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1.
Stem Cell Res ; 41: 101603, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31698193

RESUMO

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) is a rare platelet disorder caused by mutations in RUNX1. We generated an iPSC line (GENYOi005-A) from a FPDMM patient with a non-previously reported variant p.Thr196Ala. Non-integrative Sendai viruses expressing the Yamanaka reprogramming factors were used to reprogram peripheral blood mononuclear cells from this FPDMM patient. Characterization of GENYOi005-A included genetic analysis of RUNX1 locus, Short Tandem Repeats profiling, alkaline phosphatase enzymatic activity, expression of pluripotency-associated factors and differentiation studies in vitro and in vivo. This iPSC line will provide a powerful tool to study developmental alterations of FPDMM patients.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/genética , Transtornos Plaquetários/patologia , Diferenciação Celular , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células-Tronco Pluripotentes Induzidas/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucócitos Mononucleares/patologia , Mutação , Células Cultivadas , Reprogramação Celular , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade
3.
Haemophilia ; 25(2): 289-295, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30748066

RESUMO

INTRODUCTION: Haemophilia A and haemophilia B, von Willebrand disease (VWD), factor VII deficiency and factor XI deficiency are congenital bleeding disorders predisposing to bleeding during invasive procedures. The ageing population of people with congenital bleeding disorders will likely increasingly require gastrointestinal endoscopy. The bleeding risk postgastrointestinal endoscopy and optimal prophylactic treatment regimens are not well described. METHODS: We performed a retrospective chart review at the McGill University Health Centre. Adult patients with haemophilia A or B, VWD, FVII deficiency and FXI deficiency who underwent gastrointestinal endoscopic procedures were included. Bleeding prophylaxis included combinations of plasma-derived factor (VWD) or recombinant factor (haemophilia A and haemophilia B), desmopressin and/or tranexamic acid. Our primary outcome was the 72-hour postendoscopy bleeding rate. RESULTS: One hundred and four endoscopies were performed in 48 patients. Haemophilia A (45.3% of endoscopies) was the most common bleeding disorder, followed by VWD (38.5%), FXI deficiency (8.7%), haemophilia B (4.8%) and FVII deficiency (2.9%). All patients were reviewed by the Haemophilia Treatment Center with peri-procedure treatment protocols put in place as required. The overall 72-hour bleeding rate was 0.96%, confidence interval (CI) 95% (0.17%-5.25%). The colonoscopic postpolypectomy bleeding rate was 1/21 (4.8%, CI 95% (0.9%-22.7%)) in comparison with the general population rate of 0.3%-10% for high-risk endoscopy (including colonoscopic polypectomy). CONCLUSION: To the best of our knowledge, this is the largest study describing patients with inherited bleeding disorders undergoing gastrointestinal endoscopy. The bleeding risk is not significantly higher to the general population when haemostatically managed by a team experienced in bleeding disorders.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Endoscopia do Sistema Digestório/efeitos adversos , Hemorragia/etiologia , Antifibrinolíticos/uso terapêutico , Coagulantes/uso terapêutico , Feminino , Hemorragia/prevenção & controle , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Risco , Índice de Gravidade de Doença , Ácido Tranexâmico/uso terapêutico
4.
Haemophilia ; 25(2): 229-235, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30690828

RESUMO

INTRODUCTION: Among children with haemophilia and their caregivers; problems arising from the teeth and the surrounding tissues have an important role in the treatment of this disease and it affects the quality of life of children and their parents. AIM: Aim of this study is to evaluate the oral health-related quality of life of children with haemophilia from the perspective of their parents. METHODS: Paediatric oral health-related quality of life (POQL) instrument was used in this cross-sectional study for quality of life measurement. The research data collected by the questionnaire form were coded for scale items and personal information questions and transferred to SPSS, a multivariate statistical analysis program for social sciences. SPSS 23.0 (IBM Corp, Armonk, NY) package program was used for statistical analysis of the data. RESULTS: Primary dentition dmft scores of patients with haemophilia are higher than the control group; mean value of haemophilic group is 3.5 vs control group are 2.6, respectively (P = 0.034). In spite of higher dmft scores, the haemophilia and control groups have shown no significant difference in oral health-related quality of life scores; median scores were 63.9 in haemophilic group and 85.3 in control group (P = 0.336), respectively. CONCLUSION: In spite of lower oral health measures, children with haemophilia and their parents reported no difference in oral health-related quality of life from their healthy counterparts.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Cuidadores/psicologia , Saúde Bucal , Qualidade de Vida , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Emoções , Feminino , Humanos , Masculino , Inquéritos e Questionários
5.
Pediatr Dev Pathol ; 22(4): 315-328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30600763

RESUMO

Germline mutations in RUNX1 result in autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM). To characterize the hematopathologic features associated with a germline RUNX1 mutation, we reviewed a total of 42 bone marrow aspirates from 14 FPDMM patients, including 24 cases with no cytogenetic clonal abnormalities, and 18 with clonal karyotypes or leukemia. We found that all aspirate smears had ≥10% atypical megakaryocytes, predominantly characterized by small forms with hypolobated and eccentric nuclei, and forms with high nuclear-to-cytoplasmic ratios. Core biopsies showed variable cellularity and variable numbers of megakaryocytes with similar features to those in the aspirates. Granulocytic and/or erythroid dysplasia (≥10% cells per lineage) were present infrequently. Megakaryocytes with separate nuclear lobes were increased in patients with myelodysplastic syndrome (MDS) and acute leukemia. Comparison to an immune thrombocytopenic purpura cohort confirms increased megakaryocytes with hypolobated eccentric nuclei in FPDMM patients. As such, patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Plaquetários/genética , Plaquetas/patologia , Medula Óssea/patologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Estudos de Coortes , Progressão da Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Masculino , Megacariócitos/patologia , Isoformas de Proteínas , Adulto Jovem
6.
Clin Chem ; 65(2): 254-262, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30282700

RESUMO

BACKGROUND: Until recently, clinical laboratories have monitored hemophilia treatment by measuring coagulation factors before/after infusion of human-derived or recombinant factors. Substantial changes are expected in the near future based on new therapeutic approaches that have been or are being developed. CONTENT: Hemophilia treatment includes replacement therapy with human-derived/recombinant factors or treatment with bypassing agents for patients without or with inhibitors, respectively. Accordingly, laboratory methods for monitoring include one-stage clotting or chromogenic assays meant to measure either factor VIII/IX or global coagulation tests to measure the effect of bypassing agents. Recently, modified long-acting coagulation factors have been introduced for which discrepant results may be expected when measurement is performed with one-stage clotting or chromogenic assays. Currently, novel drugs not based on coagulation factors are under development and are being tested in clinical studies. These drugs do require new methods and therefore laboratory evaluation of hemophilia will undergo dramatic changes in the near future. SUMMARY: From the analysis of the current practice and literature, we draw the following conclusions: (a) Thrombin generation or thromboelastometry are the logical candidate assays to monitor bypassing agents. (b) Considerable differences are expected when measuring modified long-acting coagulation factors, depending on whether one-stage or chromogenic assays are used. Although no definitive conclusions can presently be drawn, chromogenic assays are probably more suitable than one-stage clotting. (c) Novel drugs not based on coagulation factors such as emicizumab, fitusiran, or concizumab that are entering the market do require alternative methods that are not yet well established.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/tratamento farmacológico , Testes de Coagulação Sanguínea/métodos , Coagulantes/uso terapêutico , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Transtornos Herdados da Coagulação Sanguínea/patologia , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Humanos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Índice de Gravidade de Doença
7.
Haemophilia ; 25(1): 92-100, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30461134

RESUMO

INTRODUCTION: There is currently a paucity of health utility data describing the consequences of haemophilia and related complications. AIM: To quantify the impact of distinct stages of severity of haemophilia and disease-related complications on health-related quality of life, expressed as health utilities in Europe and the United States. METHODS: Nine health state descriptions were developed based on literature review and interviews with haematologists and haemophilia patients. Three descriptions characterized the impact of mild, moderate and severe haemophilia without inhibitors. Six descriptions characterized disease-related complications added to the moderate haemophilia description (arthroscopic synovectomy, prosthetic joint replacement, chronic pain, spontaneous bleed, traumatic bleed and end-stage joint disease). Time trade-off (TTO) interviews were conducted with 100 adults from the general public in the UK, France, Germany, Italy, Sweden and the United States. Mean TTO-derived utility values were expressed on a scale from 0 (death) to 1 (full health). RESULTS: Utility values obtained for the health states corresponding to mild (0.73-0.86), moderate (0.68-0.76) and severe (0.64-0.71) haemophilia followed the increase in severity. The addition of a complication to the "moderate" state leads to a decrease in the associated utility value. The most severe disutility (0.23-0.36) across all countries was associated with the burden of end-stage joint disease. CONCLUSIONS: This study underlines the value that the French, Italian, German, Swedish, United States and UK populations ascribe to the avoidance of disease progression in haemophilia without inhibitors. Improved treatment options hold a potential for important benefits to haemophilia patients.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/psicologia , Nível de Saúde , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/patologia , Europa (Continente) , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Estados Unidos , Adulto Jovem
8.
Haemophilia ; 25(1): 21-32, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30507046

RESUMO

Patients with haemophilia who have developed inhibitors against factor VIII (FVIII) or factor IX present a significant concern to those surgeons who operate on them. The evidence base for bypassing agents such as recombinant factor VIIa and activated prothrombin complex concentrate has amassed over several decades. The literature is open to positive interpretation on the successful use of these agents in the treatment of inhibitor-positive patients. However, there are equally persistent concerns amongst surgeons, in particular orthopaedic surgeons, regarding the high complication rate of bleeding. To explore and quantify this concern, we present a literature review spanning two decades of publications on haemophilia patients with inhibitors undergoing orthopaedic surgery. Irrespective of the progress made with haemostatic protocols, trepidation on embarking on surgery is valid. The high risk of bleeding is a function of the inherent complexity of the disease and rightfully translates into difficulties in its management. Combined with the prospect of orthopaedic surgery, those involved in the care of such patients are justified in their continued anxiety and diligence when considering the benefits in quality of life against the prevalent complications.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/patologia , Hemorragia/etiologia , Isoanticorpos/sangue , Procedimentos Ortopédicos/efeitos adversos , Transtornos Herdados da Coagulação Sanguínea/cirurgia , Fatores de Coagulação Sanguínea/antagonistas & inibidores , Fatores de Coagulação Sanguínea/uso terapêutico , Bases de Dados Factuais , Fator VIIa/uso terapêutico , Hemorragia/prevenção & controle , Humanos , Proteínas Recombinantes/uso terapêutico
12.
Haemophilia ; 22(5): 700-5, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27385253

RESUMO

INTRODUCTION: Despite the availability of subcutaneous desmopressin (1-deamino-8-d-arginine vasopressin, SC-DDAVP) as a haemostatic agent for children with mild bleeding disorders, few publications specifically address the safety or efficacy of this mode of administration. AIM: Our aim was to assess whether a defined fluid restriction protocol was effective in preventing hyponatremia in children receiving perioperative SC-DDAVP, and to document adequate biological and clinical response in this setting. METHODS: We retrospectively analysed a cohort of children with mild bleeding disorders prescribed SC-DDAVP over a 5-year period following institution of a 'two-thirds maintenance' fluid restriction protocol. RESULTS: Sixty-nine patients received SC-DDAVP following this protocol, including 15 with mild haemophilia A, 49 with von Willebrand disease (VWD) and five with platelet storage pool disorder. In patients who underwent formal preoperative assessment a complete or partial response was observed in 28/29 with type 1 VWD and 14/15 with mild haemophilia A. Perioperative SC-DDAVP provided excellent haemostasis in all patients, with no requirement for factor concentrate or blood products. Mild asymptomatic hyponatremia was detected in seven children who received multiple doses of DDAVP (lowest sodium 129 mmol L(-1) ); however, adherence to the prescribed fluid restriction protocol was questionable in six of these cases. Symptomatic hyponatremia was not observed. CONCLUSION: Subcutaneous desmopressin was well-tolerated, with no serious side-effects observed, and good biological responses in preoperative trials. A two-thirds maintenance fluid regimen was effective at preventing symptomatic hyponatremia in our cohort, and is now the standard protocol for fluid restriction post-DDAVP administration in our centre.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/tratamento farmacológico , Desamino Arginina Vasopressina/uso terapêutico , Hemostáticos/uso terapêutico , Adolescente , Transtornos Herdados da Coagulação Sanguínea/patologia , Criança , Pré-Escolar , Desamino Arginina Vasopressina/efeitos adversos , Hemofilia A/tratamento farmacológico , Hemofilia A/patologia , Hemostáticos/efeitos adversos , Humanos , Hiponatremia/etiologia , Injeções Subcutâneas , Deficiência do Pool Plaquetário/tratamento farmacológico , Deficiência do Pool Plaquetário/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Doenças de von Willebrand/tratamento farmacológico , Doenças de von Willebrand/patologia
13.
Haemophilia ; 22(4): 556-63, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27194592

RESUMO

INTRODUCTION: Intracranial haemorrhage (ICH) is the most serious bleeding event for patients with inherited bleeding disorders (IBD). The risks and long-term consequences remain unknown. AIM: This single-centre service evaluation aimed to identify the incidence, risks and long-term outcomes following ICH in patients with IBD. METHODS: The IBD database and medical notes between 1987 and 2013 were reviewed. Children without apparent neurological deficit following ICH completed standardized assessments and supplementary information sheets. RESULTS: ICH was confirmed in 38/1111 children with IBD. The overall risk of ICH amongst children with IBD was 3.4% (95% CI: 2.5, 4.7%). However, 27/38 had an ICH in the first year of life, 18 of which were in the neonatal period. In children with IBD who had an ICH, the risks of ICH in the neonatal period or first year of life were 18/38 (47%) (95% CI: 32, 63%) and 27/38 (71%) (95% CI: 55, 83%) respectively. Mortality risk from ICH in children with an IBD was 5/38 (13%) (95% CI: 5.8, 27.3 %). Ten of 32 survivors had known neurological sequelae including motor disorder deficits (MDD) while 22 had no documented evidence of neurological impairment or MDD. Re-evaluation was possible in 17/22 children, 8 of whom demonstrated evidence of MDD. After re-evaluation, the risk of significant neurological MDD from ICH increased from 31% CI (95% CI: 18, 49%) to 56% CI (95% CI: 39, 72%). CONCLUSION: Risks and consequences of ICH in IBD were highest within the neonatal period and first year of life. MDD after ICH was not reliably identified in early life and ongoing monitoring in the first decade of life will facilitate educational support or physical rehabilitation.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/complicações , Hemorragias Intracranianas/etiologia , Adolescente , Transtornos Herdados da Coagulação Sanguínea/patologia , Criança , Pré-Escolar , Bases de Dados Factuais , Humanos , Incidência , Hemorragias Intracranianas/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
15.
Haemophilia ; 22(4): 590-7, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26879396

RESUMO

INTRODUCTION: Molecular testing of Inherited bleeding coagulation disorders (IBCDs) not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and in certain cases genotype-phenotype correlations are important for predicting the clinical course of the disease and to allow tailor-made follow-up of individuals. Until recently, genotyping has been mainly performed by Sanger sequencing, a technique known to be time consuming and expensive. Currently, next-generation sequencing (NGS) offers a new potential approach that enables the simultaneous investigation of multiple genes at manageable cost. AIM: The aim of this study was to design and to analyse the applicability of a 23-gene NGS panel in the molecular diagnosis of patients with IBCDs. METHODS: A custom target enrichment library was designed to capture 31 genes known to be associated with IBCDs. Probes were generated for 296 targets to cover 86.3 kb regions (all exons and flanking regions) of these genes. Twenty patients with an IBCDs phenotype were studied using NGS technology. RESULTS: In all patients, our NGS approach detected causative mutations. Twenty-one pathogenic variants were found; while most of them were missense (18), three deletions were also identified. Six novel mutations affecting F8, FGA, F11, F10 and VWF genes, and 15 previously reported variants were detected. NGS and Sanger sequencing were 100% concordant. CONCLUSION: Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/genética , Testes Genéticos/métodos , Adolescente , Adulto , Transtornos Herdados da Coagulação Sanguínea/patologia , Criança , Pré-Escolar , DNA/química , DNA/isolamento & purificação , DNA/metabolismo , Feminino , Mutação da Fase de Leitura , Deleção de Genes , Estudos de Associação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Análise de Sequência de DNA , Adulto Jovem
16.
Ann Oncol ; 27(5): 887-95, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26884589

RESUMO

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/epidemiologia , Transtornos Plaquetários/epidemiologia , Plaquetas/patologia , Neoplasias Hematológicas/epidemiologia , Leucemia Mieloide Aguda/epidemiologia , Trombocitopenia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/genética , Transtornos Plaquetários/patologia , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Predisposição Genética para Doença , Genótipo , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Lactente , Japão/epidemiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Trombocitopenia/genética , Trombocitopenia/patologia
17.
J Korean Med Sci ; 31(1): 33-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26770035

RESUMO

Hemophilia is a serious rare disease that requires continuous management and treatment for which the medicine is costly at the annual average of 100 million KRW for an individual. The aim of this study was to investigate trends in the utilization of coagulation factor (CF) used for hemophilia treatment using the National Health Insurance database from 2010 to 2013 in Korea and compare the utilization of CF with other countries. The consumption of CF per capita (IU) in Korea was not more than other countries with similar income to Korea. However, CF usage per patient IU was higher because the prevalence rate of hemophilia in Korea was lower than in other countries while the number of serious patients was much more. Therefore, it is difficult to say that the consumption of hemophilia medicine in Korea is higher than that in other countries. The consumption and cost of hemophilia medicine in Korea is likely to increase due to the increased utilization of expensive bypassing agents and the widespread use of prophylaxis for severe hemophilia. Even during the research period, it increased slightly and other countries show a similar trend. Thus, hemophilia patient management should accompany active monitoring on the health and cost outcomes of pharmaceutical treatment in the future. This study is expected to contribute to further insight into drug policies for other countries that face similar challenges with high price pharmaceuticals.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/tratamento farmacológico , Transtornos Herdados da Coagulação Sanguínea/economia , Fatores de Coagulação Sanguínea/uso terapêutico , Adolescente , Adulto , Idoso , Transtornos Herdados da Coagulação Sanguínea/patologia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , República da Coreia , Índice de Gravidade de Doença , Adulto Jovem
18.
J Thromb Thrombolysis ; 41(3): 544-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26036227

RESUMO

Congenital plasminogen deficiency is a rare autosomal recessive disorder, characterized by chronic mucosal membranous lesions. Although the most common clinical manifestation is eye involvement as ligneous conjunctivitis, extra-ocular lesions affecting other mucosal surfaces indicates a systemic disease. In this report we describe two cases with atypical extra-ocular involvement that includes pericarditis and recurrent hematocolpos, and one with paradoxical correlation between ocular lesions and plasminogen levels. In ligneous conjunctivitis, although different treatment strategies have been tried with mild success, the only effective therapy is topical or systemic plasminogen concentrates that are not commercially available. Unfortunately there is not either effective management for cases with multisystemic disease. Hence, treatment for plasminogen deficiency is still a challenge and the variability of the clinical spectrum in this pathology makes necessary a multidisciplinary approach.


Assuntos
Transtornos Herdados da Coagulação Sanguínea , Plasminogênio/administração & dosagem , Plasminogênio/deficiência , Transtornos Herdados da Coagulação Sanguínea/sangue , Transtornos Herdados da Coagulação Sanguínea/tratamento farmacológico , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Herdados da Coagulação Sanguínea/patologia , Pré-Escolar , Conjuntivite/sangue , Conjuntivite/tratamento farmacológico , Conjuntivite/genética , Conjuntivite/patologia , Feminino , Hematocolpia/sangue , Hematocolpia/tratamento farmacológico , Hematocolpia/genética , Hematocolpia/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pericardite/sangue , Pericardite/tratamento farmacológico , Pericardite/genética , Pericardite/patologia
19.
Exp Hematol ; 43(10): 849-57, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26021490

RESUMO

Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease associated with a germline mutation in the RUNX1 gene and is characterized by thrombocytopenia and an increased risk of developing myeloid malignancies. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a patient with FPD/AML possessing a nonsense mutation R174X in the RUNX1 gene. Consistent with the clinical characteristics of the disease, FPD iPSC-derived hematopoietic progenitor cells were significantly impaired in undergoing megakaryocytic differentiation and subsequent maturation, as determined by colony-forming cell assay and surface marker analysis. Notably, when we corrected the RUNX1 mutation using transcription activator-like effector nucleases in conjunction with a donor plasmid containing normal RUNX1 cDNA sequences, megakaryopoiesis and subsequent maturation were restored in FPD iPSC-derived hematopoietic cells. These findings clearly indicate that the RUNX1 mutation is robustly associated with thrombocytopenia in patients with FPD/AML, and transcription activator-like effector nuclease-mediated gene correction in iPSCs generated from patient-derived cells could provide a promising clinical application for treatment of the disease.


Assuntos
Transtornos Herdados da Coagulação Sanguínea , Transtornos Plaquetários , Códon sem Sentido , Subunidade alfa 2 de Fator de Ligação ao Core , Terapia Genética/métodos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucemia Mieloide Aguda , Trombopoese/genética , Adulto , Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Herdados da Coagulação Sanguínea/metabolismo , Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Herdados da Coagulação Sanguínea/terapia , Transtornos Plaquetários/genética , Transtornos Plaquetários/metabolismo , Transtornos Plaquetários/patologia , Transtornos Plaquetários/terapia , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Subunidade alfa 2 de Fator de Ligação ao Core/genética , DNA Complementar/genética , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia
20.
Blood ; 124(12): 1926-30, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25114263

RESUMO

Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease of the hematopoietic system that is caused by heterozygous mutations in RUNX1. FPD/AML patients have a bleeding disorder characterized by thrombocytopenia with reduced platelet numbers and functions, and a tendency to develop AML. No suitable animal models exist for FPD/AML, as Runx11/2 mice and zebra fish do not develop bleeding disorders or leukemia. Here we derived induced pluripotent stem cells (iPSCs) from 2 patients in a family with FPD/AML, and found that the FPD iPSCs display defects in megakaryocytic differentiation in vitro. We corrected the RUNX1 mutation in 1 FPD iPSC line through gene targeting, which led to normalization of megakaryopoiesis of the iPSCs in culture. Our results demonstrate successful in vitro modeling of FPD with patient-specific iPSCs and confirm that RUNX1 mutations are responsible for megakaryopoietic defects in FPD patients.


Assuntos
Transtornos Herdados da Coagulação Sanguínea/genética , Transtornos Herdados da Coagulação Sanguínea/terapia , Transtornos Plaquetários/genética , Transtornos Plaquetários/terapia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação de Sentido Incorreto , Reparo Gênico Alvo-Dirigido/métodos , Animais , Transtornos Herdados da Coagulação Sanguínea/patologia , Transtornos Plaquetários/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/química , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/transplante , Leucemia Mieloide Aguda/patologia , Camundongos , Trombopoese/genética
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