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[PMID]:28460646
[Au] Autor:Markusic DM; Nichols TC; Merricks EP; Palaschak B; Zolotukhin I; Marsic D; Zolotukhin S; Srivastava A; Herzog RW
[Ad] Endereço:Department of Pediatrics, University of Florida, Gainesville, FL, 32610, USA. dmarkusic@ufl.edu.
[Ti] Título:Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models.
[So] Source:J Transl Med;15(1):94, 2017 May 01.
[Is] ISSN:1479-5876
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Adeno-associated virus (AAV) gene therapy vectors have shown the best outcomes in human clinical studies for the treatment of genetic diseases such as hemophilia. However, these pivotal investigations have also identified several challenges. For example, high vector doses are often used for hepatic gene transfer, and cytotoxic T lymphocyte responses against viral capsid may occur. Therefore, achieving therapy at reduced vector doses and other strategies to reduce capsid antigen presentation are desirable. METHODS: We tested several engineered AAV capsids for factor IX (FIX) expression for the treatment of hemophilia B by hepatic gene transfer. These capsids lack potential phosphorylation or ubiquitination sites, or had been generated through molecular evolution. RESULTS: AAV2 capsids lacking either a single lysine residue or 3 tyrosine residues directed substantially higher coagulation FIX expression in mice compared to wild-type sequence or other mutations. In hemophilia B dogs, however, expression from the tyrosine-mutant vector was merely comparable to historical data on AAV2. Evolved AAV2-LiC capsid was highly efficient in hemophilia B mice but lacked efficacy in a hemophilia B dog. CONCLUSIONS: Several alternative strategies for capsid modification improve the in vivo performance of AAV vectors in hepatic gene transfer for correction of hemophilia. However, capsid optimization solely in mouse liver may not predict efficacy in other species and thus is of limited translational utility.
[Mh] Termos MeSH primário: Capsídeo/metabolismo
Dependovirus/genética
Fator IX/genética
Técnicas de Transferência de Genes
Engenharia Genética
[Mh] Termos MeSH secundário: Animais
Cães
Vetores Genéticos/metabolismo
Hemofilia B/genética
Hepatócitos/metabolismo
Fígado/metabolismo
Lisina/genética
Masculino
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Modelos Animais
Mutação/genética
Transdução Genética
Tirosina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
42HK56048U (Tyrosine); 9001-28-9 (Factor IX); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1186/s12967-017-1200-1


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[PMID]:29270992
[Au] Autor:Ljung RCR
[Ad] Endereço:Department of Clinical Sciences - Paediatrics, Lund University, Lund, Sweden.
[Ti] Título:How I manage patients with inherited haemophilia A and B and factor inhibitors.
[So] Source:Br J Haematol;180(4):501-510, 2018 02.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. 'Bypassing agents' may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at 'good' or 'bad risk' for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities.
[Mh] Termos MeSH primário: Inibidores dos Fatores de Coagulação Sanguínea
Hemofilia A/diagnóstico
Hemofilia A/terapia
Hemofilia B/diagnóstico
Hemofilia B/terapia
Isoanticorpos
[Mh] Termos MeSH secundário: Adulto
Fatores Etários
Inibidores dos Fatores de Coagulação Sanguínea/sangue
Inibidores dos Fatores de Coagulação Sanguínea/imunologia
Criança
Gerenciamento Clínico
Fator IX/genética
Fator IX/imunologia
Fator IX/uso terapêutico
Fator VIII/genética
Fator VIII/imunologia
Fator VIII/uso terapêutico
Hemofilia A/complicações
Hemofilia A/genética
Hemofilia B/complicações
Hemofilia B/genética
Hemorragia/etiologia
Hemorragia/prevenção & controle
Hemorragia/terapia
Seres Humanos
Isoanticorpos/sangue
Isoanticorpos/imunologia
Medição de Risco
Índice de Gravidade de Doença
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Blood Coagulation Factor Inhibitors); 0 (Isoantibodies); 9001-27-8 (Factor VIII); 9001-28-9 (Factor IX)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.15053


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Arruda, Valder R
Registro de Ensaios Clínicos
Registro de Ensaios Clínicos
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[PMID]:29211678
[Au] Autor:George LA; Sullivan SK; Giermasz A; Rasko JEJ; Samelson-Jones BJ; Ducore J; Cuker A; Sullivan LM; Majumdar S; Teitel J; McGuinn CE; Ragni MV; Luk AY; Hui D; Wright JF; Chen Y; Liu Y; Wachtel K; Winters A; Tiefenbacher S; Arruda VR; van der Loo JCM; Zelenaia O; Takefman D; Carr ME; Couto LB; Anguela XM; High KA
[Ad] Endereço:From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children's Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine
[Ti] Título:Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant.
[So] Source:N Engl J Med;377(23):2215-2227, 2017 12 07.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. METHODS: We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×10 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. RESULTS: No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. CONCLUSIONS: We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092 .).
[Mh] Termos MeSH primário: Fator IX/genética
Terapia Genética/métodos
Vetores Genéticos
Hemofilia B/terapia
Transgenes
[Mh] Termos MeSH secundário: Adolescente
Adulto
Dependovirus/imunologia
Fator IX/metabolismo
Fator IX/uso terapêutico
Vetores Genéticos/administração & dosagem
Hemofilia B/genética
Hemofilia B/metabolismo
Hemorragia/prevenção & controle
Seres Humanos
Masculino
Meia-Idade
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
9001-28-9 (Factor IX)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171207
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1708538


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[PMID]:29211662
[Au] Autor:Porteus M
[Ad] Endereço:From the Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
[Ti] Título:Closing In on Treatment for Hemophilia B.
[So] Source:N Engl J Med;377(23):2274-2275, 2017 12 07.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Fator IX
Hemofilia B
[Mh] Termos MeSH secundário: Hemofilia A
Seres Humanos
[Pt] Tipo de publicação:EDITORIAL; COMMENT
[Nm] Nome de substância:
9001-28-9 (Factor IX)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171208
[Lr] Data última revisão:
171208
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMe1713735


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[PMID]:28895852
[Au] Autor:Nathwani AC; Davidoff AM; Tuddenham EGD
[Ad] Endereço:Department of Academic Haematology, UCL Cancer Institute, Katharine Dormandy Haemophilia and Thrombosis Centre, Rowland Hill Street, London NW3 2PF, United Kingdom; National Health Service Blood and Transplant, Oak House, Reeds Crescent, Watford, Hertfordshire, WD24 4QN, United Kingdom. Electronic address: amit.nathwani@ucl.ac.uk.
[Ti] Título:Gene Therapy for Hemophilia.
[So] Source:Hematol Oncol Clin North Am;31(5):853-868, 2017 Oct.
[Is] ISSN:1558-1977
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The best currently available treatments for hemophilia A and B (factor VIII or factor IX deficiency, respectively) require frequent intravenous infusion of highly expensive proteins that have short half-lives. Factor levels follow a saw-tooth pattern that is seldom in the normal range and falls so low that breakthrough bleeding occurs. Most hemophiliacs worldwide do not have access to even this level of care. In stark contrast, gene therapy holds out the hope of a cure by inducing continuous endogenous expression of factor VIII or factor IX following transfer of a functional gene to replace the hemophilic patient's own defective gene.
[Mh] Termos MeSH primário: Terapia Genética
Hemofilia A/genética
Hemofilia A/terapia
Hemofilia B/genética
Hemofilia B/terapia
[Mh] Termos MeSH secundário: Animais
Ensaios Clínicos como Assunto
Dependovirus/genética
Fator IX/genética
Fator VIII/genética
Terapia Genética/efeitos adversos
Terapia Genética/economia
Terapia Genética/métodos
Vetores Genéticos/genética
Seres Humanos
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
9001-27-8 (Factor VIII); 9001-28-9 (Factor IX)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE


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[PMID]:28685500
[Au] Autor:Jiang L; Liu Y; Zhang L; Santoro C; Rodriguez A
[Ad] Endereço:Department of Pharmacy, West China Second University Hospital, Sichuan University, No. 17, Section Three, Ren Min Nan Lu AvenueRoad, Chengdu, Sichuan, China, 610041.
[Ti] Título:Rituximab for treating inhibitors in people with inherited severe hemophilia.
[So] Source:Cochrane Database Syst Rev;7:CD010810, 2017 07 07.
[Is] ISSN:1469-493X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 16 February 2017. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. DATA COLLECTION AND ANALYSIS: No randomized controlled trials matching the selection criteria were eligible for inclusion. MAIN RESULTS: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.
[Mh] Termos MeSH primário: Anticorpos
Fator IX/imunologia
Fator VIII/imunologia
Hemofilia A/tratamento farmacológico
Hemofilia B/tratamento farmacológico
Fatores Imunológicos/uso terapêutico
Rituximab/uso terapêutico
[Mh] Termos MeSH secundário: Fator IX/antagonistas & inibidores
Fator VIII/antagonistas & inibidores
Hemofilia A/sangue
Hemofilia B/sangue
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Antibodies); 0 (Immunologic Factors); 4F4X42SYQ6 (Rituximab); 9001-27-8 (Factor VIII); 9001-28-9 (Factor IX)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1002/14651858.CD010810.pub3


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[PMID]:28646426
[Au] Autor:Hoy SM
[Ad] Endereço:Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand. demail@springer.com.
[Ti] Título:Eftrenonacog Alfa: A Review in Haemophilia B.
[So] Source:Drugs;77(11):1235-1246, 2017 Jul.
[Is] ISSN:1179-1950
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Eftrenonacog alfa (Alprolix™) is a recombinant fusion protein comprising human factor IX (FIX) covalently linked to the constant region (Fc) domain of human IgG1 (i.e. rFIXFc). The presence of the Fc domain extends the terminal half-life (t ) of rFIXFc, permitting prolonged treatment intervals. rFIXFc is available for intravenous use for the prophylaxis and treatment of bleeding in patients with haemophilia B. In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, rFIXFc prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens. Preliminary data from an extension of both studies indicated sustained efficacy, as demonstrated by low median ABRs, with longer-term rFIXFc prophylaxis. rFIXFc was also effective in the treatment of bleeding episodes and when used in the perioperative setting in all age groups. rFIXFc was well tolerated in clinical studies in previously treated patients, with the majority of treatment-emergent adverse events considered to be unrelated to rFIXFc; there were no reports of inhibitor development. In conclusion, rFIXFc provides an effective alternative to plasma-derived and recombinant FIX products for the management of patients with haemophilia B, with its extended t permitting a less frequent administration schedule and potentially providing a prolonged protective haemostatic effect, which eases the treatment burden on the patient.
[Mh] Termos MeSH primário: Fator IX/uso terapêutico
Hemofilia B/tratamento farmacológico
Hemorragia/tratamento farmacológico
Hemorragia/prevenção & controle
Fragmentos Fc das Imunoglobulinas/uso terapêutico
Proteínas Recombinantes de Fusão/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Ensaios Clínicos como Assunto
Fator IX/administração & dosagem
Fator IX/efeitos adversos
Fator IX/farmacocinética
Meia-Vida
Seres Humanos
Fragmentos Fc das Imunoglobulinas/administração & dosagem
Fragmentos Fc das Imunoglobulinas/efeitos adversos
Proteínas Recombinantes de Fusão/administração & dosagem
Proteínas Recombinantes de Fusão/efeitos adversos
Proteínas Recombinantes de Fusão/farmacocinética
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin Fc Fragments); 0 (Recombinant Fusion Proteins); 0 (factor IX Fc fusion protein); 9001-28-9 (Factor IX)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE
[do] DOI:10.1007/s40265-017-0778-1


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[PMID]:28508290
[Au] Autor:Huai C; Jia C; Sun R; Xu P; Min T; Wang Q; Zheng C; Chen H; Lu D
[Ad] Endereço:Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Room C613, Building for School of Life Sciences, Fudan University, No. 2005 Songhu Rd, Shanghai, 200433, China.
[Ti] Título:CRISPR/Cas9-mediated somatic and germline gene correction to restore hemostasis in hemophilia B mice.
[So] Source:Hum Genet;136(7):875-883, 2017 Jul.
[Is] ISSN:1432-1203
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Hemophilia B (HB) is an X-linked disorder caused by defects of F9 encoded coagulation factor IX, which is an ideal model for gene therapy. Most existing HB gene therapies are based on viral mediated gene supplementation, which could increase immunoreaction. In this study, CRISPR/Cas9 system was used for gene correction in an F9 mutant HB mouse model in both adult mice (in vivo) and in germline cells (ex vivo). In vivo, naked Cas9-sgRNA plasmid and donor DNA were delivered to HB mice livers to recover the mutation via hydrodynamic tail vein (HTV) injection. 62.5% of the HTV-treated mice showed a detectable gene correction (>1%) in the F9 alleles of hepatocytes, which was sufficient to remit the coagulation deficiency. Ex vivo, three different forms of Cas9 were microinjected into germline cells of HB mice to investigate their efficiency and safety in gene correction. Cas9 protein showed higher gene recovery rates, less embryo toxicity, and lower mosaic repair percentage, making it more suitable for germline gene therapy. Our study strongly supports that CRISPR/Cas9-mediated genome editing is feasible in gene therapy of genetic disorders.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas/genética
Edição de Genes
Hemofilia B/genética
[Mh] Termos MeSH secundário: Alelos
Sequência de Aminoácidos
Animais
Sequência de Bases
Modelos Animais de Doenças
Fator IX/genética
Fator IX/metabolismo
Feminino
Loci Gênicos
Terapia Genética
Células Germinativas
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Mutação
Plasmídeos
Alinhamento de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9001-28-9 (Factor IX)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170517
[St] Status:MEDLINE
[do] DOI:10.1007/s00439-017-1801-z


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[PMID]:28490568
[Au] Autor:Hudecova I; Jiang P; Davies J; Lo YMD; Kadir RA; Chiu RWK
[Ad] Endereço:Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, Hong Kong, China.
[Ti] Título:Noninvasive detection of -related inversions and sequence variants in maternal plasma of hemophilia carriers.
[So] Source:Blood;130(3):340-347, 2017 Jul 20.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Direct detection of and sequence variants in maternal plasma of hemophilia carriers has been demonstrated by microfluidics digital PCR. Noninvasive prenatal assessment of the most clinically relevant group of sequence variants among patients with hemophilia, namely, those involving -related inversions disrupting the gene, poses additional challenges because of its molecular complexity. We investigated the use of droplet digital PCR (ddPCR) and targeted massively parallel sequencing (MPS) for maternal plasma DNA analysis to noninvasively determine fetal mutational status in pregnancies at risk for hemophilia. We designed family-specific ddPCR assays to detect causative sequence variants scattered across the and genes. A haplotype-based approach coupled with targeted MPS was applied to deduce fetal genotype by capturing a 7.6-Mb region spanning the gene in carriers with -related inversions. The ddPCR analysis correctly determined fetal hemophilia status in 15 at-risk pregnancies in samples obtained from 8 to 42 weeks of gestation. There were 3 unclassified samples, but no misclassification. Detailed fetal haplotype maps of the gene region involving -related inversions obtained through targeted MPS enabled correct diagnoses of fetal mutational status in 3 hemophilia families. Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited -related inversions, whereas ddPCR represents an affordable approach for the identification of and sequence variants in maternal plasma. These advancements may bring benefits for the pregnancy management for carriers of hemophilia sequence variants; in particular, the common -related inversions, associated with the most severe clinical phenotype.
[Mh] Termos MeSH primário: Fator VIII/genética
Doenças Fetais/diagnóstico
Hemofilia A/diagnóstico
Heterozigoto
Diagnóstico Pré-Natal/métodos
Inversão de Sequência
[Mh] Termos MeSH secundário: Adulto
Fator IX/genética
Fator IX/metabolismo
Fator VIII/metabolismo
Feminino
Doenças Fetais/sangue
Doenças Fetais/genética
Doenças Fetais/patologia
Feto
Idade Gestacional
Hemofilia A/sangue
Hemofilia A/genética
Hemofilia A/patologia
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Dispositivos Lab-On-A-Chip
Masculino
Reação em Cadeia da Polimerase/instrumentação
Reação em Cadeia da Polimerase/métodos
Gravidez
Diagnóstico Pré-Natal/instrumentação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9001-27-8 (Factor VIII); 9001-28-9 (Factor IX)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170824
[Lr] Data última revisão:
170824
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170512
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-12-755017


  10 / 4557 MEDLINE  
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[PMID]:28406575
[Au] Autor:Nummi V; Jouppila A; Lassila R
[Ad] Endereço:Faculty of Medicine, University of Helsinki, Helsinki, Finland.
[Ti] Título:Monitoring once-weekly recombinant factor IX prophylaxis in hemophilia B with thrombin generation assay and factor IX activity.
[So] Source:Int J Lab Hematol;39(4):359-368, 2017 Aug.
[Is] ISSN:1751-553X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Prophylaxis is the recommended treatment mode for severe hemophilia B. However, no single treatment regimen fits for all patients. Once-weekly prophylaxis with high-dose recombinant factor IX (rFIX) is efficacious, nevertheless, laboratory outcomes following 72 h after administration are lacking. METHODS: In a prospective open-label noncomparative study, 10 severe/moderate (FIX ≤2 IU/dL) adult patients received rFIX dose (60-100 IU/kg) after >72 h washout on two occasions, separated by 7 days. We measured one-stage and chromogenic FIX, ROTEM, and thrombin generation (TG) assay in plasma after washout, 30 min after infusion, and at days 3, 4, and 7. RESULTS: Median FIX clotting/chromogenic activity increased from 1.5/2.0 to 87/62 IU/dL following rFIX administration, chromogenic assay resulting in 30% lower recovery. Correspondingly TG was severely reduced at baseline and improved at recovery (peak thrombin 6.0 to 54 nm). Standard ROTEM failed to detect FIX deficiency. Both FIX activity and TG remained increased from days 3 to 7, with median trough levels of FIX clotting/chromogenic 3.0/3.0 IU/dL (≥1 IU/dL in all severe patients) and peak thrombin 9.1 nm measured on day 7. FIX and TG assays were equally consistent between weeks 1 and 2. CONCLUSIONS: Once-weekly rFIX prophylaxis results in favorable laboratory outcome.
[Mh] Termos MeSH primário: Fator IX/metabolismo
Fator IX/uso terapêutico
Hemofilia B/sangue
Hemofilia B/tratamento farmacológico
Pré-Medicação
Proteínas Recombinantes/uso terapêutico
Trombina/biossíntese
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Substituição de Aminoácidos
Coagulação Sanguínea
Testes de Coagulação Sanguínea
Análise Mutacional de DNA
Gerenciamento Clínico
Fator IX/genética
Fator IX/farmacologia
Hemofilia B/diagnóstico
Hemofilia B/genética
Seres Humanos
Masculino
Meia-Idade
Mutação
Proteínas Recombinantes/farmacologia
Tromboelastografia
Fatores de Tempo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); 9001-28-9 (Factor IX); EC 3.4.21.5 (Thrombin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1111/ijlh.12634



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