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1.
Hematology ; 26(1): 684-690, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34493173

RESUMO

BACKGROUND: Sickle cell anaemia affects about 4 million people across the globe, making it an inherited disorder of public health importance. Red cell lysis consequent upon haemoglobin crystallization and repeated sickling leads to anaemia and a baseline strain on haemopoiesis. Vaso-occlusion and haemolysis underlies majority of the chronic complications of sickle cell. We evaluated the clinical and laboratory features observed across the various clinical phenotypes in adult sickle cell disease patients. METHODS: Steady state data collected prospectively in a cohort of adult sickle cell disease patients as out-patients between July 2010 and July 2020. The information included epidemiological, clinical and laboratory data. RESULTS: About 270 patients were captured in this study (165 males and 105 females). Their ages ranged from 16 to 55 years, with a median age of 25 years. Sixty-eight had leg ulcers, 43 of the males had priapism (erectile dysfunction in 8), 42 had AVN, 31 had nephropathy, 23 had osteomyelitis, 15 had osteoarthritis, 12 had cholelithiasis, 10 had stroke or other neurological impairment, 5 had pulmonary hypertension, while 23 had other complications. Frequency of crisis ranged from 0 to >10/year median of 2. Of the 219 recorded, 148 of the patients had been transfused in the past, while 71 had not. CONCLUSION: The prevalence of SLU, AVN, priapism, nephropathy and the other complications of SCD show some variations from other studies. This variation in the clinical parameters across different clinical phenotypes indicates an interplay between age, genetic and environmental factors.


Assuntos
Anemia Falciforme , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Colelitíase/etiologia , Colelitíase/metabolismo , Colelitíase/patologia , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Nefropatias/epidemiologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Úlcera da Perna/epidemiologia , Úlcera da Perna/etiologia , Úlcera da Perna/metabolismo , Úlcera da Perna/patologia , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Osteoartrite/epidemiologia , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteomielite/epidemiologia , Osteomielite/etiologia , Osteomielite/metabolismo , Osteomielite/patologia , Priapismo/epidemiologia , Priapismo/etiologia , Priapismo/metabolismo , Priapismo/patologia , Estudos Prospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
3.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203861

RESUMO

Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.


Assuntos
Anemia Falciforme/patologia , Anemia Falciforme/fisiopatologia , Citoproteção , Hemopexina/metabolismo , Animais , Humanos , Imunomodulação , Lipoproteínas/metabolismo , Microvasos/patologia
4.
Ann Hematol ; 100(8): 1947-1951, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34136949

RESUMO

Priapism is a persistent, painful erection, which can lead to permanent penile damage and reduced quality of life. Patients with sickle cell disease have an increased risk of priapism which has been related to chronic hemolysis. This study investigates the prevalence of priapism in all major hereditary and acquired forms of hemolytic disorders. Patients with hemolytic disorders were identified in the nationwide Danish Hemolysis Cohort. Each patient was age-sex-matched with 50 comparisons from the general population without hemolysis. We identified the episodes of hospital-registered priapism events for both patients with hemolysis disorders and comparisons in the Danish National Patient Register between 1977 and 2016. We identified 4181 male patients with hemolytic disorders and 205,994 male comparisons, with 2,294,027 person-years of total observation time. Totally, 101 episodes of priapism occurred during follow-up period. Six episodes of priapism were recorded in three patients with a hemolytic disorder, all affected by sickle cell disease. Two of these patients had verified genotype HbSS. The incidence rate for first priapism in sickle cell disease was 432.8 per 100,000 person-years [95% CI: 139.6; 1341.8] versus 0.84 per 100,000 person-years [95% CI 0.54; 1.32] in comparisons. Using a large nationwide cohort, we found that only sickle cell disease is associated with priapism among patients with hemolytic disorders. The incidence rate of priapism in patients with sickle cell disease was lower than previously reported.


Assuntos
Doenças Hematológicas/complicações , Priapismo/etiologia , Adolescente , Adulto , Idoso , Anemia Falciforme/complicações , Anemia Falciforme/patologia , Criança , Feminino , Doenças Hematológicas/patologia , Hemólise , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Priapismo/patologia , Estudos Retrospectivos , Adulto Jovem
5.
Pediatr Blood Cancer ; 68(8): e29075, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34061431

RESUMO

We surveyed published papers and an international sickle cell disease (SCD) registry to detect susceptibility and clinical course of coronavirus disease 2019 (COVID-19) in SCD patients. COVID-19 presentation was mild in children and moderate in many SCD adults. Regarding increased comorbidities with age, it seems severe COVID-19 to be more common in older SCD patients. Although the overall outcome of COVID-19 was favorable in SCD children, a high rate of pediatric intensive care unit admission should be considered in managing these patients. To explain COVID-19 outcome in SCD patients, the possible benefits of hydroxyurea therapy could be considered. The obtained results should be interpreted, considering low cases from sub-Saharan people, younger age of SCD patients compared to general population, a bias toward registry of the more severe form of disease, the effect of pre-existing comorbidities with multisystem organ damage, and the role of health socio-economic determinants.


Assuntos
Anemia Falciforme/mortalidade , COVID-19/mortalidade , SARS-CoV-2 , Adolescente , Adulto , Fatores Etários , Anemia Falciforme/patologia , Anemia Falciforme/virologia , COVID-19/patologia , Criança , Suscetibilidade a Doenças/mortalidade , Suscetibilidade a Doenças/patologia , Suscetibilidade a Doenças/virologia , Feminino , Humanos , Masculino , Fatores de Risco , Índice de Gravidade de Doença
6.
Nat Biomed Eng ; 5(7): 713-725, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33820980

RESUMO

Simple and fast methods for the detection of target genes with single-nucleotide specificity could open up genetic research and diagnostics beyond laboratory settings. We recently reported a biosensor for the electronic detection of unamplified target genes using liquid-gated graphene field-effect transistors employing an RNA-guided catalytically deactivated CRISPR-associated protein 9 (Cas9) anchored to a graphene monolayer. Here, using unamplified genomic samples from patients and by measuring multiple types of electrical response, we show that the biosensors can discriminate within one hour between wild-type and homozygous mutant alleles differing by a single nucleotide. We also show that biosensors using a guide RNA-Cas9 orthologue complex targeting genes within the protospacer-adjacent motif discriminated between homozygous and heterozygous DNA samples from patients with sickle cell disease, and that the biosensors can also be used to rapidly screen for guide RNA-Cas9 complexes that maximize gene-targeting efficiency.


Assuntos
Técnicas Biossensoriais/métodos , Proteína 9 Associada à CRISPR/metabolismo , DNA/genética , Polimorfismo de Nucleotídeo Único , Anemia Falciforme/genética , Anemia Falciforme/patologia , Técnicas Biossensoriais/instrumentação , Proteína 9 Associada à CRISPR/química , DNA/metabolismo , Genoma Humano , Grafite/química , Heterozigoto , Homozigoto , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , RNA Guia/metabolismo , Superóxido Dismutase-1/genética , Transistores Eletrônicos
7.
Lancet Haematol ; 8(5): e334-e343, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33894169

RESUMO

BACKGROUND: There are no approved treatments for vaso-occlusive crises in sickle cell disease. Sevuparin is a novel non-anticoagulant low molecular weight heparinoid, with anti-adhesive properties. In this study, we tested whether sevuparin could shorten vaso-occlusive crisis duration in hospitalised patients with sickle cell disease. METHODS: We did a multicentre, double-blinded, placebo-controlled, phase 2 study in 16 public access clinical hospitals in the Netherlands, Lebanon, Turkey, Bahrain, Oman, Saudi Arabia, and Jamaica. Patients aged 12-50 years with a diagnosis of sickle cell disease (types HbSS, HbSC, HbSß0-thalassaemia, or HbSß+-thalassaemia) on a stable dose of hydroxyurea, hospitalised with vaso-occlusive crisis for parenteral opioid analgesia with a projected stay of more than 48 h were included in the study. Patients were randomly assigned (1:1) using a computer-generated randomisation scheme to receive sevuparin (18 mg/kg per day) or placebo (NaCl, 0·9% solution) intravenously for 2-7 days until vaso-occlusive crisis resolution. All individuals involved in the trial were masked to treatment allocation. The analysis was done in the intention-to-treat population. The primary endpoint was time to vaso-occlusive crisis resolution defined as freedom from parenteral opioid use (in preceding 6-10 h); and readiness for discharge as judged by the patient or physician. The trial is registered with ClinicalTrials.gov, NCT02515838. FINDINGS: Between Oct 7, 2015, and Feb 10, 2019, 144 patients were randomly assigned and administered sevuparin (n=69) or placebo (n=75). The median age was 22·2 years (range 12·2-33·6), 104 (72%) 144 were adults (18 years or older), and 90 (63%) were male and 54 (37%) were female. The intention-to-treat analysis for the primary endpoint showed no significant difference in median time to vaso-occlusive crisis resolution between the sevuparin and placebo groups (100·4 h [95% CI 85·5-116·8]) vs 86·4 h [70·6-95·1]; hazard ratio 0·89 [0·6-1·3]; p=0·55). Serious adverse events occurred in 16 (22%) of 68 patients in the sevuparin group and in 21 (22%) of patients in the placebo group. The most frequent treatment-emergent adverse events were pyrexia (17 [25%] in the sevuparin group vs 17 [22%] in the placebo group), constipation (12 [18%] vs 17 [22%]), and decreased haemoglobin (18 [26%] vs 9 [12%]). There were no deaths in the sevuparin group and there was one (1%) death in the placebo group after a hyper-haemolytic episode due to alloimmunisation. INTERPRETATION: This result, as well as the results seen in other clinical studies of inhibitors of adhesion in sickle cell disease, suggest that selectin-mediated adhesion might be important in the initiation, but not maintenance of vaso-occlusion, indicating that strategies to treat vaso-occlusive crises differ from strategies to prevent this complication. FUNDING: Modus Therapeutics.


Assuntos
Dor Aguda/tratamento farmacológico , Anemia Falciforme/patologia , Heparina/análogos & derivados , Dor Aguda/complicações , Adolescente , Adulto , Anemia Falciforme/complicações , Criança , Feminino , Febre/etiologia , Hemoglobinas/análise , Heparina/efeitos adversos , Heparina/uso terapêutico , Humanos , Masculino , Tempo de Tromboplastina Parcial , Efeito Placebo , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto Jovem
8.
Nat Med ; 27(4): 677-687, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33737751

RESUMO

ß-Thalassemia pathology is due not only to loss of ß-globin (HBB), but also to erythrotoxic accumulation and aggregation of the ß-globin-binding partner, α-globin (HBA1/2). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in ß-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize ß-globin:α-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing ß-thalassemia.


Assuntos
Terapia Genética , Células-Tronco Hematopoéticas/metabolismo , Hemoglobinas/metabolismo , alfa-Globinas/genética , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/terapia , Anemia Falciforme/patologia , Animais , Antígenos CD34/metabolismo , Dependovirus/genética , Eritrócitos/metabolismo , Edição de Genes , Genes Reporter , Loci Gênicos , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , RNA Guia/genética
11.
PLoS One ; 16(2): e0247324, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33617594

RESUMO

Vaso-occlusive episodes (VOEs) are a hallmark of sickle cell disease (SCD), and account for >90% of health care encounters for this patient population. The Cooperative Study of Sickle Cell Disease, a large study enrolling >3000 patients, showed that the majority of SCD patients (80%) experienced 0-3 major pain crises/year. Only a small minority (~5%) experienced ≥6 VOEs/year. Our study sought to further understand this difference in VOE frequency between SCD patients. We analyzed 25 patients (13M/12F, mean age of 28.8) with ≥6 ED visits or hospitalizations/year (high utilizers), and compared these with 9 patients (6M/3F, mean age of 37.6) who had ≤2 ED visits or hospitalizations/year (low utilizers). All subjects were given a demographic survey along with questionnaires for depression, anxiety, and Health Locus of Control. Each subject then underwent quantitative sensory testing (QST) with three different modalities: pressure pain sensitivity, heat and cold sensitivity, and Von Frey monofilament testing. Laboratory and clinical data were collected through subjects' medical records. CBC and chemistry analysis showed high utilizers had higher WBC (p<0.01), ANC (p<0.01), total bilirubin (p = 0.02), and lower MCV (p = 0.03). Opioid use (morphine equivalents) over the past 6 months was significantly higher in the high utilizer group (12125.7 mg vs 2423.1 mg, p = 0.005). QST results showed lower pressure pain threshold at the ulna (224.4 KPa vs 338.9 KPa, p = 0.04) in the high utilizer group. High utilizers also had higher anxiety (9.0 vs 4.6, p = 0.04) and depression scores (10.0 vs 6.0, p = 0.051). While the low utilizer group had higher education levels with more associate and bachelor degrees (p = 0.009), there was no difference in income or employment. These data show that many biological and psychosocial factors contribute to high health care utilization in SCD. A multi-disciplinary and multi-faceted approach will be required to address this complex problem.


Assuntos
Anemia Falciforme/patologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Adulto , Analgésicos Opioides/uso terapêutico , Anemia Falciforme/psicologia , Ansiedade/psicologia , Estudos Transversais , Depressão/psicologia , Feminino , Humanos , Masculino , Dor/tratamento farmacológico , Dor/patologia , Dor/psicologia , Medição da Dor/métodos
12.
Exp Biol Med (Maywood) ; 246(3): 332-341, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33517776

RESUMO

Sickle cell disease is the most common hemoglobinopathy and affects millions worldwide. The disease is associated with severe organ dysfunction, acute and chronic pain, and significantly decreased life expectancy. The large body of work demonstrating that hemolysis results in rapid consumption of the endogenous vasodilator nitric oxide, decreased nitric oxide production, and promotion of vaso-occlusion provides the basis for the hypothesis that nitric oxide bioavailability is reduced in sickle cell disease and that this deficit plays a role in sickle cell disease pain. Despite initial promising results, large clinical trials using strategies to increase nitric oxide bioavailability in sickle cell disease patients yielded no significant change in duration or frequency of acute pain crises. Further, recent investigations showed that sickle cell disease patients and mouse models have elevated baseline levels of blood nitrite, a reservoir for nitric oxide formation and a product of nitric oxide metabolism, regardless of pain phenotype. These conflicting results challenge the hypotheses that nitric oxide bioavailability is decreased and that it plays a significant role in the pathogenesis in sickle cell disease acute pain crises. Conversely, a large body of work demonstrates that nitric oxide, as a neurotransmitter, has a complex role in pain neurobiology, contributes to the development of central sensitization, and can mediate hyperalgesia in inflammatory and neuropathic pain. These results support an alternative hypothesis: one proposing that altered nitric oxide signaling may contribute to the development of neuropathic and/or inflammatory pain in sickle cell disease through its role as a neurotransmitter.


Assuntos
Anemia Falciforme/patologia , Hiperalgesia/fisiopatologia , Neuralgia/fisiopatologia , Óxido Nítrico/metabolismo , Hemólise/fisiologia , Humanos , Transdução de Sinais/fisiologia
13.
PLoS One ; 16(2): e0246700, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33596221

RESUMO

BACKGROUND: Despite ~90% of sickle cell disease (SCD) occurring in low-and middle-income countries (LMICs), the vast majority of people are not receiving evidence-based interventions (EBIs) to reduce SCD-related adverse outcomes and mortality, and data on implementation research outcomes (IROs) and SCD is limited. This study aims to synthesize available data on EBIs for SCD and assess IROs. METHODS: We conducted a systematic review of RCTs reporting on EBIs for SCD management implemented in LMICs. We identified articles from PubMed/Medline, Global Health, PubMed Central, Embase, Web of Science medical subject heading (MeSH and Emtree) and keywords, published from inception through February 23, 2020, and conducted an updated search through December 24, 2020. We provide intervention characteristics for each study, EBI impact on SCD, and evidence of reporting on IROs. MAIN RESULTS: 29 RCTs were analyzed. EBIs identified included disease modifying agents, supportive care agents/analgesics, anti-malarials, systemic treatments, patient/ provider education, and nutritional supplements. Studies using disease modifying agents, nutritional supplements, and anti-malarials reported improvements in pain crisis, hospitalization, children's growth and reduction in severity and prevalence of malaria. Two studies reported on the sustainability of supplementary arginine, citrulline, and daily chloroquine and hydroxyurea for SCD patients. Only 13 studies (44.8%) provided descriptions that captured at least three of the eight IROs. There was limited reporting of acceptability, feasibility, fidelity, cost and sustainability. CONCLUSION: EBIs are effective for SCD management in LMICs; however, measurement of IROs is scarce. Future research should focus on penetration of EBIs to inform evidence-based practice and sustainability in the context of LMICs. CLINICAL TRIAL REGISTRATION: This review is registered in PROSPERO #CRD42020167289.


Assuntos
Anemia Falciforme/terapia , Medicina Baseada em Evidências/métodos , Anemia Falciforme/patologia , Antidrepanocíticos/uso terapêutico , Países em Desenvolvimento , Gerenciamento Clínico , Hospitalização , Humanos , Pobreza , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Resultado do Tratamento
14.
Blood ; 137(11): 1538-1549, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33512489

RESUMO

Neutrophils play a crucial role in the intertwined processes of thrombosis and inflammation. An altered neutrophil phenotype may contribute to inadequate resolution, which is known to be a major pathophysiological contributor of thromboinflammatory conditions such as sickle cell disease (SCD). The endogenous protein annexin A1 (AnxA1) facilitates inflammation resolution via formyl peptide receptors (FPRs). We sought to comprehensively elucidate the functional significance of targeting the neutrophil-dependent AnxA1/FPR2/ALX pathway in SCD. Administration of AnxA1 mimetic peptide AnxA1Ac2-26 ameliorated cerebral thrombotic responses in Sickle transgenic mice via regulation of the FPR2/ALX (a fundamental receptor involved in resolution) pathway. We found direct evidence that neutrophils with SCD phenotype play a key role in contributing to thromboinflammation. In addition, AnxA1Ac2-26 regulated activated SCD neutrophils through protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2) to enable resolution. We present compelling conceptual evidence that targeting the AnxA1/FPR2/ALX pathway may provide new therapeutic possibilities against thromboinflammatory conditions such as SCD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anemia Falciforme/metabolismo , Anexina A1/metabolismo , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Transdução de Sinais , Trombose/metabolismo , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/patologia , Animais , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Neutrófilos/patologia , Trombose/etiologia , Trombose/patologia , Adulto Jovem
15.
Br J Haematol ; 192(1): 151-157, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32789861

RESUMO

The visual system is primarily affected in sickle cell disease (SCD), and eye examination is recommended starting in late childhood. So far, to our knowledge, all studies have focused on the retina, neglecting the changes that might be present in the cortical portion of the visual system. We performed a multimodal magnetic resonance imaging (MRI) evaluation of the visual cortex in 25 children with SCD (mean age: 12·3 ± 1·9 years) and 31 controls (mean age: 12·7 ± 1·6 years). At ophthalmologic examination, 3/25 SCD children had mild visual acuity deficits and 2/25 had mild tortuosity of the retinal vessels. None showed optic pathway infarcts at MRI or Transcranial Doppler abnormal blood velocities, and 6/25 disclosed posterior cerebral artery stenosis (five mild and one severe) at MR-angiography. Compared to controls, SCD children had increased posterior pericalcarine cortical thickness, with a different trajectory of cortical maturation and decreased connectivity within medial and ventral visual neural networks. Our findings suggest that SCD affects the development and the tuning of the visual cortex, leading to anatomical and functional changes in childhood even in the absence of retinopathy, and set the basis for future studies to determine if these changes can represent useful predictors of visual impairment in adulthood, biomarkers of disease progression or treatment response.


Assuntos
Anemia Falciforme/patologia , Córtex Visual/patologia , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Córtex Visual/diagnóstico por imagem , Vias Visuais/diagnóstico por imagem , Vias Visuais/patologia
16.
J Clin Pathol ; 74(3): 198-201, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32796052

RESUMO

Screening of haemoglobinopathies is indicated for the detection of sickle cell anaemia; thus, neonates can benefit from early and adequate treatment that prevents neurological damage, reduces morbidity and mortality associated with the disease. These types of programmes sometimes lead to unexpected findings. We present a new haemoglobin (Hb) variant (Hb Miguel Servet) detected by newborn screening. During neonatal screening of haemoglobinopathies by cation-exchange high-performance liquid chromatography (CE-HPLC) newborn, an Hb variant was detected. An analysis at 8 months of age using capillary zone electrophoresis (CZE) confirmed the presence of this new Hb. The molecular characterisation was performed by automatic sequencing of the α and ß globin genes in an ABI PRISM 3100 Genetic Analyzer. Hb analysis by CE-HPLC ß-thalassaemia short programmedid not indicate the presence of abnormal Hbs. By CZE showed a peak in the zone 12 zone comprising 3.3% of the total Hb. A new analysis by CE-HPLC on a Tosoh G8-2 (Horiba) shown a peak, in the region of HbA1b, did not interfere with the quantification of HbA1c. Sequencing of the ß gene revealed the substitution of a guanine for a thymine (GGT >TGT) in codon 69 of the second exon, resulting in substitution of cysteine for the amino acid glutamine (HBB:c.208G>T). Hb Miguel Servet is a ß-chain globin variant detected by CE-HPLC newborn (BioRad), by CZE and by CE-HPLC-CE Tosoh G8-2 (Horiba), but no by CE-HPLC-CE ß-thalassaemia short programme (BioRad). In fact, for all the techniques that are visualised, what would be detected would be the glutathione variant of Hb (Miguel Servet).


Assuntos
Anemia Falciforme/diagnóstico , Hemoglobinopatias/diagnóstico , Talassemia beta/diagnóstico , Anemia Falciforme/genética , Anemia Falciforme/patologia , Cromatografia Líquida de Alta Pressão , Eletroforese Capilar , Hemoglobinopatias/genética , Hemoglobinopatias/patologia , Humanos , Masculino , Globinas beta/genética , Talassemia beta/genética , Talassemia beta/patologia
18.
Acta Haematol ; 144(2): 182-189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32987383

RESUMO

BACKGROUND: Thrombospondin 1 (TSP-1) is a multifunctional glycoprotein secreted by platelets. In sickle cell disease (SCD), TSP-1 promotes red cell adhesion to the endothelium by binding to von Willebrand factor (vWF) and inhibiting its degradation by the protease ADAMTS-13. We investigated a possible correlation between TSP-1, vWF and ADAMTS-13 in adult and pediatric SCD patients. METHODS: Using commercially available ELISA kits, TSP-1, vWF and ADAMTS-13 levels were measured in 59 SCD patients (20 children and 39 adults) and compared with 59 age- and sex-matched controls. Associations between TSP-1 and parameters of interest were analyzed using Pearson's correlation coefficient. RESULTS: Although TSP-1 levels were higher in adult and pediatric SCD patients than in controls, the increase was not statistically significant (p > 0.05). We found a significant positive correlation between TSP-1 and platelet count in both adult (r = 0.402, p = 0.01) and pediatric (r = 0.589, p = 0.01) patients, which is expected due to increased platelet activation in SCD. There was a positive correlation between TSP-1 and vWF in normal adults (r = 0.305, p = 0.049) and children (r = 0.633, p = 0.005) but not in patients (p > 0.05). A significant negative correlation between TSP-1 and ADAMTS-13 activity (r = -0.41, p = 0.01) was found in adult patients. Also, a significant negative correlation between TSP-1 and ADAMTS-13/vWF antigen ratio in both normal controls (r = -0.595, p = 0.009) and patients (r = -0.493, p = 0.032) is reported for the pediatric group. CONCLUSIONS: Our findings confirm the inhibitory effects of TSP-1 on ADAMTS-13 activity in adult SCD patients. The negative correlation reported between TSP-1 and ADAMTS-13/vWF antigen ratio in pediatric subjects suggests a possible protective mechanism in younger individuals, although this is not related to the presence of SCD. This work emphasizes the impact of age on interpreting results related to the regulation of vWF expression and interaction with TSP-1 and ADAMTS-13 in SCD.


Assuntos
Proteína ADAMTS13/metabolismo , Anemia Falciforme/patologia , Trombospondina 1/metabolismo , Fator de von Willebrand/metabolismo , Proteína ADAMTS13/análise , Adulto , Anemia Falciforme/etnologia , Anemia Falciforme/genética , Árabes , Contagem de Células Sanguíneas , Estudos de Casos e Controles , Criança , Feminino , Hemólise , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Trombospondina 1/análise , Fator de von Willebrand/análise
19.
Br J Haematol ; 192(3): 634-642, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33249569

RESUMO

Although most individuals with sickle cell disease (SCD) live in sub-Saharan Africa, the natural history of the disease on this continent remains largely unknown. Intravascular haemolysis results in activation of circulating blood cells and release of microparticles (MPs) that exert pro-inflammatory effects and contribute to vascular damage. We designed a case-control study nested in the CADRE cohort (Coeur-Artère-DRÉpanocytose, clinical trials.gov identifier NCTO3114137) and based on extreme phenotypes, to analyse blood cell-derived MPs in 232 adult SS patients at steady state in Bamako and Dakar. Thirty-six healthy adult controls matched by age and sex were recruited in Bamako. The MPs concentrations were higher in SS patients compared to AA controls with a predominance of erythrocyte- and reticulocyte-derived MPs. These erythroid-derived MPs were significantly lower in patients with retinopathy (P = 0·022). Reticulocyte-derived MPs were significantly negatively and positively associated with a history of priapism (P = 0·020) and leg ulcers (P = 0·041) respectively. We describe for the first time the comparative patterns of plasma MPs in healthy subjects and patients with SCD living in sub-Saharan Africa and exhibiting various complications. Because our present results show no clear pattern of correlation between erythroid MPs and the classical hyper-haemolytic complications, we hypothesise a weak relevance of the hyper-haemolysis versus hyper-viscous paradigm in Africa.


Assuntos
Anemia Falciforme/complicações , Micropartículas Derivadas de Células/patologia , Doenças Vasculares/etiologia , Adulto , África ao Sul do Saara/epidemiologia , Anemia Falciforme/patologia , Estudos de Casos e Controles , Feminino , Hemólise , Humanos , Masculino , Doenças Vasculares/patologia , Adulto Jovem
20.
J Pediatr Hematol Oncol ; 43(1): e19-e25, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33235145

RESUMO

Despite broad support for hydroxyurea (HU) therapy, suboptimal adherence is reported for youth with sickle cell disease. Valid adherence measurement is crucial to understanding the relationship between medication behavior, disease response, and patient-centered health outcomes. The current pilot study examined the feasibility of the Wise electronic device for longitudinal HU adherence measurement in a sample of 36 youths prescribed HU. The study also explored the association between HU adherence, as measured by the Wise device, with other adherence measures (ie, family report, lab values, pill count, and medication possession ratio). A measure of family-reported acceptability was also completed. Overall, results supported the feasibility of the Wise device (rate of consent=82%, device use=75%, device failure=3%) for HU adherence measurement and most families rated their experience using their device positively (favorable responses ranged from 67% to 100%). Associations between HU adherence, as measured by the Wise device, and other adherence measures were not significant. Overall, the feasibility was supported. The Wise device allows longitudinal measurement of adherence with HU from initiation as a young child (ie, with liquid formulations) through adolescence and provides a novel means of adherence measurement for both clinical and research use.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Hidroxiureia/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Monitorização Fisiológica/métodos , Tecnologia sem Fio/instrumentação , Adolescente , Anemia Falciforme/patologia , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Projetos Piloto , Prognóstico
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