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1.
Am J Hematol ; 94(7): 741-750, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30945320

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (P = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non-skin-related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.

3.
Am J Hematol ; 93(7): 882-888, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29659042

RESUMO

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.

4.
Blood ; 131(20): 2183-2192, 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29549173

RESUMO

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

5.
BMJ Open ; 8(1): e018421, 2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29306887

RESUMO

OBJECTIVES: To assess the feasibility and acceptability of a mindfulness-based stress reduction (MBSR)-based intervention and determine if the intervention is associated with a significant signal on empathy and emotional competencies. DESIGN: Two pre-post proof-of-concept studies. SETTING: Participants were recruited at the University of Montreal's Psychology Department (Study 1) and the CHU Sainte-Justine Department of Hematology-Oncology (Study 2). PARTICIPANTS: Study 1: 12 students completed the 8-week programme (mean age 24, range 18-34). Study 2: 25 professionals completed the 8-week programme (mean age 48, range 27-63). INTERVENTION: Standard MBSR programme including 8-week mindfulness programme consisting of 8 consecutive weekly 2-hour sessions and a full-day silent retreat. OUTCOMES MEASURES: Mindfulness as measured by the Mindful Attention Awareness Scale; empathy as measured by the Interpersonal Reactivity Index (IRI)'s Perspective Taking and Empathic Concern subscales; identification of one's own emotions and those of others as measured by the Profile of Emotional Competence (PEC)'s Identify my Emotions and Identify Others' Emotions subscales; emotional acceptance as measured by the Acceptance and Action Questionnaire-II (AAQ-II) and the Emotion Regulation Scale (ERQ)'s Expressive Suppression subscale; and recognition of emotions in others as measured by the Geneva Emotion Recognition Test (GERT). RESULTS: In both studies, retention rates (80%-81%) were acceptable. Participants who completed the programme improved on all measures except the PEC's Identify Others' Emotions and the IRI's Empathic Concern (Cohen's d median=0.92, range 45-1.72). In Study 2, favourable effects associated with the programme were maintained over 3 months on the PEC's Identify my Emotions, the AAQ-II, the ERQ's Expressive Suppression and the GERT. CONCLUSIONS: The programme was feasible and acceptable. It was associated with a significant signal on the following outcomes: perspective taking, the identification of one's own emotions and emotional acceptance, thus, justifying moving towards efficacy trials using these outcomes.


Assuntos
Inteligência Emocional/fisiologia , Empatia , Pessoal de Saúde/psicologia , Atenção Plena , Estresse Psicológico/prevenção & controle , Adulto , Canadá , Estudos de Viabilidade , Feminino , Humanos , Masculino , Estudo de Prova de Conceito , Estresse Psicológico/psicologia , Adulto Jovem
7.
NPJ Genom Med ; 22017 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-28690869

RESUMO

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide CNV analysis by single nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic CNVs in 11 of 67 patients tested (16.4%). In four of these patients, identification of CNV was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic CNVs by other methods. Of the 19 patients with pathogenic CNVs, four had compound-heterozygosity of a CNV with a nucleotide-level mutation. Pathogenic CNVs were associated with more extensive non-hematological organ system involvement (p=0.0006), developmental delay (p=0.006) and short stature (p=0.04) compared to nucleotide-level mutations. In conclusion, a significant proportion of patients with IBMFSs harbor pathogenic CNVs which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of IBMFSs but without identification of pathogenic nucleotide-level mutations should undergo specific testing for CNVs.

8.
Haematologica ; 102(3): 484-497, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28082345

RESUMO

Mutations in GFI1B are associated with inherited bleeding disorders called GFI1B-related thrombocytopenias. We show here that mice with a megakaryocyte-specific Gfi1b deletion exhibit a macrothrombocytopenic phenotype along a megakaryocytic dysplasia reminiscent of GFI1B-related thrombocytopenia. GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton. Gfi1b-null megakaryocytes are also unable to form proplatelets, a process independent of integrin signaling. GFI1B-deficient megakaryocytes exhibit aberrant expression of several components of both the actin and microtubule cytoskeleton, with a dramatic reduction of α-tubulin. Inhibition of FAK or ROCK, both important for actin cytoskeleton organization and integrin signaling, only partially restored their response to integrin ligands, but the inhibition of PAK, a regulator of the actin cytoskeleton, completely rescued the responsiveness of Gfi1b-null megakaryocytes to ligands, but not their ability to form proplatelets. We conclude that Gfi1b controls major functions of megakaryocytes such as integrin-dependent cytoskeleton organization, spreading and migration through the regulation of PAK activity whereas the proplatelet formation defect in GFI1B-deficient megakaryocytes is due, at least partially, to an insufficient α-tubulin content.


Assuntos
Citoesqueleto/metabolismo , Integrinas/metabolismo , Megacariócitos/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Actinas/química , Actinas/metabolismo , Animais , Diferenciação Celular/genética , Células Cultivadas , Perfilação da Expressão Gênica , Estudos de Associação Genética , Megacariócitos/efeitos dos fármacos , Megacariócitos/patologia , Megacariócitos/ultraestrutura , Camundongos , Camundongos Knockout , Microtúbulos/metabolismo , Fenótipo , Contagem de Plaquetas , Inibidores de Proteínas Quinases/farmacologia , Multimerização Proteica , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/metabolismo , Transcriptoma
9.
J Biol Chem ; 281(35): 25703-11, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16787915

RESUMO

Hypoxia-inducible factor-1 (HIF-1) regulates the transcription of genes whose products play critical roles in energy metabolism, erythropoiesis, angiogenesis, and cell survival. Limited information is available concerning its function in mammalian hematopoiesis. Previous studies have demonstrated that homozygosity for a targeted null mutation in the Hif1alpha gene, which encodes the hypoxia-responsive alpha subunit of HIF-1, causes cardiac, vascular, and neural malformations resulting in lethality by embryonic day 10.5 (E10.5). This study revealed reduced myeloid multilineage and committed erythroid progenitors in HIF-1alpha-deficient embryos, as well as decreased hemoglobin content in erythroid colonies from HIF-1alpha-deficient yolk sacs at E9.5. Dysregulation of erythropoietin (Epo) signaling was evident from a significant decrease in mRNA levels of Epo receptor (EpoR) in Hif1alpha-/- yolk sac as well as Epo and EpoR mRNA in Hif1alpha-/- embryos. The erythropoietic defects in HIF-1alpha-deficient erythroid colonies could not be corrected by cytokines, such as vascular endothelial growth factor and Epo, but were ameliorated by Fe-SIH, a compound delivering iron into cells independently of iron transport proteins. Consistent with profound defects in iron homeostasis, Hif1alpha-/- yolk sac and/or embryos demonstrated aberrant mRNA levels of hepcidin, Fpn1, Irp1, and frascati. We conclude that dysregulated expression of genes encoding Epo, EpoR, and iron regulatory proteins contributes to defective erythropoiesis in Hif1alpha-/- yolk sacs. These results identify a novel role for HIF-1 in the regulation of iron homeostasis and reveal unexpected regulatory differences in Epo/EpoR signaling in yolk sac and embryonic erythropoiesis.


Assuntos
Eritropoetina/fisiologia , Regulação da Expressão Gênica , Fator 1 Induzível por Hipóxia/deficiência , Ferro/metabolismo , Animais , Eritropoese , Hemoglobinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores da Eritropoetina/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Saco Vitelino/metabolismo
11.
Blood ; 103(5): 1937-40, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-14604959

RESUMO

The first congenital defect of hypoxia-sensing homozygosity for VHL 598C>T mutation was recently identified in Chuvash polycythemia. Subsequently, we found this mutation in 11 unrelated individuals of diverse ethnic backgrounds. To address the question of whether the VHL 598C>T substitution occurred in a single founder or resulted from recurrent mutational events in human evolution, we performed haplotype analysis of 8 polymorphic markers covering 340 kb spanning the VHL gene on 101 subjects bearing the VHL 598C>T mutation, including 72 homozygotes (61 Chuvash and 11 non-Chuvash) and 29 heterozygotes (11 Chuvash and 18 non-Chuvash), and 447 healthy unrelated individuals from Chuvash and other ethnic groups. The differences in allele frequencies for each of the 8 markers between 447 healthy controls (598C) and 101 subjects bearing the 598T allele (P < 10(-7)) showed strong linkage disequilibrium. Haplotype analysis indicated a founder effect. We conclude that the VHL 598C>T mutation, the most common defect of congenital polycythemia yet found, was spread from a single founder 1,000 to 62,000 years ago.


Assuntos
Efeito Fundador , Mutação , Policitemia/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Alelos , Análise Mutacional de DNA , Frequência do Gene , Variação Genética , Haplótipos , Homozigoto , Humanos , Modelos Genéticos , Mutação de Sentido Incorreto , Polimorfismo Genético , Proteína Supressora de Tumor Von Hippel-Lindau
12.
Blood ; 101(8): 3294-301, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12515724

RESUMO

Essential thrombocythemia (ET) and polycythemia vera (PV) are clonal myeloproliferative disorders that are often difficult to distinguish from other causes of elevated blood cell counts. Assays that could reliably detect clonal hematopoiesis would therefore be extremely valuable for diagnosis. We previously reported 3 X-chromosome transcription-based clonality assays (TCAs) involving the G6PD, IDS, and MPP1 genes, which together were informative in about 65% of female subjects. To increase our ability to detect clonality, we developed simple TCA for detecting the transcripts of 2 additional X-chromosome genes: Bruton tyrosine kinase (BTK) and 4-and-a-half LIM domain 1 (FHL1). The combination of TCA established the presence or absence of clonal hematopoiesis in about 90% of female subjects. We show that both genes are subject to X-chromosome inactivation and are polymorphic in all major US ethnic groups. The 5 TCAs were used to examine clonality in 46 female patients along with assays for erythropoietin-independent erythroid colonies (EECs) and granulocyte PRV-1 mRNA levels to discriminate polycythemias and thrombocytoses. Of these, all 19 patients with familial polycythemia or thrombocytosis had polyclonal hematopoiesis, whereas 22 of 26 patients with clinical evidence of myeloproliferative disorder and 1 patient with clinically obscure polycythemia were clonal. Interestingly, interferon alpha therapy in 2 patients with PV was associated with reversion of clonal to polyclonal hematopoiesis. EECs were observed in 14 of 14 patients with PV and 4 of 12 with ET, and increased granulocyte PRV-1 mRNA levels were found in 9 of 13 patients with PV and 2 of 12 with ET. Thus, these novel clonality assays are useful in the diagnosis and follow-up of polycythemic conditions and disorders with increased platelet levels.


Assuntos
Cromossomos Humanos X/genética , Células Precursoras Eritroides/efeitos dos fármacos , Eritropoetina/farmacologia , Marcadores Genéticos , Granulócitos/metabolismo , Proteínas de Homeodomínio/sangue , Policitemia/diagnóstico , Proteínas Tirosina Quinases/sangue , RNA Mensageiro/sangue , Receptores de Superfície Celular/biossíntese , Trombocitose/diagnóstico , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia , Idoso , Criança , Células Clonais/patologia , Ensaio de Unidades Formadoras de Colônias , Diagnóstico Diferencial , Compensação de Dosagem (Genética) , Células Precursoras Eritroides/química , Éxons/genética , Feminino , Proteínas Ligadas por GPI , Hematopoese/genética , Proteínas de Homeodomínio/genética , Humanos , Interferon-alfa/farmacologia , Isoantígenos , Glicoproteínas de Membrana , Pessoa de Meia-Idade , Policitemia/genética , Policitemia/patologia , Policitemia Vera/diagnóstico , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Policitemia Vera/patologia , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , Proteínas Tirosina Quinases/genética , RNA Mensageiro/biossíntese , Receptores de Superfície Celular/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trombocitose/genética , Trombocitose/patologia
13.
Blood ; 101(4): 1591-5, 2003 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-12393546

RESUMO

The congenital polycythemic disorders with elevated erythropoietin (Epo) have been until recently an enigma, and abnormality in the hypoxia-sensing pathway has been hypothesized as a possible mechanism. The tumor suppressor von Hippel-Lindau (VHL) participates in the hypoxia-sensing pathway, as it binds to the proline-hydroxylated form of the hypoxia-inducible factor 1alpha (HIF-1alpha) and mediates its ubiquitination and proteosomal degradation. The loss of VHL function may result in the accumulation of HIF-1alpha and overproduction of HIF-1 downstream target genes including Epo. VHL syndrome is an autosomal dominant disorder predisposing to the development of tumors, due to inherited mutations in the VHL gene. Some rare patients with VHL syndrome have polycythemia, which has been attributed to Epo production by a tumor. It was recently found that homozygosity for the VHL Arg200Trp mutation is the cause of Chuvash polycythemia, an autosomal recessive polycythemic disorder characterized by elevated serum Epo and hypersensitivity of erythroid cells to Epo. We evaluated the role of VHL in 8 children with a history of polycythemia and an elevated serum Epo level and found 3 different germline VHL mutations in 4 of them. One child was homozygous for the Arg200Trp VHL mutation, and another compound heterozygous for the Arg200Trp and the Val130Leu mutations. Two children (siblings) were heterozygous for an Asp126Tyr mutation, one of them fulfilling some criteria of VHL syndrome. We propose that mutations of the VHL gene represent an important cause of pediatric sporadic polycythemias with an inappropriately high serum Epo concentration.


Assuntos
Ligases/genética , Mutação , Policitemia/genética , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Adolescente , Adulto , Arginina , Ácido Aspártico , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Células Precursoras Eritroides/efeitos dos fármacos , Eritropoetina/sangue , Eritropoetina/farmacologia , Feminino , Heterozigoto , Homozigoto , Humanos , Leucina , Masculino , Linhagem , Policitemia/congênito , Análise de Sequência de DNA , Triptofano , Tirosina , Valina , Proteína Supressora de Tumor Von Hippel-Lindau
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