Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Br J Haematol ; 2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33368157

RESUMO

Detection of somatic mutations may help verify the diagnosis of myelodysplastic syndrome (MDS) in patients with persistent cytopenias or with MDS-predisposition syndromes, prior to the development of overt leukemia. However, the spectrum and consequences of acquired changes in paediatric patients have not been fully evaluated, and especially not in the context of an underlying syndrome. We incorporated a targeted next-generation-sequencing panel of 54 genes for the detection of somatic mutations in paediatric and young adult patients with inherited or acquired cytopenias. Sixty-five patients were included in this study, of whom 17 (26%) had somatic mutations. We detected somatic mutations in 20% of individuals with inherited MDS-predisposition syndromes, including in patients with severe congenital neutropenia and Fanconi anaemia, and with germline mutations in SAMD9L. Thirty-eight per cent of children with acquired cytopenias and suspected MDS had somatic changes, most commonly in genes related to signal transduction and transcription. Molecularly abnormal clones often preceded cytogenetic changes. Thus, routine performance of somatic panels can establish the diagnosis of MDS and determine the optimal timing of haematopoietic stem cell transplantation, prior to the development of leukaemia. In addition, performing somatic panels in patients with inherited MDS-predisposition syndromes may reveal their unique spectrum of acquired mutations.

2.
Blood ; 136(17): 1956-1967, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-32693407

RESUMO

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.

3.
Mol Diagn Ther ; 24(4): 397-407, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32557003

RESUMO

Congenital anemias are a wide spectrum of diseases including hypoproliferative anemia syndromes, dyserythropoietic anemias, sideroblastic anemias, red blood cell membrane and enzymatic defects, hemoglobinopathies, and thalassemia syndromes. The various congenital anemia syndromes may have similar clinical and laboratory presentations, making the diagnosis challenging. The traditional work-up, which includes a complete blood count, blood smears, bone marrow studies, flow cytometry, and the osmotic fragility test, does not always lead to the diagnosis. Specialized tests such as red blood cell enzyme activity and ektacytometry are not widely available. In addition, red blood cell transfusions may mask some of the laboratory characteristics. Therefore, genetic testing is crucial for accurate diagnosis of patients with congenital anemias. However, gene-by-gene testing is labor intensive because of the large number of genes involved. Thus, targeted next-generation sequencing using custom-made gene panels has been increasingly utilized, with a high success rate of diagnosis. Accurate genetic diagnosis is important for determining specific therapeutic modalities, as well as for avoiding splenectomy when contraindicated. In addition, molecular diagnosis can allow for genetic counseling and prenatal diagnosis in severe cases. We suggest a work-up scheme for patients with congenital anemias, including early incorporation of targeted next-generation sequencing panels.

4.
Br J Haematol ; 190(6): 909-915, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32342506

RESUMO

Splenectomy is considered therapeutic in various non-malignant haematologic diseases. Adverse events - specifically infections and thromboembolism - are not extensively documented in the paediatric population, maintaining the concern over risks-versus-benefits of the procedure. We studied a cohort of paediatric haematology patients undergoing splenectomy between 1977 and 2015 to determine short- and long-term complications. We summarised all the patients of the haematology clinic in our major Israeli tertiary centre undergoing splenectomy for therapeutic reasons, capturing infectious and thromboembolic events. The data of 103 patients, comprising 1657 follow-up years, were analysed. The cohort included 33 patients with transfusion-dependent thalassaemia, seven with non-transfusion-dependent thalassaemia, four with sickle-thalassaemia, 41 with hereditary spherocytosis, and 18 with immune thrombocytopenia. Standard presplenectomy vaccinations were noted in most. No typical cases of overwhelming postsplenectomy infection (OPSI) were identified, nor were typical OPSI bacteria isolated. Thalassaemics with central lines were most prone to infection and thrombosis. Beyond this subgroup, thrombotic events were anecdotal. This is the largest study to date to comprehensively analyse infectious and thrombotic complications of childhood splenectomy for the treatment of haematologic diseases. The use of splenectomy appears to be a relatively safe therapeutic option in paediatric patients with proper preoperative vaccination and follow-up care; use of central venous lines or catheters increase the risk in thalassaemic patients and should be avoided if possible.

5.
Pediatr Blood Cancer ; 67(6): e28237, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277798

RESUMO

BACKGROUND: The SRP54 (signal recognition protein 54) is a conserved component of the ribonucleoprotein complex that mediates cotranslational targeting and translocation of proteins to the endoplasmic reticulum. In 2017, mutations in the gene have been described as a cause of congenital neutropenia with or without pancreatic insufficiency, and since then, only limited cases were added to the literature. METHODS: Two patients with neutropenia underwent hematological, immunological, and genetic work-up, including lymphocyte phenotyping, immunoglobulins, and complement levels, antineutrophil and antinuclear antibodies, bone marrow FISH panel for myelodysplastic syndrome, whole-exome sequencing, and in silico proteomic analysis. RESULTS: Clinical findings in the two families revealed a wide spectrum of immunological and clinical manifestations, ranging from mild asymptomatic neutropenia during febrile illnesses to severe neutropenia and life-threatening infection requiring leg amputation. Immunological and hematological work-up showed isolated neutropenia with normal lymphocyte subpopulations, immunoglobulin and complement levels, and negative autoimmune tests. Bone marrow aspirations showed variability ranging from normal myelopoiesis to myeloid maturation arrest at the promyelocytic stage, with normal FISH panel for myelodysplastic syndrome. Genetic analysis identified a novel, de novo, in-frame deletion in the SRP54 gene, c.342-344delAAC, p.T115del. In silico proteomic analysis suggested impaired SRP54 protein function due to reduced GTP activity and stability. CONCLUSIONS: We describe congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene.


Assuntos
Mutação , Neutropenia/congênito , Neutropenia/patologia , Partícula de Reconhecimento de Sinal/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neutropenia/genética , Neutropenia/metabolismo , Linhagem , Prognóstico , Proteômica , Sequenciamento Completo do Exoma
6.
Pediatr Blood Cancer ; 67(5): e28183, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32124556

RESUMO

BACKGROUND: Essential thrombocythemia (ET) is rare in children, and pediatric guidelines are lacking. Therefore, we aimed to evaluate ET diagnosis and treatment in a pediatric cohort. PROCEDURE: Data of patients with ET from three hospitals were reviewed. Molecular diagnosis included JAK2V617F, CALR, and MPL mutations. Patients were evaluated for acquired von Willebrand syndrome (AVWS). Follow-up included clinical symptoms, adverse events, and treatment. RESULTS: Twelve children (median age: 8 years, range 1-14.5) were included. Mean lag period between the first documentation of thrombocytosis until ET diagnosis was 36 months. Six patients were positive for JAK2V617F and two for CALR mutations. In six of nine patients, AVWS was diagnosed. At diagnosis, only 33% of patients started therapy with aspirin (n = 4) and hydroxyurea (n = 2). In three of eight untreated patients, therapy was added during follow-up. The cohort was followed for a median of 32.5 months (range: 4-108 months). Clinical follow-up disclosed vascular complications in 4 of 12 patients (deep vein thrombosis, n = 1; transient ischemic attack, n = 3). Two females experienced excessive bleeding; both were diagnosed with AVWS. Neither leukemia nor myelofibrosis evolved in our cohort. CONCLUSION: Increased awareness to pediatric ET is warranted, as delayed diagnosis is common. Compared to adults, AVWS may be more prevalent among children with ET.


Assuntos
Calreticulina/genética , Janus Quinase 2/genética , Mutação , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Trombocitemia Essencial/terapia
7.
Acta Haematol ; 143(5): 432-437, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935715

RESUMO

BACKGROUND/OBJECTIVE: Alpha-thalassemia is one of the most prevalent genetic diseases, with the -α3.7 deletion being the most common mutation. Molecular studies have suggested mechanisms to explain the mild phenotype of "silent carrier" heterozygotes. However, the correlation between the clinical laboratory picture and the -α3.7 heterozygous state remains unclear, thus we chose to investigate. METHODS: We analyzed the medical files of 192 children evaluated for microcytosis at our tertiary center between 2007 and 2017 and diagnosed as heterozygotes for the -α3.7 deletion. Additional α-thalassemia mutations, iron deficiency anemia, and ß-thalassemia were ruled out. Laboratory parameters were compared to age- and sex-matched reference values. RESULTS: The -α3.7 carriers had significantly lower Hb and mean corpuscular volume (MCV) than the reference population, and significantly higher red blood cell counts across all age groups. The greatest reduction in Hb level appeared among male adolescents, while MCV was consistently 2 SDs lower than normal in most patients older than 2 years. CONCLUSION: Heterozygosity for the -α3.7 deletion was associated with clinically significant microcytosis and mild anemia in our pediatric population. In the absence of iron deficiency and ß-thalassemia, this finding provides a diagnosis for mild microcytic anemia, making additional investigations of microcytosis unnecessary.


Assuntos
Talassemia alfa , Talassemia beta , Adolescente , Criança , Índices de Eritrócitos , Heterozigoto , Humanos , Masculino , Mutação
8.
Haematologica ; 105(7): 1825-1834, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31558676

RESUMO

Fanconi anemia (FA), an inherited bone marrow failure (BMF) syndrome, caused by mutations in DNA repair genes, is characterized by congenital anomalies, aplastic anemia, high risk of malignancies and extreme sensitivity to alkylating agents. We aimed to study the clinical presentation, molecular diagnosis and genotype-phenotype correlation among patients with FA from the Israeli inherited BMF registry. Overall, 111 patients of Arab (57%) and Jewish (43%) descent were followed for a median of 15 years (range: 0.1-49); 63% were offspring of consanguineous parents. One-hundred patients (90%) had at least one congenital anomaly; over 80% of the patients developed bone marrow failure; 53% underwent hematopoietic stem-cell transplantation; 33% of the patients developed cancer; no significant association was found between hematopoietic stem-cell transplant and solid tumor development. Nearly 95% of the patients tested had confirmed mutations in the Fanconi genes FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) and FANCD1 (2%), including twenty novel mutations. Patients with FANCA mutations developed cancer at a significantly older age compared to patients with mutations in other Fanconi genes (mean 18.5 and 5.2 years, respectively, P=0.001); however, the overall survival did not depend on the causative gene. We hereby describe a large national cohort of patients with FA, the vast majority genetically diagnosed. Our results suggest an older age for cancer development in patients with FANCA mutations and no increased incidence of solid tumors following hematopoietic stem-cell transplant. Further studies are needed to guide individual treatment and follow-up programs.

10.
Proc Natl Acad Sci U S A ; 115(20): 5241-5246, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29712865

RESUMO

BRCA1 is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development. Patients who are compound heterozygous for BRCA1 truncating mutations and missense alleles that retain some DNA repair capacity may survive, albeit with very high risk of early onset breast or ovarian cancer and features of Fanconi anemia. However, a mechanism enabling survival of patients homozygous for BRCA1 truncating mutations has not been described. We studied two unrelated families in which four children presented with multiple congenital anomalies and severe chromosomal fragility. One child developed T cell acute lymphocytic leukemia (ALL), and a second child developed neuroblastoma. Each of the four children was homozygous for a nonsense mutation in BRCA1 exon 11. Homozygosity for the nonsense mutations was viable thanks to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5' of the mutations. The mutations did not affect the alternative splice site, but transcription from it produced an in-frame BRCA1 message with deletion of 3,309 bp. The translated BRCA1 protein was only 40% of normal length, but with intact N- and C-terminal sequences. These patients extend the range of BRCA1-related phenotypes and illustrate how naturally occurring alternative splicing can enable survival, albeit with severe consequences, of otherwise lethal genotypes of an essential gene.


Assuntos
Processamento Alternativo , Proteína BRCA1/genética , Neoplasias da Mama/genética , Códon sem Sentido , Homozigoto , Neoplasias Ovarianas/genética , Adolescente , Adulto , Neoplasias da Mama/patologia , Criança , Pré-Escolar , Feminino , Humanos , Neoplasias Ovarianas/patologia , Linhagem
11.
Eur J Haematol ; 101(3): 297-304, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29786897

RESUMO

BACKGROUND: Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes. OBJECTIVE: We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing. METHODS: Genetic diagnosis was performed by gene capture followed by next-generation sequencing of 76 genes known to cause anemia syndromes. RESULTS: Genetic diagnosis was achieved in 13 out of 21 patients (62%). Six patients were diagnosed with pyruvate kinase deficiency, 4 with dehydrated hereditary stomatocytosis, 2 with sideroblastic anemia, and 1 with CDA type IV. Eight novel mutations were found. In 7 patients, the genetic diagnosis differed from the pretest presumed diagnosis. The mean lag time from presentation to diagnosis was over 13 years. CONCLUSIONS: Targeted next-generation sequencing led to an accurate diagnosis in over 60% of patients with rare anemias. These patients do not need further diagnostic workup. Earlier incorporation of this method into the workup of patients with congenital anemia may improve patients' care and enable genetic counseling.


Assuntos
Anemia/congênito , Anemia/diagnóstico , Estudos de Associação Genética , Adolescente , Adulto , Anemia/sangue , Anemia/terapia , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/genética , Anemia Diseritropoética Congênita/terapia , Anemia Hemolítica Congênita/diagnóstico , Anemia Hemolítica Congênita/genética , Anemia Hemolítica Congênita não Esferocítica/diagnóstico , Anemia Hemolítica Congênita não Esferocítica/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Medula Óssea/patologia , Criança , Pré-Escolar , Biologia Computacional , Índices de Eritrócitos , Feminino , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Masculino , Mutação , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Erros Inatos do Metabolismo dos Piruvatos/diagnóstico , Erros Inatos do Metabolismo dos Piruvatos/genética , Doenças Raras , Adulto Jovem
12.
Blood Cells Mol Dis ; 71: 1-4, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29395830

RESUMO

Poor adherence of transfusion-dependent patients to chelation treatment is often the cause of persistent iron overload and ensuing morbidity. However, a tool to assess patient compliance with therapy is lacking in clinical practice. Labile plasma iron (LPI, the redox-active component of non-transferrin bound iron) has been studied as an indicator of systemic iron overload and of chelation efficacy, and may particularly reflect recent iron equilibrium. We considered the use of LPI as a potential indicator for recent chelation treatment in 18 transfusion-dependent pediatric patients. Samples were collected under chelation treatment or after a short interruption of the treatment, and LPI was measured by the FeROS assay (Aferrix, Tel Aviv, Israel). LPI was significantly higher after a short-term interruption of the chelation (median of 0.4 µM off-therapy [range:0-4] vs 0 µM on-therapy [range:0-2.8] (p < .001)). Conversely, serum iron, serum ferritin and calculated transferrin saturation were not significantly higher in the "off-therapy" samples compared to "on-therapy". In addition, in multivariate logistic regression analysis LPI was the variable most significantly associated with recent chelation treatment (p = .001). We conclude that LPI could serve as a useful indicator of compliance to chelation therapy.


Assuntos
Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/epidemiologia , Ferro/sangue , Adesão à Medicação , Adolescente , Biomarcadores , Transfusão de Sangue , Terapia por Quelação , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Masculino , Prognóstico , Sensibilidade e Especificidade , Transferrina/metabolismo , Resultado do Tratamento , Adulto Jovem
13.
Artigo em Inglês | MEDLINE | ID: mdl-28667000

RESUMO

Whole-exome sequencing (WES) has been increasingly useful for the diagnosis of patients with rare causes of anemia, particularly when there is an atypical clinical presentation or targeted genotyping approaches are inconclusive. Here, we describe a 20-yr-old man with a lifelong moderate-to-severe anemia with accompanying splenomegaly who lacked a definitive diagnosis. After a thorough clinical workup and targeted genetic sequencing, we identified a paternally inherited ß-globin mutation (HBB:c.93-21G>A, IVS-I-110:G>A), a known cause of ß-thalassemia minor. As this mutation alone was inconsistent with the severity of the anemia, we performed WES. Although we could not identify any relevant pathogenic single-nucleotide variants (SNVs) or small indels, copy-number variant (CNV) analyses revealed a likely triplication of the entire α-globin cluster, which was subsequently confirmed by multiplex ligation-dependent probe amplification. Treatment and follow-up was redefined according to the diagnosis of ß-thalassemia intermedia resulting from a single ß-thalassemia mutation in combination with an α-globin cluster triplication. Thus, we describe a case where the typical WES-based analysis of SNVs and small indels was unrevealing, but WES-based CNV analysis resulted in a definitive diagnosis that informed clinical decision-making. More generally, this case illustrates the value of performing CNV analysis when WES is otherwise unable to elucidate a clear genetic diagnosis.


Assuntos
Variações do Número de Cópias de DNA/genética , alfa-Globinas/genética , Talassemia beta/genética , Exoma/genética , Genótipo , Humanos , Masculino , Mutação/genética , Sequenciamento Completo do Exoma/métodos , Adulto Jovem , alfa-Globinas/metabolismo , Globinas beta/genética
14.
Platelets ; 28(7): 676-681, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28060550

RESUMO

Platelet function disorders (PFDs) are a common cause of mild bleeding tendency. However, they cannot be recognized by standard screening studies. The gold standard test for PFD is platelet aggregation, performed by light transmission aggregometry (LTA). A newer and less validated method is the closure time (CT), performed by the platelet function Analyzer 100 (PFA-100). Data regarding the validity of these tests in children are limited. The aim of this study was to evaluate the usefulness of LTA and PFA-100 for the diagnosis of pediatric patients with bleeding tendency. This retrospective study included patients one month-18 year old that had LTA tests performed at the coagulation laboratory of Rabin Medical Center between the years 2006-2015. Bleeding severity was assessed using a pediatric bleeding score. Patients were excluded from analysis if they had thrombocytopenia, thrombocytosis or coagulation factors deficiencies. One hundred and thirty-seven (137) patients were included in the analysis. The median age was 7.5 years (range one month-18 years). Most patients (93%) had a bleeding score of 2 or more. Abnormal LTA was found in 40% and prolonged CT in 23% of the patients. Abnormal LTA was significantly more common in patients with a bleeding score of 2 or more compared to patients with a lower bleeding scores (P = 0.04). No significant correlation was found between the bleeding severity and the number of agonists which induced abnormal responses (p = 0.52) or the CT (p = 0.35). Furthermore, no correlation was found between abnormal LTA and prolonged CT. To conclude, we were able to diagnose 40% of children who presented with bleeding tendency with platelet aggregation defects by LTA. Abnormal LTA was significantly more prevalent in patients with a bleeding score of 2 and above. In contrast, CT was not found to be sensitive as a screening tool for PFD. Therefore, our data extend the validity of the use of LTA for the evaluation of pediatric patients with bleeding tendency.


Assuntos
Plaquetas/patologia , Hemorragia/diagnóstico , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Adolescente , Ácido Araquidônico/farmacologia , Automação Laboratorial , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Criança , Pré-Escolar , Epinefrina/farmacologia , Feminino , Hemorragia/sangue , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Função Plaquetária , Estudos Retrospectivos , Índice de Gravidade de Doença
15.
J Pediatr Hematol Oncol ; 38(7): e260-2, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27258031

RESUMO

Diamond Blackfan anemia (DBA) is an inherited syndrome usually presenting with severe macrocytic anemia in infancy, paucity of erythroid precursors in the bone marrow, and congenital anomalies. We describe a child with mild, transfusion independent normocytic anemia whose diagnosis of DBA was established by identification of a novel de novo mutation disrupting normal splicing of the ribosomal protein RPL5. The diagnosis of DBA was confirmed by elevated erythrocyte adenosine deaminase levels and an abnormal ribosomal RNA profile. This case demonstrates the usefulness of genomic analysis in establishing the diagnosis of DBA in patients with a nonclassical presentation of the disease.


Assuntos
Anemia de Diamond-Blackfan/diagnóstico , Mutação , Proteínas Ribossômicas/genética , Adenosina Desaminase/sangue , Anemia de Diamond-Blackfan/genética , Feminino , Humanos , Lactente
16.
Semin Hematol ; 53 Suppl 1: S64-6, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27312170

RESUMO

The purpose of this study was to assess the efficacy and side effect profile of the repeated use of anti-D for the treatment of pediatric immune thrombocytopenia (ITP) in a large pediatric hematology center. We performed a retrospective analysis of patient records for children (aged 4 months-18 years) treated for ITP at Schneider Children's Medical Center of Israel from 1995-2015. Demographic and clinical data, reported adverse events, and therapy response were extracted from written and electronic files for all patients having received anti-D. Therapy response was defined as time to platelet count >30 x 10(9)/L. Thirty-six patients received 170 treatments of anti-D at a dose of 75 µg/kg. The majority were previously treated with corticosteroids and/or intravenous immunoglobulin (IVIG). Minimal adverse events were recorded including fever (3.5%), vomiting (2.9%), and headaches (1.7%). Notably only 1/170 treatments required blood transfusion and no life-threatening events occurred. The average time to platelets >30 x 10(9)/L was 2.3 days, with a median of 1 day, range 1-12 days. Despite the reported severe adverse events in mainly elderly patients, the use of anti-D can be safe and effective in carefully chosen, low-risk pediatric patients with ITP.


Assuntos
Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Imunoglobulina rho(D)/uso terapêutico , Adolescente , Criança , Pré-Escolar , Humanos , Lactente
17.
Cell Stem Cell ; 18(1): 73-78, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26607381

RESUMO

Multipotent and pluripotent stem cells are potential sources for cell and tissue replacement therapies. For example, stem cell-derived red blood cells (RBCs) are a potential alternative to donated blood, but yield and quality remain a challenge. Here, we show that application of insight from human population genetic studies can enhance RBC production from stem cells. The SH2B3 gene encodes a negative regulator of cytokine signaling and naturally occurring loss-of-function variants in this gene increase RBC counts in vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem and progenitor cells enhanced the maturation and overall yield of in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by CRISPR/Cas9 genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation. Our findings therefore highlight the potential for combining human genome variation studies with genome editing approaches to improve cell and tissue production for regenerative medicine.


Assuntos
Eritrócitos/citologia , Células-Tronco/citologia , Sistemas CRISPR-Cas , Diferenciação Celular , Citocinas/metabolismo , Células-Tronco Embrionárias/citologia , Sangue Fetal/citologia , Técnicas Genéticas , Variação Genética , Genoma Humano , Células-Tronco Hematopoéticas/citologia , Hemoglobinas/análise , Humanos , Mutação , Células-Tronco Pluripotentes/citologia , Medicina Regenerativa/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...