. Her peripheral blood smears showed acanthocytosis and magnetic resonance imaging revealed atrophied head of caudate nuclei and putaminal hyperintensities on T2-weighted and fluid attenuated inversion recovery images. Work-up for autoimmune and metabolic causes was negative. She was diagnosed with chorea-acanthocytosis, an entity under neuroacanthocytosis syndrome and the patient was offered symptomatic treatment.

An unusual cause of anemia in cirrhosis: spur cell anemia, a case report with review of literature.

Chronic anemia is common in liver cirrhosis. In this setting, the pathogenesis of anemia is complex and multifactorial. Spur cell anemia is a serious disorder in cirrhotic patients and is associated with poor prognosis. Liver transplantation constitutes the only therapeutic tool. We report a case with severe spur cell anemia in alcoholic liver cirrhosis. In the attempt to investigate the origin of the disorder, we have evaluated the lipoprotein profile and found a significant reduction of apolipoprotein AI and HDL3 subclass as a possible cause of the disease.

Untangling the Thorns: Advances in the Neuroacanthocytosis Syndromes.

There have been significant advances in neuroacanthocytosis (NA) syndromes in the past 20 years, however, confusion still exists regarding the precise nature of these disorders and the correct nomenclature. This article seeks to clarify these issues and to summarise the recent literature in the field. The four key NA syndromes are described here-chorea-acanthocytosis, McLeod syndrome, Huntington's disease-like 2, and pantothenate kinase- associated neurodegeneration. In the first two, acanthocytosis is a frequent, although not invariable, finding; in the second two, it occurs in approximately 10% of patients. Degeneration affecting the basal ganglia is the key neuropathologic finding, thus the clinical presentations can be remarkably similar. The characteristic phenotype comprises a variety of movement disorders, including chorea, dystonia, and parkinsonism, and also psychiatric and cognitive symptoms attributable to basal ganglia dysfunction. The age of onset, inheritance patterns, and ethnic background differ in each condition, providing diagnostic clues. Other investigations, including routine blood testing and neuroimaging can be informative. Genetic diagnosis, if available, provides a definitive diagnosis, and is important for genetic counseling, and hopefully molecular therapies in the future. In this article I provide a historical perspective on each NA syndrome. The first 3 disorders, chorea-acanthocytosis, McLeod syndrome, Huntington's disease-like 2, are discussed in detail, with a comprehensive review of the literature to date for each, while pantothenate kinase-associated neurodegeneration is presented in summary, as this disorder has recently been reviewed in this journal. Therapy for all of these diseases is, at present, purely symptomatic.

Clinical, hematological, and imaging observations in a 25-year-old woman with abetalipoproteinemia.

Abetalipoproteinemia is an uncommon cause of ataxia and retinitis pigmentosa (RP). Most of the neurological and ocular manifestations occur secondary to deficiency syndromes that is consequent to fat malabsorption from the small intestine. In this report, we have described the phenotype of a young adult female who manifested with recurrent diarrheal illness in her first decade, followed by anemia, RP, and neurological involvement with progressive deafness, cerebellar and sensory ataxia, and subclinical neuropathy in her second decade of life. While RP and sensory ataxia due to vitamin E deficiency are well-recognized features of abetalipoproteinemia, deafness is rarely described. In addition, we have highlighted the abnormal posterior column signal changes in the cervical cord in this patient. Early recognition avoids unnecessary investigations and has a potential to retard the disease progression by replacing some of the deficient vitamins.