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1.
Expert Opin Drug Saf ; 20(4): 387-396, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33612049

RESUMO

INTRODUCTION: Emicizumab is a bispecific-humanized monoclonal antibody that improves hemostasis by bridging activated factor IX and factor X to substitute for the function of missing activated FVIII. It is an alternative to prophylaxis with factor VIII replacement and is associated with improved outcomes in individuals with hemophilia A with and without inhibitors. AREAS COVERED: Emicizumab is efficacious in reducing bleeding events when compared to on-demand treatment and factor-based prophylaxis. Except for the few thrombotic microangiopathy and thrombotic event cases mainly seen in the HAVEN 1 trial, emicizumab has an overall excellent safety profile with minimal side effects. EXPERT OPINION: Knowledge gaps include the efficacy and safety of emicizumab in younger age groups and those with mild or moderate hemophilia A. Future directions for research include exploring the risk of inhibitor recurrence in patients with a history of high titer inhibitor who have been successfully tolerized, who switch from factor prophylaxis to emicizumab, as well as conducting 'real world studies' to evaluate the patient's perception of emicizumab in regard to ease and tolerability in order to optimize individualized treatment plans.


Assuntos
Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Hemofilia A/tratamento farmacológico , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Fator VIII/administração & dosagem , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Trombose/induzido quimicamente
2.
Clin Appl Thromb Hemost ; 27: 1076029621989811, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33587652

RESUMO

Antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) is indicated for the treatment and prevention of bleeding in patients with hemophilia A. We aimed to assess the safety and efficacy of standard prophylaxis versus on-demand treatment with rAHF in previously treated Chinese patients with severe/moderately severe hemophilia A. This open-label, sequential, interventional, postapproval study (NCT02170402) conducted in China included patients of any age with hemophilia A with factor VIII (FVIII) level ≤2%. Patients received 6 months' on-demand rAHF then 6 months' rAHF prophylaxis (20-40 IU/kg every 48 ± 6 hours). The primary objective was percentage reduction in annualized bleeding rate (ABR) in the per-protocol analysis set (PPAS); secondary objectives included ABR by bleeding subtype, hemostatic efficacy, immunogenicity, and safety. Of 72 patients who received ≥1 rAHF dose, 61 were included in the PPAS. Total ABR was lower during prophylaxis (mean 2.5, 95% CI 1.5-3.7; median 0) versus on-demand treatment (mean 58.3, 95% CI 52.5-64.7; median 53.9), representing a 95.9% risk reduction. Similar findings in favor of prophylaxis were observed for all types of bleeding event by cause and location. rAHF hemostatic efficacy was rated as "excellent"/"good" in 96.1% of treated bleeding events. Transient FVIII inhibitors (0.6-1.7 BU) in 4 patients resolved before study end; no unexpected safety issues were observed. rAHF prophylaxis in this study of previously treated Chinese patients with severe/moderately severe hemophilia A resulted in a clear reduction in bleeding events versus rAHF on-demand treatment, with no change in safety profile.


Assuntos
Coagulantes/administração & dosagem , Fator VIII/administração & dosagem , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Adolescente , Adulto , Criança , Pré-Escolar , China , Coagulantes/efeitos adversos , Coagulantes/farmacocinética , Esquema de Medicação , Fator VIII/efeitos adversos , Fator VIII/farmacocinética , Hemofilia A/sangue , Hemofilia A/complicações , Hemofilia A/diagnóstico , Hemorragia/etiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
3.
BMJ Case Rep ; 14(1)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514621

RESUMO

Around the world, with the availability of factor concentrates, patients with haemophilia have undergone major and minor surgeries. Inhibitor development in early postoperative period leading to inadequate factor recovery and ongoing bleeding is a nightmare for both operating surgeon as well as haematologists. We describe a case of an elderly man with mild haemophilia A, who was diagnosed with pancreatic carcinoma and underwent Whipple's procedure. After an uneventful procedure, he developed high-titre inhibitors and bleeding a week after surgery posing major challenges in his management. The case highlights the importance of experienced surgeons, trained haematologists, regular monitoring of factor assay/inhibitors, adequate factor and bypassing-agent support while performing such procedures.


Assuntos
Fatores de Coagulação Sanguínea/antagonistas & inibidores , Hemofilia A/imunologia , Neoplasias Pancreáticas/cirurgia , Hemorragia Pós-Operatória/tratamento farmacológico , Idoso , Formação de Anticorpos/imunologia , Fatores de Coagulação Sanguínea/imunologia , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Evolução Fatal , Hematologia/normas , Hemofilia A/complicações , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Hemorragias Intracranianas/complicações , Masculino , Neoplasias Pancreáticas/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/imunologia , Hemorragia Pós-Operatória/etiologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Fatores de Risco , Cirurgiões/estatística & dados numéricos
4.
Medicine (Baltimore) ; 99(43): e22926, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120848

RESUMO

RATIONALE: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies directed against the activity of factor VIII (FVIII) and presents with prolonged bleeding. 5.7% of systemic lupus erythematosus (SLE) patients are affected by AHA. PATIENT CONCERNS: A 51-year-old female patient with SLE presenting with the fatigue and spontaneous clinical bleeding symptoms such as hematuria and ecchymoses for 1 week. DIAGNOSIS: Laboratory examinations revealed prolongation of the activated partial thromboplastin time (APTT) (65.7 s), decreased FVIII activity (1.4%), and a titer of FVIII inhibitors of 8.5 Bethesda units/mL. INTERVENTIONS: Transfusion of recombinant human FVIII (ADVATE) in combination with intravenous methylprednisolone, cyclophosphamide, plasmapheresis, and fresh frozen plasma successfully stopped the bleeding and reduced the level of FVIII inhibitor. OUTCOMES: The size of the hematoma slowly decreased. The skin ecchymosis was gradually absorbed, the hemoglobin count increased, and the coagulation index gradually improved. There was no new bleeding or bleeding site. The patient was discharged and transferred to a local hospital for hospice care. LESSONS: AHA in a patient with SLE is rare. Once it occurs, it can be life-threatening. Clinicians should remain aware that because some cases of AHA may have features of SLE, appropriate distinction and diagnosis of these different but associated diseases is necessary.


Assuntos
Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/etiologia , Lúpus Eritematoso Sistêmico/complicações , Administração Intravenosa , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Testes de Coagulação Sanguínea/métodos , Coagulantes/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Equimose/diagnóstico , Equimose/etiologia , Fator VIII/administração & dosagem , Feminino , Hematúria/diagnóstico , Hematúria/etiologia , Hemofilia A/terapia , Hemorragia/diagnóstico , Hemorragia/etiologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial/métodos , Tempo de Tromboplastina Parcial/estatística & dados numéricos , Plasma , Plasmaferese/métodos , Resultado do Tratamento
5.
Ann Hematol ; 99(11): 2689-2698, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32974838

RESUMO

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0-tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 ( ClinicalTrials.gov identifier). Date of registration: July 9, 2019.


Assuntos
Fator VIII , Hemofilia A , Adolescente , Adulto , Idoso , Estudos Cross-Over , Fator VIII/administração & dosagem , Fator VIII/farmacocinética , Meia-Vida , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética
6.
J Stroke Cerebrovasc Dis ; 29(7): 104859, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32389557

RESUMO

No previous study has reported endovascular treatment (EVT) in a patient with hemophilia who had an acute ischemic stroke (AIS). Herein, we report the case of a patient with hemophilia A who presented with hyperacute stroke due to a near occlusion of the proximal internal carotid artery (ICA). A 54-year-old man was admitted to our emergency department with a sudden onset of left-sided weakness that occurred 4 hours prior to admission. He had been diagnosed with congenital hemophilia A during his childhood. Although brain computed tomography revealed no evidence of hemorrhage, we did not consider intravenous thrombolysis because of his bleeding-prone condition. Diffusion-weighted imaging revealed a restricted diffusion in the right anterior and middle cerebral artery territories. Magnetic resonance angiography revealed that the right proximal ICA was nearly occluded and had a residual stump. Digital subtraction angiography revealed a near occlusion of the right proximal ICA with a thread-like lumen. Balloon angioplasty was performed in the proximal ICA, and distal flow was restored, but residual stenosis was observed. Stepwise revascularization by carotid endarterectomy (CEA) was planned instead of immediate carotid stenting. He underwent CEA with preoperative and postoperative coverage of factor VIII and recovered without any bleeding complication.


Assuntos
Angioplastia com Balão , Isquemia Encefálica/etiologia , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/terapia , Endarterectomia das Carótidas , Hemofilia A/complicações , Acidente Vascular Cerebral/etiologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatologia , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/fisiopatologia , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/fisiopatologia , Circulação Cerebrovascular , Coagulantes/administração & dosagem , Esquema de Medicação , Fator VIII/administração & dosagem , Hemofilia A/diagnóstico , Hemofilia A/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Resultado do Tratamento
7.
Thromb Haemost ; 120(5): 728-736, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369844

RESUMO

BACKGROUND: Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection. OBJECTIVES: In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds. METHODS: Sixty-three patients (median [range] age, 28 [7-59] years) with severe hemophilia A (229 bleeds) were included. FVIII levels at time of each bleed were estimated from single-dose individual pharmacokinetics. The highest estimated FVIII level at which patients experienced a bleed was considered the "potentially effective trough level" for that bleed type. Kaplan-Meier estimates of proportions of patients with no bleeds above certain estimated FVIII levels were determined. Those not experiencing a bleed in the trial were assumed to have a bleed at 0 IU/dL (pragmatic approach) or at their median trough level (conservative approach). RESULTS: Kaplan-Meier estimates based on pragmatic approach predicted zero all bleeds, joint bleeds, and spontaneous joint bleeds in 1 year in 40, 43, and 63% of patients, respectively, when the potentially effective trough FVIII level was set at 1 IU/dL. Between 1 and 10 IU/dL, every 1 IU/dL rise in estimated FVIII level was associated with an additional 2% of patients having zero all bleeds. CONCLUSION: This post hoc analysis confirms benefits with trough levels of approximately 1 to 3 IU/dL in most patients starting tertiary prophylaxis; prophylaxis with higher trough levels may help patients to achieve zero bleeds.


Assuntos
Fator VIII/farmacocinética , Hemartrose/prevenção & controle , Hemofilia A/tratamento farmacológico , Hemostasia/efeitos dos fármacos , Hemostáticos/farmacocinética , Modelos Biológicos , Prevenção Terciária , Adolescente , Adulto , Canadá , Criança , Europa (Continente) , Fator VIII/administração & dosagem , Hemartrose/sangue , Hemartrose/diagnóstico , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemostáticos/administração & dosagem , Hemostáticos/sangue , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Estados Unidos , Adulto Jovem
8.
Thromb Haemost ; 120(5): 747-757, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32369846

RESUMO

BACKGROUND: The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. METHODS: Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). RESULTS: A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (-1.0%, 95% CI: -9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children. CONCLUSION: We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.


Assuntos
Fator VIII/farmacocinética , Hemofilia A/tratamento farmacológico , Hemostáticos/farmacocinética , Modelos Biológicos , Proteínas Recombinantes de Fusão/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemostáticos/administração & dosagem , Hemostáticos/efeitos adversos , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Sistema de Registros , Reprodutibilidade dos Testes , Reino Unido , Adulto Jovem
9.
JAAPA ; 33(6): 24-26, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32452957

RESUMO

Acquired hemophilia A in postoperative patients can cause major bleeding and an accurate diagnosis is required for effective treatment. Standard treatment is costly, difficult to obtain, and takes 4 to 6 weeks to be effective. This article describes a patient successfully treated with recombinant factor VIIa, porcine factor VIII, plasmapheresis, rituximab, and high-dose corticosteroids.


Assuntos
Hemofilia A/diagnóstico , Hemofilia A/etiologia , Hemorragia Pós-Operatória/tratamento farmacológico , Hemorragia Pós-Operatória/etiologia , Corticosteroides/administração & dosagem , Animais , Fator VIII/administração & dosagem , Fator VIIa/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Plasmaferese , Proteínas Recombinantes/administração & dosagem , Rituximab/administração & dosagem , Suínos , Resultado do Tratamento
10.
Haemophilia ; 26(1): 156-163, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31809565

RESUMO

Factor replacement therapy with factor VIII (FVIII) concentrates is the current standard of care for patients with haemophilia A. Postadministration monitoring of FVIII activity during on-demand or prophylactic treatment is important, for example to guide a suitable dosing regimen. While the use of two-stage chromogenic substrate (CS) assays is increasing, activated partial thromboplastin time (APTT)-based one-stage clotting (OSC) assays are most commonly used to measure FVIII activity in clinical laboratories. Substantial variations in activity measurements have been observed in association with some OSC assay reagents when assessing extended half-life FVIII molecules. Certain silica-based APTT reagents have previously been shown to underestimate FVIII activity with the polyethylene glycol (PEG)-conjugated product turoctocog alfa pegol (N8-GP [ESPEROCT® ]; Novo Nordisk A/S). As a wide range of assay reagents are used in clinical laboratories worldwide, it is essential to establish which can be used to accurately measure activity with modified FVIII concentrates. Here, we describe the approach taken by Novo Nordisk to determine the suitability and accuracy of assays and reagents to measure FVIII activity in samples that contain N8-GP. While accurate activity measurements were possible with all tested CS assays and most of the OSC APTT reagents tested, three APTT reagents that contain silica as a contact activator were found to underestimate N8-GP recovery (APTT-SP, TriniCLOT™, STA® PTT-Automate). The data demonstrate the importance of characterizing the accuracy of each FVIII activity assay. Any limitations should be communicated to treating physicians and the clinical laboratories that test samples containing N8-GP.


Assuntos
Bioensaio , Monitoramento de Medicamentos , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Polietilenoglicóis/química , Glicosilação , Humanos , Tempo de Tromboplastina Parcial
11.
Anesth Analg ; 130(3): 740-751, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31490252

RESUMO

BACKGROUND: Infants undergoing cardiac surgery are at risk for bleeding and massive transfusion due to an immature coagulation system, complex surgeries, and cardiopulmonary bypass (CPB) effects. Hemodilution from CPB promotes an acquired hypofibrinogenemia that results in impaired fibrin formation, inadequate clot formation, and increased bleeding. In North America, the current standard of care to supplement fibrinogen is cryoprecipitate. An alternative option is the off-label use of fibrinogen concentrate (FC; RiaSTAP; CSL Behring, Marburg, Germany), a purified fibrinogen. Because perioperative allogenic transfusions are associated with increased morbidity and mortality, we sought to determine whether FC would be an acceptable alternative to cryoprecipitate in a post-CPB transfusion algorithm in infants undergoing open-heart surgery. METHODS: We randomized 60 infants (<12 months) undergoing nonemergent cardiac surgery with CPB at 2 tertiary care children's hospitals to receive either cryoprecipitate or FC in a post-CPB transfusion algorithm. Infants underwent a stratified randomization based on institution and surgical complexity. The primary outcome was the difference in number of intraoperative allogenic blood product transfusions. Secondary outcomes included 24-hour chest tube output (CTO), mechanical ventilation time, adverse events (AEs), intensive care unit (ICU) length of stay (LOS), hospital LOS, postoperative thrombosis, and death within 30 days of surgery. The primary analysis followed the intent-to-treat (ITT) principle and was performed using linear regression adjusted for institution and complexity of surgery. A per-protocol (PP) analysis was also performed. RESULTS: Between June 2016 and January 2018, we enrolled 60 patients with complete data available for 25 patients who received cryoprecipitate and 29 patients who received FC. Patients in the cryoprecipitate group (median age: 4 months [2-6 months]) received 5.5 (4.0-7.0) allogeneic blood units in the ITT analysis and 6.0 units (5.0-7.0 units) in the PP analysis. Patients in the FC group (median age: 4 months [2-5]) received 4 units (3.0-5.0 units) in the ITT analysis and 4.0 units (3.0-5.0 units) in the PP analysis. In the adjusted ITT analysis, the FC group received 1.79 units (95% confidence interval [CI], 0.64-2.93; P = .003) less than the cryoprecipitate group. In the adjusted PP analysis, the FC group received 2.67 units (95% CI, 1.75-3.59; P < .001) less than the cryoprecipitate group. There were no significant differences in secondary outcomes or AEs. CONCLUSIONS: Our findings suggest that FC may be considered as an alternative to cryoprecipitate for the treatment of hypofibrinogenemia in infants with bleeding after CPB. Although we found no significant differences between secondary outcomes or AEs, further studies are needed to assess safety.


Assuntos
Afibrinogenemia/tratamento farmacológico , Algoritmos , Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Protocolos Clínicos , Coagulantes/administração & dosagem , Fator VIII/administração & dosagem , Fibrinogênio/administração & dosagem , Hemorragia Pós-Operatória/terapia , Afibrinogenemia/sangue , Afibrinogenemia/etiologia , Fatores Etários , Coagulação Sanguínea/efeitos dos fármacos , Coagulantes/efeitos adversos , Fator VIII/efeitos adversos , Feminino , Fibrinogênio/efeitos adversos , Humanos , Lactente , Masculino , Hemorragia Pós-Operatória/sangue , Hemorragia Pós-Operatória/etiologia , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
12.
CPT Pharmacometrics Syst Pharmacol ; 8(12): 894-903, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31668021

RESUMO

Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic-repeated time-to-event model-based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65-0.69), 0.78 (95% CI, 0.76-0.80), and 0.79 (95% CI, 0.77-0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required.


Assuntos
Fator VIII/administração & dosagem , Hemofilia A/prevenção & controle , Hemorragia/prevenção & controle , Adolescente , Adulto , Área Sob a Curva , Teorema de Bayes , Ensaios Clínicos como Assunto , Cálculos da Dosagem de Medicamento , Fator VIII/farmacocinética , Feminino , Humanos , Masculino , Medicina de Precisão , Adulto Jovem
14.
J Med Econ ; 22(12): 1328-1337, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530050

RESUMO

Aims: Cumulative exogenous factor VIII (FVIII) exposure is an important predictor of developing neutralizing antibodies (inhibitors) to FVIII in patients with persons with hemophilia A (PwHA). The aim of this study was to model the costs of emicizumab versus FVIII prophylaxis and total treatment costs for patients with severe HA.Materials and Methods: An Excel-based decision model was developed to calculate cumulative costs in PwHA over a 20-year time horizon from the US payer perspective. The model considered persons with severe HA beginning at age 12 months with no prior FVIII exposure and initiating prophylaxis with emicizumab or FVIII. PwHA could develop inhibitors on accumulation of 20 FVIII exposure days. PwHA with inhibitors replaced FVIII with bypassing agents until inhibitors resolved spontaneously, following immune tolerance induction (ITI), or at the end of the time horizon. The primary model outcome was the difference in emicizumab versus FVIII treatment costs in 2019 USD. Sensitivity analyses were performed to test the robustness of results.Results: Total incremental cost over 20 years was -$1,945,480 (emicizumab arm, $4,919,058; FVIII arm, $6,864,538). Prophylaxis costs (emicizumab arm, $4,096,105; FVIII arm, $6,290,919) comprised the majority of costs in both groups, followed by breakthrough bleed treatment for the FVIII arm ($342,652) and ITI costs for the emicizumab arm ($733,671). Higher costs in the FVIII group reflected earlier inhibitor development (FVIII, 4 months; emicizumab, 162 months) and switch to bypassing agents.Limitations: The model design reflects a simplified treatment pathway for patients with severe HA who initiate FVIII or emicizumab prophylaxis. In the absence of clinical data, a key conservative assumption of the model is that patients receiving emicizumab and FVIII prophylaxis have the same risk of developing inhibitors.Conclusions: This study suggests that prophylaxis with emicizumab results in cost savings compared to FVIII prophylaxis in HA.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/prevenção & controle , Anticorpos Biespecíficos/economia , Anticorpos Biespecíficos/imunologia , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/imunologia , Coagulantes/administração & dosagem , Coagulantes/imunologia , Fator VIII/administração & dosagem , Fator VIII/imunologia , Humanos , Modelos Econômicos , Índice de Gravidade de Doença
15.
BMC Musculoskelet Disord ; 20(1): 402, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31481049

RESUMO

BACKGROUND: The lower limb joints, including hip and knee, are the most commonly involved joints in haemophilic arthropathy. With a higher risk of transfusion, total hip and knee arthroplasty (THA and TKA) are still the first choice after failure of conservative treatment. In the present study, we aimed to analyze clinical outcomes and complications rate after total joint arthroplasty of the lower limbs using tranexamic acid (TXA) or not. METHODS: Thirty-four patients with haemophilia A undergoing 24 TKA and 18 THA were evaluated in this retrospective study (No. 201302009). Based on using TXA or not, they were divided into either TXA (12 knees and 10 hips) or Non-TXA groups (12 knees and 8 hips). Total blood loss, intraoperative blood loss, total amount of FVIII usage, range of motion, inflammatory biomarkers, joint function, pain status, complication rate and patient satisfaction were assessed and compared at a mean follow-up of 68 months. RESULTS: Usage of TXA can decrease not only the perioperative blood loss (p = 0.001), transfusion rate (p = 0.017) and supplemental amount of FVIII (p < 0.001) but also swelling ratio, surgical joint pain. Moreover, compared with non-TXA group, the patients in TXA group had a lower level of inflammatory biomarkers and better joint function. CONCLUSION: The hemophiliacs treated with TXA had less perioperative blood loss, hidden blood loss, transfusion rate, a lower ratio of postoperative knee swelling, less postoperative joint pain, lower levels of inflammatory biomarkers and better joint function. Further studies need performing to assess the long-term effects of TXA in these patients.


Assuntos
Antifibrinolíticos/administração & dosagem , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Hemofilia A/complicações , Ácido Tranexâmico/administração & dosagem , Administração Intravenosa , Adulto , Antifibrinolíticos/efeitos adversos , Artralgia/epidemiologia , Artralgia/etiologia , Artralgia/prevenção & controle , Perda Sanguínea Cirúrgica/prevenção & controle , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Transfusão de Sangue/estatística & dados numéricos , Fator VIII/administração & dosagem , Feminino , Hemofilia A/diagnóstico , Hemofilia A/tratamento farmacológico , Articulação do Quadril/fisiologia , Articulação do Quadril/cirurgia , Humanos , Articulação do Joelho/fisiologia , Articulação do Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/complicações , Osteoartrite do Quadril/fisiopatologia , Osteoartrite do Quadril/cirurgia , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/fisiopatologia , Osteoartrite do Joelho/cirurgia , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/prevenção & controle , Cuidados Pré-Operatórios/métodos , Estudos Prospectivos , Amplitude de Movimento Articular , Recuperação de Função Fisiológica , Estudos Retrospectivos , Ácido Tranexâmico/efeitos adversos , Resultado do Tratamento
16.
Blood Coagul Fibrinolysis ; 30(1S Suppl 1): S1-S3, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517707

RESUMO

: Prophylaxis entails long-term continuous intravenous administration of concentrates of the deficient factor with a view to preventing spontaneous bleeds and the development of hemophilic arthropathy. Initiation of prophylaxis at an early age and continuous uninterrupted factor administration in patients with hemophilia have been hailed as essential by such organizations.The most widely used prophylaxis regimens include the Swedish (Malmö), the Dutch and the Canadian protocols. Different international groups have hailed prophylaxis as the most effective treatment in patients with hemophilia.Prophylaxis is effectiveness in preventing bleeding and arthropathy in children with (particularly early-onset) hemophilia. Although some retrospective trials confirm the benefits of prophylaxis, others point to a lack of conclusive data to support switching adult patients with established hemophilic arthropathy who always received on-demand treatment to prophylactic treatment.The potential effects of prophylaxis on the patients' sex lives, renal status, prostate involvement and cataract must be analyzed before indicating prophylactic treatment in elderly patients.The high efficacy of prophylactic treatment in patients with hemophilia and inhibitors has been widely reported in the literature.


Assuntos
Hemofilia A/prevenção & controle , Administração Intravenosa , Adulto , Idoso , Criança , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Hemartrose/prevenção & controle , Hemorragia/prevenção & controle , Humanos , Artropatias/prevenção & controle
17.
Expert Rev Hematol ; 12(sup1): 1-13, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31282771

RESUMO

Introduction: Prophylaxis with factor replacement therapy is the gold standard for the treatment of hemophilia, but this often requires frequent infusions. A number of long-acting factor products have been developed to reduce the burden on patients. Areas covered: This is an overview of information presented at two symposia held at the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis - Scientific and Standardization Committee annual meetings. The pharmacokinetic, safety and efficacy data for long-acting recombinant products are reviewed, with a focus on recombinant factor IX albumin fusion protein (rIX-FP) and rVIII-SingleChain. This overview also provides a guide for managing a patient's switch to long-acting products. Expert opinion: Long-acting products may allow patients to maintain or decrease bleeding rates whilst increasing their dosing interval, which may in turn reduce the burden on patients and caregivers. When switching patients to long-acting products health-care professionals should provide balanced and thorough education to the patient, whilst supporting their emotional well-being. Regimens should address patients' needs and goals but should also be guided by clinical phenotype and pharmacokinetic assessment. Follow-up should assess safety concerns, bleeding rates, joint health and the impact of the regimen on patients' lifestyle.


Assuntos
Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Gerenciamento Clínico , Fator IX/administração & dosagem , Fator IX/farmacocinética , Fator VIII/administração & dosagem , Fator VIII/farmacocinética , Hemorragia/prevenção & controle , Humanos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico
18.
Curr Med Res Opin ; 35(12): 2079-2087, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31355677

RESUMO

Objectives: To compare the efficacy of emicizumab prophylaxis with that of factor VIII (FVIII) prophylaxis in patients with hemophilia A without inhibitors using two approaches: network meta-analyses (NMA) and additional sub-group analyses from the HAVEN 3 trial.Methods: The NMA used data from trials identified using a systematic literature review and compared bleed rates in patients receiving emicizumab prophylaxis and patients receiving FVIII prophylaxis using a Bayesian, random effects generalized linear model with log link Poisson likelihood. Additional sub-groups of the HAVEN 3 trial included here were defined as patients whose dose-taking behavior met either European label or World Federation of Hemophilia guidelines. A negative binomial regression model was used to conduct an intra-patient comparison of bleed rates within the sub-groups, during treatment with FVIII prophylaxis before entering HAVEN 3 and treatment with emicizumab prophylaxis during HAVEN 3.Results: Four studies were included in the base-case NMA. Evidence showed that the total treated bleed rate was lower with emicizumab prophylaxis compared with FVIII prophylaxis (rate ratio [RR] = 0.36 [95% credible interval (CrI) = 0.13-0.95]). Similar associations were observed in sensitivity analyses. The additional HAVEN 3 analyses also showed lower rates of treated bleeds with emicizumab prophylaxis than with FVIII prophylaxis (RRs [95% confidence interval (CI)] = 0.380 [0.186-0.790] and 0.472 [0.258-0.866] in two sub-groups). These results confirm the original HAVEN 3 intra-patient comparison findings.Conclusions: Combined findings from NMA and additional sub-group analyses of HAVEN 3 support the superiority of emicizumab prophylaxis over FVIII prophylaxis in patients with hemophilia A without inhibitors.


Assuntos
Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Fator VIII , Hemofilia A/tratamento farmacológico , Hemorragia , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Quimioprevenção/métodos , Coagulantes/administração & dosagem , Coagulantes/efeitos adversos , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Hemofilia A/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Metanálise em Rede , Medição de Risco/métodos , Resultado do Tratamento
19.
Rev Med Chil ; 147(3): 378-383, 2019 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-31344177

RESUMO

Due to blood derivative requirements, many patients with hemophilia were exposed to Hepatitis C virus infection (HCV) before the availability of HCV testing. We report a 46-year-old male with Hemophilia A with a hepatitis virus C infection since 2004 causing a cirrhosis. Due to a hepatopulmonary syndrome, he received a liver allograph using a factor VIII replacement protocol, after eradicating the virus C. He had a good postoperative evolution, and no more factor VIII was required after transplantation until his last assessment.


Assuntos
Hemofilia A/complicações , Hepatite C/complicações , Cirrose Hepática/cirurgia , Transplante de Fígado/métodos , Fator IX/administração & dosagem , Fator VIII/administração & dosagem , Hemofilia A/terapia , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade
20.
J Thromb Haemost ; 17(11): 1815-1826, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31301687

RESUMO

BACKGROUND: Vascular remodeling associated with hemophilic arthropathy (HA) may contribute to bleed propagation, but the mechanisms remain poorly understood. OBJECTIVES: To explore molecular mechanisms of HA and the effects of hemostasis correction on synovial vascular remodeling after joint injury in hypocoagulable mice. METHODS: Factor VIII (FVIII)-deficient mice +/- FVIII treatment and hypocoagulable wild-type mice (Hypo BALB/c) were subjected to subpatellar puncture. Hypo BALB/c mice were treated with warfarin and anti-FVIII before injury, after which warfarin was continued for 2 weeks or reversed +/- continuous anti-FVIII until harvest. Synovial vascularity was analyzed at baseline and 2 to 4 weeks post injury by histology, musculoskeletal ultrasound with power Doppler (microvascular flow), and Evans blue extravasation (vascular permeability). Synovial gene expression and systemic markers of vascular collagen turnover were studied in FVIII-deficient mice by RNA sequencing and enzyme-linked immunosorbent assay. RESULTS: Vascular changes occurred in FVIII-deficient and Hypo BALB/c mice after injury with minimal effect of hemostasis correction. Increased vascular permeability was only significant in FVIII-deficient mice, who exhibited more pronounced vascular remodeling than Hypo BALB/c mice despite similar bleed volumes. FVIII-deficient mice exhibited a strong transcriptional response in synovium that was only partially affected by FVIII treatment and involved genes relating to angiogenesis and extracellular matrix remodeling, with vascular collagen turnover markers detected systemically. CONCLUSIONS: Intact hemostasis at the time of hemarthrosis and during healing are both critical to prevent vascular remodeling, which appears worse with severe and prolonged FVIII deficiency. Unbiased RNA sequencing revealed potential targets for intervention and biomarker development to improve management of HA.


Assuntos
Permeabilidade Capilar , Fator VIII/metabolismo , Hemartrose/metabolismo , Hemofilia A/metabolismo , Membrana Sinovial/irrigação sanguínea , Remodelação Vascular , Animais , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Fator VIII/administração & dosagem , Fator VIII/genética , Feminino , Hemartrose/genética , Hemartrose/fisiopatologia , Hemartrose/prevenção & controle , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Hemofilia A/fisiopatologia , Hemostasia , Hemostáticos/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fatores de Tempo , Remodelação Vascular/efeitos dos fármacos
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