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1.
Rev Infirm ; 68(253): 26-27, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31472779

RESUMO

The pharmacological treatment of patients with haemophilia has evolved considerably over recent years. In the past, treatments were restrictive for patients and targeted only bleeding incidents. Nowadays, thanks to research, patients have access to prophylactic treatments which offer easier injection methods and are set to evolve further.


Assuntos
Hemofilia A/tratamento farmacológico , Difusão de Inovações , Humanos
2.
Zhonghua Xue Ye Xue Za Zhi ; 40(8): 673-677, 2019 Aug 14.
Artigo em Chinês | MEDLINE | ID: mdl-31495135

RESUMO

Objective: To compare the differences in population pharmacokinetic (PK) parameters between two recombinant coagulation factor Ⅷ (FⅧ) preparations, Kogenate FS and Advate, in patients with hemophilia A, and to provide the theoretical basis of precise individualized treatment for those patients. Methods: Patients with moderate or severe hemophilia A who had at least one injection of Kogenate FS or Advate at 41 international hemophilia centers were enrolled as subjects from the WAPPS-Hemo project since January 2015 to December 2017. The half-lives of the two drugs and the time of FⅧ activity reaching 2% (TAT 2%) were calculated, and the differences of PK between the two drugs among different age and dose subgroups were further analyzed. Results: ①The mean age of patients in the Kogenate FS (n=117) and Advate groups (n=120) were (27.6±17.7) and (23.4±16.2) years old, respectively. All patients in the two groups were males. ②The administration doses in the Kogenate FS and Advate groups were (31.5±13.1) IU/kg and (38.17±14.83) IU/kg, respectively; the half-lives of the two drugs were (12.3±3.5) h and (10.8±2.9) h, respectively; and the TAT 2% were (65.2±21.7) h and (57.0±17.9) h, respectively. ③In the Kogenate FS group, the drug half-lives in patients aged ≥12 and <12 years old were (12.7±3.7) h and (11.1±2.5) h, respectively; the TAT 2% were (68.6±22.9) h and (55.8±14.6) h, respectively. In the Advate group, the drug half-lives in patients aged ≥12 and <12 years old were (11.4±3.1) h and (9.4±1.8) h, respectively; and the TAT 2% were (61.1±18.0) h and (45.2±11.3) h, respectively. ④In the Kogenate FS group, the drug half-lives in <20 IU/kg, (20-29) IU/kg, (30-39) IU/kg and ≥40 IU/kg groups were (13.3±4.0) h, (12.3±3.6) h, (12.2±3.5) h and (11.6±2.6) h, respectively; and the TAT 2% were (61.5±21.4) h, (63.9±22.4) h, (67.0±24.3) h and (68.0±19.5) h, respectively. In the Advate group, the drug half-lives in <20 IU/kg, (20-29) IU/kg, (30-39) IU/kg and <40 IU/kg groups were (11.5±3.8) h, (11.4±3.7) h, (11.0±2.9) h and (10.4±2.3) h, respectively; and the TAT 2% were (50.8±19.2) h, (56.7±21.0) h, (58.2±18.8) h and (58.1±15.8) h, respectively. Conclusion: The PK parameters of Kogenate FS are superior to those of Advate among different age and dose subgroups.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A , Adolescente , Adulto , Testes de Coagulação Sanguínea , Criança , Hemofilia A/tratamento farmacológico , Humanos , Masculino , Proteínas Recombinantes , Adulto Jovem
3.
Medicine (Baltimore) ; 98(30): e16524, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348267

RESUMO

Anti-hepatitis C virus (HCV) treatment for human immunodeficiency virus (HIV)/HCV co-positive patients with hemophilia A presents numerous problems in terms of safety and effectiveness. The emergence of direct-acting antiviral (DAA) regimens has led to tremendous changes in the management of HIV/HCV co-infection over the past few years, but the application of DAA in patients with hemophilia complicated with HIV/HCV co-infection has rarely been reported.We retrospectively analyzed the clinical course and outcome of hemophilia A patients with HIV/HCV co-infection receiving DAA with a focus on the virological response, changes in cluster of differentiation 4 lymphocyte (CD4) count, side effects, and impact on bleeding before and after DAA therapy.A total of 12 hemophilia A patients with HIV/HCV co-infection were included, 9 of which were severe. All the patients were in stable states with CD4 counts >200/mm and plasma HIV ribonucleic acid (RNA) suppressed (<40 IU/mL) while taking the antiretroviral regimen. Majority of the patients (n = 9, 75.0%) were infected with HCV genotype (GT) 1b, while 2 and 1 was infected with HCV GT 2i and HCV GT 3, respectively.After 12 weeks of DAA treatment, 11 patients (91.7%) obtained sustained virologic response within 24 weeks of discontinuation of treatment (SVR24), except 1 patient who was treated with sofosbuvir (SOF) + pegylated interferon + ribavirin (PR), which was then switched to daclatasvir (DCV) + asunaprevir (ASV) for 12 weeks; this patient then achieved SVR24. During DAA treatment, HIV RNA in all the patients was constantly suppressed, while CD4 counts showed no obvious change.The most common treatment-emergent adverse events were weakness and loss of appetite (generally mild). There was no evidence of an increased tendency of bleeding, and changes in response to replacement.DAA therapy offered a safe and well-tolerated management strategy for HIV/HCV co-infected patients with hemophilia A. An awareness of the potential drug-drug interactions (DDI) between DAA and combination antiretroviral therapy (cART) by clinicians is important for optimal management of co-infected patients.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hemofilia A/tratamento farmacológico , Hepatite C/tratamento farmacológico , Adulto , Contagem de Linfócito CD4 , Coinfecção/imunologia , Coinfecção/virologia , Quimioterapia Combinada , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1 , Hemofilia A/imunologia , Hemofilia A/virologia , Hepacivirus , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Imidazóis/uso terapêutico , Interferons/uso terapêutico , Isoquinolinas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada
4.
Drugs ; 79(10): 1147-1156, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31218660

RESUMO

Damoctocog alfa pegol (Jivi®) is approved in the USA, EU, Japan and Canada for the treatment and prophylaxis of previously treated patients aged ≥ 12 years with haemophilia A. Formulated with a 60 kDa polyethylene glycol (PEG) moiety, damoctocog alfa pegol is an intravenously (IV) administered recombinant factor VIII (rFVIII) product with a longer terminal half-life than non-PEGylated FVIII and rFVIII products. In the multinational phase II/III PROTECT VIII trial, prophylaxis with damoctocog alfa pegol reduced the likelihood of bleeding in previously treated patients aged ≥ 12 years with severe haemophilia A, with dosing schedules ranging from twice weekly to once every 7 days. Interim data from the ongoing extension phase indicated that the reduced annualized bleeding rates (ABRs) were maintained for up to 5.2 years of prophylaxis with damoctocog alfa pegol. Damoctocog alfa pegol was also effective in treating bleeding episodes and in providing haemostatic control during surgery. Damoctocog alfa pegol was generally well tolerated in adult and adolescent patients with severe haemophilia A, with most adverse events considered to be unrelated to treatment. There were no new or confirmed cases of FVIII inhibitor development and anti-PEG antibodies, observed in some patients, were of low titre and transient. Damoctocog alfa pegol extends the available treatment options in previously treated adults and adolescents with haemophilia A, offering the possibility of up to once-weekly administration for suitable patients.


Assuntos
Fator VIII/química , Hemofilia A/tratamento farmacológico , Polietilenoglicóis/química , Proteínas Recombinantes/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Criança , Relação Dose-Resposta a Droga , Esquema de Medicação , Aprovação de Drogas , Europa (Continente) , Feminino , Hemorragia/tratamento farmacológico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/química , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Adulto Jovem
5.
Medicine (Baltimore) ; 98(24): e15897, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192923

RESUMO

RATIONALE: Hemophilia A (HA) is an X-linked recessive disorder caused by clotting factor VIII (FVIII) deficiency. There is limited data on the use of replacement therapy in cardiac surgery. Since no international guideline for anticoagulation in such patient exists, careful thought should be taken to design an individualized anticoagulation strategy. PATIENT CONCERNS: We report a 54-year-old male with severe HA with FVIII activity of 0.8% when he was first diagnosed, who underwent successful mitral valve repair and coronary artery bypass graft with FVIII replacement perioperatively. DIAGNOSES: Transthoracic echocardiography and coronary angiography confirmed the HA patient with the diagnosis of severe mitral valve regurgitation and left anterior descending artery stenosis. INTERVENTIONS: Before surgery, a bolus of 1000 IU FVIII was injected, which obtained an FVIII of 80%. After induction, a 3750 IU bolus of FVIII was injected and subsequent FVIII level reached 135%. Mitral valve repair and coronary artery bypass graft with FVIII replacement were performed. After the surgery, a repeat FVIII activity level was 50.6%. The 400 mL of autologous blood and 700 mL of cardiopulmonary bypass (CPB) machine blood was returned to the patient as well as 4 units of fresh frozen plasma with an additional bolus of 1000 IU FVIII. 100 mg aspirin per day alone was given after surgery. OUTCOMES: The patient recovered uneventfully and 1-year follow-up showed no complications. LESSONS: The anticoagulant or antiplatelet regimen of HA patient following surgery should be individualized based on the evaluation of the risk factors for bleeding and thrombosis and the lowest FVIII activity ever recorded after FVIII replacement therapy.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Fator VIII/administração & dosagem , Hemofilia A/tratamento farmacológico , Insuficiência da Valva Mitral/cirurgia , Ponte de Artéria Coronária , Fator VIII/uso terapêutico , Implante de Prótese de Valva Cardíaca , Hemofilia A/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/etiologia , Resultado do Tratamento
6.
Ann Hematol ; 98(9): 2035-2044, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31236667

RESUMO

BAY 94-9027 is an extended-half-life, recombinant factor VIII (rFVIII) product conjugated with a 60-kDa branched polyethylene glycol (PEG) molecule indicated for use in previously treated patients (aged ≥ 12 years) with hemophilia A. This randomized, open-label, two-way crossover study compared the pharmacokinetics (PK) of BAY 94-9027 and rFVIII Fc fusion protein (rFVIIIFc) in patients with hemophilia A. Patients aged 18-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII were randomized to receive intravenous single-dose BAY 94-9027 60 IU/kg followed by rFVIIIFc 60 IU/kg or vice versa, with ≥ 7-day wash-out between doses. FVIII activity was measured by one-stage assay. PK parameters, including area under the curve from time 0 to the last data point (AUClast, primary parameter), half-life, and clearance were calculated. Eighteen patients were randomized and treated. No adverse events were observed. In the analysis set excluding one outlier, geometric mean (coefficient of variation [%CV, 95% confidence interval {CI}]) AUClast was significantly higher for BAY 94-9027 versus rFVIIIFc (2940 [37.8, 2440-3550] IU h/dL versus 2360 [31.8, 2010-2770] IU h/dL, p = 0.0001). A population PK model was developed to simulate time to reach FVIII threshold levels; median time to 1 IU/dL was approximately 13 h longer for BAY 94-9027 versus rFVIIIFc after a single infusion of 60 IU/kg. In conclusion, BAY 94-9027 had a superior PK profile versus rFVIIIFc. ClinicalTrials.gov : NCT03364998.


Assuntos
Fator VIII , Hemofilia A , Polietilenoglicóis , Proteínas Recombinantes de Fusão , Adolescente , Adulto , Idoso , Estudos Cross-Over , Fator VIII/administração & dosagem , Fator VIII/farmacocinética , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Hemofilia A/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacocinética
7.
Rinsho Ketsueki ; 60(5): 475-479, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31168016

RESUMO

Regular prophylaxis using factor (F) VIII products to prevent bleeding in patients with hemophilia A (PWHAs) results in markedly suppressed onset of arthropathy and greatly contributes to improved quality of life. However, some issues remain with the use of clotting factor replacement therapy. The need for multiple intravenous infusions is associated with substantial mental and physical burden, and the inhibitor development results in difficulty of hemostatic management. To overcome these unmet needs, a recombinant humanized anti-FIXa/FX bispecific antibody mimicking FVIIIa function (emicizumab) was created. In phase 1/2 clinical studies, Japanese patients with PWHAs were treated with once-weekly subcutaneous administration of emicizumab. The annual bleeding rates were markedly reduced, irrespective of inhibitor use. A phase 3 global study for PWHA with inhibitor demonstrated a statistically significant efficacy, whereas thrombotic microangiopathy and thromboembolism were reported in 5 patients treated with emicizumab concomitantly with multiple infusions of activated prothrombin complex concentrates. In Japan, emicizumab (HEMLIBRA®) was approved for treatment of PWHAs with inhibitor on March 2018. In conclusion, emicizumab has promising features. Its subcutaneous bioavailability and long half-life (T1/2; approximately 30 days) enable effective bleeding prophylactic treatment at inhibitor status. Additional studies are warranted to establish clinical data on its safety and to define suitable assays for hemostatic monitoring.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemostáticos/uso terapêutico , Ensaios Clínicos como Assunto , Fator VIII , Humanos , Japão , Qualidade de Vida
9.
Cochrane Database Syst Rev ; 4: CD011385, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-31002742

RESUMO

BACKGROUND: Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease (VWD). The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date. This is an update of a previously published Cochrane Review. OBJECTIVES: Primarily, we aim to assess the efficacy of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or VWD undergoing oral or dental procedures.Secondary objectives are to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or VWD and to establish the effects of these agents on bleeding in oral or dental procedures for each of these patient populations. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched PubMed, Embase, Cinahl and the Cochrane Library. Additional searches were performed in ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP).Date of last search of the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 01 March 2019. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials in people with haemophilia or VWD undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid (EACA)) to prevent perioperative bleeding compared to no intervention or usual care with or without placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened the titles and abstracts of all identified articles. Full texts were obtained for potentially relevant abstracts and two authors independently assessed these for inclusion based on the selection criteria. A third author verified trial eligibility. Two authors independently performed data extraction and risk of bias assessments using standardised forms. MAIN RESULTS: While there were no eligible trials in people with VWD identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of EACA published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference (RD) of -0.64 (95% confidence interval (CI) -0.93 to - 0.36) and the EACA trial a RD of -0.50 (95% CI 0.77 to -0.22). The combined RD of both trials was -0.57 (95% CI -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping EACA (combined RD of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the EACA trial, but overall the risk of bias appeared to be low for both trials. AUTHORS' CONCLUSIONS: Despite the discovery of a beneficial effect of systemically administered tranexamic acid and EACA in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with VWD.


Assuntos
Antifibrinolíticos/uso terapêutico , Hemofilia A/complicações , Hemorragia Bucal/prevenção & controle , Doenças de von Willebrand/complicações , Hemofilia A/tratamento farmacológico , Humanos , Procedimentos Cirúrgicos Menores/efeitos adversos , Hemorragia Pós-Operatória/prevenção & controle , Cirurgia Bucal , Extração Dentária/efeitos adversos
10.
Blood Coagul Fibrinolysis ; 30(3): 127-132, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30958453

RESUMO

: We hypothesized that inhibitor specificity may predict the outcome of antifactor VIII autoantibodies eradication treatment in acquired hemophilia A. Our objective was to analyze the association between factor VIII domains recognized by inhibitors and outcome of the immunosuppressive therapies (ISTs) in a prospective, observational study. 16 patients were recruited. Inhibitor specificities were assessed at diagnosis and throughout the study. Their association with IST outcome was addressed. First-line IST succeeded in 56% of patients. Inhibitors reacted mainly with light chain domains (69%) and/or the A2 domain (44%). 31% inhibitors recognized more than one domain. Significantly, the number of patients whose inhibitors recognized the light chain was significantly higher in the group of those who did not reach complete remission after first line IST when compared with those who did [6/7 (85.7%) vs. 4/9 (44.4%), P < 0.05]. Therefore, inhibitor specificity could predict the success of IST in acquired hemophilia A.


Assuntos
Especificidade de Anticorpos , Autoanticorpos/imunologia , Fator VIII/imunologia , Hemofilia A/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Estudos Prospectivos , Domínios Proteicos , Resultado do Tratamento
11.
BMJ Case Rep ; 12(4)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962210

RESUMO

Haemophilia is a hereditary X-linked recessive disorder caused by a deficiency of either clotting factor VIII (haemophilia A) or IX (haemophilia B). Conventional treatment is currently based on the use of either plasma derived or recombinant coagulation factors. This paper reports on the case of a patient with severe haemophilia who presented with mesial decay and interproximal tartar build-up, for which extraction and scaling to remove tartar deposits were indicated. Following extraction, the usual haemostasis techniques were applied, and postoperative prophylactic antihaemophilic treatment was indicated for 2 or 3 days. The patient presented with moderate bleeding for a few minutes immediately after the procedure. Administration of factor VIII before surgery as well as the patient's favourable pharmacokinetic response allowed for an optimal result. This treatment has afforded patients with haemophilia a better quality of life, and safe and efficient access to invasive surgical procedures.


Assuntos
Fator VIII/administração & dosagem , Hemofilia A/tratamento farmacológico , Cuidados Pré-Operatórios/métodos , Extração Dentária/métodos , Fator IX , Fator VIII/farmacocinética , Hemofilia A/complicações , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Proteínas Recombinantes/uso terapêutico , Extração Dentária/efeitos adversos
12.
Lancet Haematol ; 6(6): e295-e305, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003963

RESUMO

BACKGROUND: Emicizumab, a subcutaneously administered, humanised, bispecific, monoclonal antibody, is approved to treat people with haemophilia A of all ages with and without coagulation factor VIII (FVIII) inhibitors. HAVEN 4 assessed emicizumab prophylaxis administered as one dose every 4 weeks in adults and adolescents with haemophilia A, regardless of FVIII inhibitor status. METHODS: In this phase 3, multicentre, open-label, two-stage study, patients aged 12 years and older with severe congenital haemophilia A (<1% of normal FVIII activity in blood) or haemophilia A with FVIII inhibitors, undergoing treatment with either FVIII concentrates or bypassing agents were recruited from three sites in Japan and Spain for a run-in cohort, and from 17 sites in Australia, Belgium, Japan, Poland, Spain, and the USA for a subsequent expansion cohort. Participants in the run-in and expansion cohorts were given emicizumab subcutaneously 6 mg/kg every 4 weeks for 24 weeks or more; for patients in the expansion cohort this regimen was preceded by four loading doses of 3 mg/kg once weekly. In the run-in cohort, we assessed pharmacokinetics after single and multiple (every 4 weeks) subcutaneous administration of 6 mg/kg emicizumab and safety. In the expansion cohort, the efficacy endpoint was efficacy of prophylactic emicizumab in maintaining adequate bleed prevention, assessed in all patients who received at least one dose of emicizumab and reported as annualised bleed rates for treated bleeds, all bleeds (treated and untreated), treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds. Safety was assessed in all participants given emicizumab. This study is registered with ClinicalTrials.gov, number NCT03020160, and is ongoing. FINDINGS: Between Jan 30, 2017, and Feb 27, 2017, seven patients were enrolled into the initial run-in cohort, which confirmed the expected pharmacokinetic profile and safety of the regimen based on model-based simulations, providing sufficient evidence for opening of the expansion cohort (n=41), which was recruited and enrolled between May 24, 2017, and June 30, 2017. The annualised rate of treated bleeds was 2·4 (95% CI 1·4-4·3). 23 (56·1%; 95% CI 39·7-71·5) of 41 reported no treated bleeds and 37 (90%; 76·9-97·3) reported zero to three treated bleeds. The annualised bleed rate was 4·5 (95% CI 3·1-6·6) for all bleeds, 0·6 (0·3-1·5), for treated spontaneous bleeds, 1·7 (0·8-3·7) for treated joint bleeds, and 1·0 (0·3-3·3) for treated target joint bleeds. The most frequent treatment-related adverse event was injection-site reaction (nine [22%] of 41 patients). We observed no thrombotic events or development of de-novo antidrug antibodies with neutralising potential or FVIII inhibitors. INTERPRETATION: Emicizumab given once every 4 weeks showed clinically meaningful bleed control while being well tolerated. This regimen could improve patient care by decreasing treatment burden and increasing adherence to effective prophylaxis, potentially decreasing the development of secondary complications for people with haemophilia A. FUNDING: F Hoffmann-La Roche and Chugai Pharmaceutical.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemofilia A/tratamento farmacológico , Adolescente , Adulto , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Esquema de Medicação , Meia-Vida , Hemofilia A/patologia , Hemorragia/epidemiologia , Humanos , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Nasofaringite/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
13.
Blood Rev ; 35: 43-50, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30922616

RESUMO

Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.


Assuntos
Coagulação Sanguínea , Fator VIII/metabolismo , Hemofilia A/sangue , Hemostasia , Animais , Fatores de Coagulação Sanguínea/metabolismo , Encéfalo/fisiopatologia , Comorbidade , Fator VIII/genética , Fator VIII/uso terapêutico , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Hemorragia/diagnóstico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Mutação , Trombina/biossíntese
14.
Ther Drug Monit ; 41(2): 192-212, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30883513

RESUMO

Hemophilia A and hemophilia B are hereditary bleeding disorders, caused by a deficiency of clotting factor VIII or clotting factor IX, respectively. To treat and prevent bleedings, patients can administer clotting factor concentrates (hemophilia A and B) or desmopressin (hemophilia A). Both clotting factor concentrates and desmopressin are currently dosed according to the patients' body weight. However, clotting factor concentrates exhibit considerable pharmacokinetic (PK) variability. Therefore, several alternative dosing strategies to individualize dosing of clotting factor concentrates and desmopressin in hemophilia A and B have been proposed. In this study, a review of the existing literature on the individualization of dosing based on PK guidance was performed. In total, 79 articles were included. The methods to individualize dosing were divided into 3 categories: (1) methods using clinical parameters, (2) empirical individual PK-guided methods, and (3) maximum a posteriori (MAP) Bayesian estimation methods. The clinical parameter mainly used to individualize dosing is bleeding phenotype. Dosing based on bleeding phenotype may decrease clotting factor consumption. However, with this method, it is not possible to individualize on-demand dosing during bleeding events or in the perioperative setting. Empirical individual PK-guided methods can be used both for prevention and treatment of bleedings. These methods include dose individualization using a nomogram and individualized in vivo recovery. In the perioperative setting, adjustment of the rate of continuous infusion can be applied to obtain a specific target level. The final category, MAP Bayesian estimation methods, relies on the availability of a population PK model. In total, 22 population PK models describing clotting factor concentrate or desmopressin dosing are currently available in literature. MAP Bayesian estimates can be used to calculate the individualized doses required to achieve or maintain a target level in every setting. The application of PK-guided and pharmacodynamic-guided dosing of clotting factor concentrates and desmopressin seems promising, although further investigation is warranted. Prospective studies analyzing its potential benefit are on the way.


Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Desamino Arginina Vasopressina/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Medicina de Precisão/métodos , Humanos
15.
Niger J Clin Pract ; 22(3): 416-421, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30837433

RESUMO

Introduction: Inhibitor formation is a major complication of hemophilia treatment because it interferes with the clinical response to factor replacement and causes significant morbidity. This cross-sectional study was conducted to assess the presence and frequency of inhibitors among registered person with hemophilia and to identify risk factors associated with inhibitor development. Patients and Methods: A total of 143 hemophilics, 118 with hemophilia A (HA) and 25 with hemophilia B (HB), were enrolled for the study. Participant's clinical data were obtained through patient's medical records. Factor VIII and IX levels and the presence of inhibitors were assessed using a fully automated coagulometer. From the results of a Bethesda assay, patients were divided into those with high titers (≥5 BU) and those with low titers (<5 BU). Results: The patient's age ranged from 1 to 67 years with median of 13.8 years. Inhibitors were detected in 18.6% and none of HA and HB patients, respectively. Of the 22 patients with HA and inhibitors, 18 (82%) had high titer inhibitors. The frequency of inhibitors was significantly higher among patients with severe hemophilia, a history of early exposure (≤3 months) to factor VIII concentrate, and family histories of autoimmune disease and immune system challenges (P < 0.05). The independent risk factors associated with inhibitor development were severe hemophilia (95% CIs = 1.02-55.6, OR = 7.5) and immune system challenges (95% CIs = 1.14-5.99, OR = 2.6). Conclusion: Inhibitors were common among HA patients, and both severe HA and immune system challenges (surgery and trauma) are independent risk factors for inhibitor development.


Assuntos
Fator IXa/antagonistas & inibidores , Fator VIII/antagonistas & inibidores , Hemofilia A/sangue , Hemofilia B/sangue , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Fator IXa/metabolismo , Fator IXa/uso terapêutico , Fator VIII/metabolismo , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Hemostáticos/efeitos adversos , Hemostáticos/uso terapêutico , Humanos , Lactente , Iraque , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
16.
Acta Haematol ; 141(3): 129-134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30783064

RESUMO

The development of factor VIII inhibitors remains a significant clinical challenge in the management of hemophilia A. We present a patient of mixed ethnicity with severe hemophilia A who was found to have a F8 gene hemizygous c.5815G>T mutation resulting in an Ala1939Ser substitution (Ala1920Ser in legacy nomenclature) and possible splice site change that has been reported in only 1 patient previously. He developed an inhibitor shortly after starting replacement recombinant factor VIII (Advate®; Baxalta, Bannockburn, IL, USA) and was successfully treated with immune tolerance therapy. Our report describes the second patient reported to have severe hemophilia due to this mutation and the only case of a factor VIII inhibitor associated with this mutation.


Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII , Hemofilia A , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Fator VIII/administração & dosagem , Fator VIII/genética , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Humanos , Recém-Nascido , Masculino
17.
Acta Haematol ; 141(3): 151-155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30783066

RESUMO

The development of inhibitors against factor VIII (FVIII) concentrates represents a significant treatment complication for hemophilia. Immune tolerance induction (ITI) therapy eradicates inhibitors in 60-80% of patients, resulting in a normal FVIII response. This article, based on presentations at the 6th International Coagulation Meeting, held in Barcelona, Spain, in September 2017, provides an overview of management approaches for patients with inhibitors and briefly tabulates four cases of ITI therapy (first-line or rescue ITI therapy in pediatric and adult patients) with successful outcomes. Switching FVIII product from recombinant FVIII to plasma-derived FVIII/VWF concentrate may be helpful in eradicating inhibitors. The rate of decline of inhibitor titer in the initial stages of ITI therapy is a good indicator of the success or failure of therapy, although prognostic biomarkers are needed. The development of the bispecific monoclonal antibody emicizumab, which was recently shown to reduce bleeding in inhibitor patients, offers a potential alternative therapeutic option. However, the benefits of inhibitor eradication, including a wider choice of cheaper therapeutic products for preventing and treating bleeds, suggest that at least one attempt of ITI therapy should be offered to patients who develop inhibitors.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores dos Fatores de Coagulação Sanguínea , Fator VIII , Hemofilia A , Tolerância Imunológica/efeitos dos fármacos , Inibidores dos Fatores de Coagulação Sanguínea/antagonistas & inibidores , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Inibidores dos Fatores de Coagulação Sanguínea/imunologia , Congressos como Assunto , Fator VIII/antagonistas & inibidores , Fator VIII/uso terapêutico , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Humanos
18.
Haemophilia ; 25(2): 213-220, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30724422

RESUMO

INTRODUCTION: Prospectively collected real-world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non-interventional study (NIS; NCT02476942) prospectively collected real-world data in PwHA who were treated per local routine clinical practice. AIM: Assess annualized bleeding rate (ABR), haemophilia treatment practices and adverse events (AEs) in adult/adolescent PwHA without inhibitors. METHODS: Eligible participants aged ≥12 years with severe HA without history of inhibitors prospectively collected bleeding and treatment information. RESULTS: Ninety-four participants were enrolled (median [range] age, 34 [12-76] years) and monitored for a median (range) of 29.8 (12.4-47.7) weeks. In the episodic (n = 45) and prophylactic (n = 49) treatment groups, respectively, 872/1066 (81.8%) and 151/189 (79.9%), bleeds were treated; ABRs (95% confidence interval) were 36.1 (30.8-42.3) and 5.0 (3.3-7.5), respectively, for treated bleeds and 43.1 (36.5-50.9) and 6.2 (4.2-9.2), respectively, for all bleeds, and median (interquartile range) ABRs were 31.1 (19.8-51.6) and 1.9 (0.0-8.2), respectively, for treated bleeds and 35.3 (21.7-62.9) and 2.7 (0.0-9.4), respectively, for all bleeds. Half of the participants on FVIII prophylaxis had relatively high adherence to treatment, using 2.9 and 2.1 median doses/wk of standard and extended half-life FVIII, respectively. Serious AEs included gastrointestinal polyp haemorrhage and haemarthrosis; the most common AE was viral upper respiratory tract infection. CONCLUSION: PwHA without inhibitors continue to bleed on prophylaxis, consistent with the literature, and require treatment for breakthrough bleeds. This prospective NIS demonstrates the need for more efficacious haemostatic approaches.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A/diagnóstico , Adolescente , Adulto , Idoso , Criança , Fator VIII/efeitos adversos , Fator VIII/farmacocinética , Hemorragia Gastrointestinal/etiologia , Meia-Vida , Hemartrose/etiologia , Hemofilia A/tratamento farmacológico , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Respiratórias/etiologia , Adulto Jovem
19.
Haemophilia ; 25(2): 236-243, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30748057

RESUMO

INTRODUCTION: In sub-Saharan African countries, research on haemophilia is limited. Since 2015, a partnership has been established through the World Federation of Hemophilia (WFH)'s twinning programme between the haemophilia treatment centre (HTC) of the Centre Hospitalier universitaire of Yopougon in Abidjan, Côte d'Ivoire, and the Cliniques universitaires Saint-Luc of Brussels, Belgium. AIM: This study sought to collect accurate, and detailed demographic, clinical, and laboratory data on the whole identified Ivorian haemophilia population. METHODS: A prospective study was conducted in 2017 in Yopougon's HTC. Participants were assessed through multidisciplinary workups including interviews, logbook review, pedigree establishment, clinical examination and laboratory testing. RESULTS: Data on 81 patients with haemophilia (PWH) (78 severe and moderate) were collected. Postcircumcision bleeding was the most common diagnosis reason (32%). Mouth bleeds and skin wounds accounted for 55.2% of bleeds. Pedigrees revealed 63 deaths in affected relatives among 33 families. Most PWHs (76.5%) were treated on demand, and 21% had never been exposed to clotting factor. Non-substitutive therapies (tranexamic acid [43%], physiotherapy [11%] and DDAVP [0%]) were underused. Overweight was uncommon. Knees were the most clinically affected joints at the Hemophilia Joint Health Score. Inhibitors were present in 7.8% of previously treated PWHs. CONCLUSIONS: This study highlights the value of simple, feasible and inexpensive tools to collect data in the Ivorian haemophilia population and provides the basis for developing and implementing locally appropriate strategies to improve screening, diagnosis, preventive care, treatment and education. It demonstrated the WFH twinning programme benefits for haemophilia care in the developing world.


Assuntos
Hemofilia A/patologia , Hemofilia B/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Costa do Marfim , Estudos Transversais , Fator VIII/uso terapêutico , Fibrinogênio/uso terapêutico , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemofilia B/complicações , Hemofilia B/tratamento farmacológico , Hemorragia/prevenção & controle , Humanos , Lactente , Recém-Nascido , Artropatias/complicações , Artropatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Prospectivos , Índice de Gravidade de Doença , Adulto Jovem
20.
Haemophilia ; 25(2): 258-263, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30748062

RESUMO

INTRODUCTION: Haemophilia is a disorder complicated by bleeding episodes that require emergent medical evaluation. Factor replacement dosing can present challenges for emergency department (ED) care. AIMS: We aimed to reduce out-of-range factor dosing in the ED. Specifically, we sought to increase the number of haemophilia ED patient visits between encounters where sub-optimal factor dosing was administered from a baseline of 4-15 encounters. METHODS: A chart review was completed on all patients with haemophilia A (HA) or B (HB) seen in the ED for injuries requiring factor concentrate from September 2015 to August 2016. Injuries were classified as minor-requiring a 50% factor correction or major-requiring a 100% factor correction. Optimal dosing range was defined as 90%-120% of the institutional guideline goal for the degree of injury. The predicted optimal dose range for each patient was compared to the actual dose administered. RESULTS: Baseline data demonstrated optimal dosing range in 70% of encounters. There was no difference between patients with HA or HB in frequency of out-of-range dosing (P = 0.15). There was no difference in frequency of out-of-range dosing between types of clotting factor concentrate used. After initiation of quality improvement (QI) interventions, we achieved 16 encounters between out-of-range dosing, exceeding our goal of 15. However, this success was not sustained. CONCLUSION: Optimal coagulation factor dosing is important for patient care and resource management. QI interventions promoted increased accuracy of factor dosing for patients with haemophilia seen in the ED.


Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Cálculos da Dosagem de Medicamento , Serviço Hospitalar de Emergência , Humanos , Lactente , Melhoria de Qualidade , Adulto Jovem
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