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1.
N Engl J Med ; 383(11): 1018-1027, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32905674

RESUMO

BACKGROUND: Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS: In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS: No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS: In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).


Assuntos
Fator VIII/metabolismo , Hemofilia A/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Fator VIII/antagonistas & inibidores , Meia-Vida , Hemofilia A/metabolismo , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacocinética , Adulto Jovem
2.
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
3.
Cochrane Database Syst Rev ; 8: CD010810, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32761818

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: 19 March 2020. 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.


Assuntos
Fator IX/imunologia , Fator VIII/imunologia , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Anticorpos , Fator IX/antagonistas & inibidores , Fator VIII/antagonistas & inibidores , Hemofilia A/sangue , Hemofilia B/sangue , Humanos
4.
Ann Hematol ; 99(9): 2105-2112, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621181

RESUMO

Immunosuppressive therapy (IST) is administered to patients with acquired hemophilia A (AHA) to eradicate autoantibodies against coagulation factor VIII (FVIII). Data from registries previously demonstrated that IST is often complicated by adverse events, in particular infections. This pilot study was set out to assess the feasibility of reduced-intensity, risk factor-stratified IST. We followed a single-center consecutive cohort of twenty-five patients with AHA receiving IST according to a new institutional treatment standard. Based on results from a previous study, GTH-AH 01/2020, patients were stratified into "poor risk" (FVIII < 1 IU/dl or inhibitor ≥ 20 Bethesda units (BU)/ml) or "good risk" (FVIII ≥ 1 IU/dl and inhibitor < 20 BU/ml). Outcomes were compared between the current cohort and the GTH registry as a historic control (n = 102). Baseline characteristics of the cohort were not different from the historic control. Partial remission, defined as FVIII recovered to > 50 IU/dl, was achieved by 68% of patients after a median time of 112 days, which was lower and significantly later than in the historic control (hazard ratio: 1.8, 95% confidence interval 1.2-2.8). Complete remission, overall survival, and frequency of fatal infections were not different. Grade 3 and 4 infections were more frequent. The impact of risk factors that was observed in the historic cohort was no longer apparent, as partial and complete remission and overall survival were similar in "good risk" and "poor risk" patients. In conclusion, reduced-intensity, risk factor-stratified IST is feasible in AHA but did not decrease the risk of infections and mortality in this cohort.


Assuntos
Hemofilia A/diagnóstico , Hemofilia A/tratamento farmacológico , Imunossupressores/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Hemofilia A/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendências
5.
Rinsho Ketsueki ; 61(6): 617-620, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32624534

RESUMO

A 7-month-old male infant with severe hemophilia A who received on-demand therapy with recombinant factor VIII (rFVIII) vomited because of acute intracranial bleeding. With rFVIII treatment for suppressing bleeding, there was development of high-titer (≤673 BU/ml) inhibitors. The patient was administered bypassing agents followed by immune tolerance induction therapy (ITI) with 50 U/kg of FVIII thrice weekly. In addition, he was treated with weekly and thrice weekly prophylaxis with 50 U/kg of activated prothrombin complex concentrate (aPCC). Despite ITI and aPCC prophylaxis treatments, it was difficult to control the hemorrhage, and the annualized bleeding ratio (ABR) remained high (5-13 bleeding episodes per year). We started emicizumab 2 weeks after completing the administration of aPCC. Weekly subdermal injections of 1.5 mg/kg emicizumab after loading dramatically decreased ABR (one bleeding episode per year), although biweekly injections of 3 mg/kg emicizumab for several months were associated with one joint hemorrhage. Compared to regular aPCC administration, our observations suggest that weekly emicizumab treatments can improve the ABR in a hemophilia patient with inhibitors and improve the quality of life of patient without limitations in terms of school events.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Hemofilia A , Fator VIII , Hemofilia A/tratamento farmacológico , Humanos , Lactente , Masculino , Qualidade de Vida
6.
Rinsho Ketsueki ; 61(5): 536-541, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32507821

RESUMO

Regular prophylaxis using clotting factor (F) VIII products to prevent hemorrhage in patients with hemophilia A results in considerable suppression in chronic arthropathy development and greatly improves their quality of life. However, there have been some concerns regarding hemostatic treatment for these patients, such as frequent intravenous infusion of FVIII and the development of FVIII inhibitors. A humanized recombinant anti-FIXa/FX bispecific antibody and FVIIIa cofactor function-mimetic (emicizumab) was developed. Several clinical trials have demonstrated that emicizumab remarkably decreases bleeding events by simple subcutaneous infusion and it is currently available as a regular infusion to prevent hemorrhage in congenital hemophilia A patients with or without FVIII inhibitors. There is now a paradigm shift in hemophilia treatment with emicizumab, which is a non-factor product. However, there are some concerns with emicizumab that require clinical attention, such as thromboembolism in cases of concomitant treatment with a bypassing agent, hemostasis monitoring, perioperative hemostatic management, and preventative effects in patients with a proactive lifestyle.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemofilia A , Fator VIII , Hemofilia A/tratamento farmacológico , Humanos , Qualidade de Vida
7.
Med Sci (Paris) ; 36(4): 341-347, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32356710

RESUMO

The use of therapeutic proteins induces in some patients the appearance of neutralizing antibodies. This is the case of pro-coagulant factor VIII (FVIII) used in patients with hemophilia A. Several parameters related to the protein itself, to the type of pathology or to the patients, condition the immunogenicity of a therapeutic protein. Understanding these parameters would help to anticipate or prevent the development of neutralizing antibodies. In the case of FVIII, we propose that the development of neutralizing antibodies does not result from an unpredicted immune response but rather from the inability of the patient's organism to develop an anti-inflammatory or regulatory response.


Assuntos
Anticorpos Neutralizantes/metabolismo , Fator VIII/imunologia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia A/terapia , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/fisiologia , Hemofilia A/imunologia , Humanos , Tolerância Imunológica/fisiologia
8.
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
9.
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
10.
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
11.
World Neurosurg ; 139: 158-162, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32283321

RESUMO

BACKGROUND: Hemophilia is generally considered a contraindication to deep brain stimulation (DBS) and other elective intracranial surgery because of the elevated risk of perioperative hemorrhage. Two prior case reports have suggested, however, that DBS may be safe in patients with hemophilia who undergo appropriate factor replacement. Here, we describe a third case of DBS surgery for medically refractory essential tremor (ET) in a patient with hemophilia A. CASE DESCRIPTION: A 68-year-old right-handed man with mild hemophilia A presented for a 10-year history of bilateral (right greater than left), medically refractory ET. The patient was considered an appropriate candidate for DBS by a multidisciplinary movement disorders conference, and hematology consultation was obtained. Baseline preoperative laboratory results showed a quantitative factor VIII (FVIII) level of 38%. Perioperative management consisted of daily intravenous bolus doses of recombinant FVIII from the morning of surgery to postoperative day 10. The patient underwent uncomplicated unilateral DBS placement in the left ventralis intermedius thalamus. Intra- and postoperative imaging showed no hemorrhage. His postoperative course was uncomplicated except for a single self-limited episode of hematuria requiring no intervention. CONCLUSIONS: DBS placement for ET may be safe in patients with coexisting hemophilia A if appropriate FVIII replacement is given, which may be delivered as bolus infusions rather than continuous infusion.


Assuntos
Coagulantes/uso terapêutico , Estimulação Encefálica Profunda , Tremor Essencial/terapia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Procedimentos Neurocirúrgicos/métodos , Assistência Perioperatória/métodos , Idoso , Perda Sanguínea Cirúrgica/prevenção & controle , Tremor Essencial/complicações , Hemofilia A/complicações , Humanos , Infusões Intravenosas , Masculino , Hemorragia Pós-Operatória/prevenção & controle , Implantação de Prótese/métodos , Proteínas Recombinantes , Núcleos Ventrais do Tálamo/cirurgia
12.
Arterioscler Thromb Vasc Biol ; 40(5): 1148-1154, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32237902

RESUMO

Emicizumab is a humanized anti-FIXa/FX (factor IXa/X) bispecific monoclonal antibody that mimics FVIIIa (activated factor VIII) cofactor function. The hemostatic efficacy of emicizumab has been confirmed in clinical studies of patients with hemophilia A, irrespective of the presence of FVIII inhibitors. Emicizumab differs in some properties from FVIIIa molecule. Emicizumab requires no activation by thrombin and is not inactivated by activated protein C, but emicizumab-mediated coagulation is regulatable and maintains hemostasis. A small amount of FIXa (activated factor IX) is required to initiate emicizumab-mediated hemostasis, whereas tissue factor/FVIIa (activated factor VII)-mediated FXa (activated factor X) and thrombin activation initiates FVIIIa-mediated hemostasis. Fibrin formation, followed by fibrinolysis, appears to be similar between emicizumab- and FVIIIa-mediated hemostasis. These results suggest possible future uses of emicizumab for treating hemorrhagic diseases other than hemophilia A and reveal previously unobservable behaviors of procoagulation and anticoagulation factors in conventional hemostasis. Here, we have reviewed novel insights and new developments regarding coagulation highlighted by emicizumab.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Hemofilia A/tratamento farmacológico , Hemostáticos/uso terapêutico , Animais , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemostáticos/efeitos adversos , Humanos , Fatores de Risco , Resultado do Tratamento
13.
Zhonghua Xue Ye Xue Za Zhi ; 41(2): 138-142, 2020 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-32135631

RESUMO

Objective: To reveal the related factors of inhibitors and differences ofhemorrhage and joint disease before and after the production of inhibitors in children with hemophilia A (HA) . Methods: Retrospective analyses of the clinical data of 381 children with HA under the age of 16 registered in the Registration Management Center of Hemophilia in Henan Provincial from January 2015 to August 2018. Results: A total of the 381 children were enrolled with 116 (30.4%) mild, 196 (51.4%) moderate, and 69 (18.1%) severe cases; 54 patients (14.2%) had inhibitors, including 22 high and 32 low titer inhibitors. Positive family history was positively associated with inhibitors[P<0.001, OR=3.299 (95%CI 1.743-5.983) ], and high-intensity exposure was associated with inhibitors[P=0.002, OR=2.587 (95%CI 1.414-4.731) ]. High-intensity exposure was associated with high titer inhibitor production[P=0.001, OR=8.689 (95%CI 2.464-30.638) ], and high-intensity exposure increased the risk of high titer inhibitors in HA patients. After inhibitors occurred in 54 patients with HA, the rates of overall joint annual bleeding (z=-3.440, P=0.001) and traumatic annual bleeding (z=-2.232, P=0.026) increased, but the rates of the annual joint bleeding (z=-1.342, P=0.180) and spontaneous annual bleeding (z=-1.414, P=0.157) remained to be not statistically significant. The joint ultrasound score did not change significantly after the inhibitor information (z=-0.632, P=0.527) . Conclusions: Positive family history and high-intensity exposure could increase the risk of F Ⅷ inhibitors in HA patients, and high-intensity exposure increased the risk of high titer inhibitors. The rates of the overall joint annual bleeding and traumatic annual bleeding increased after the inhibitor information.


Assuntos
Fator VIII/uso terapêutico , Hemofilia A , Criança , Hemartrose , Hemofilia A/tratamento farmacológico , Hemorragia , Humanos , Estudos Retrospectivos
15.
Int J Hematol ; 111(6): 779-785, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32030609

RESUMO

A combined product of plasma-derived factor (F)VIIa and FX (pd-FVIIa/FX; Byclot®) is currently available for the hemostatic treatment of hemophilia A and B patients with inhibitors in Japan. Limited information is available, however, on its coagulant effect in acquired hemophilia A (AHA). In the present study, we assessed the coagulant effect of pd-FVIIa/FX on impairment of coagulation potentials in AHA. The bypassing agents, pd-FVIIa/FX, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrates (aPCC) were spiked with normal plasma preincubated with anti-FVIII monoclonal antibody (AHA-model plasma), and added to plasmas from AHA patients. Clot waveform analysis (CWA) triggered by the mixture of tissue factor and ellagic acid was subsequently performed. In the AHA-model, pd-FVIIa/FX improved all of the CWA parameters in a dose-dependent manner, irrespective of epitope specificity, with significant improvements relative to rFVIIa and aPCC. The coagulant effect of pd-FVIIa/FX at 1.6 µg/mL (corresponding to 120 µg/kg infusion) at the maximum therapeutic dose was outside the normal range. Moreover, the addition of pd-FVIIa/FX led to a greater improvement in the coagulant potentials in AHA plasmas than those of rFVIIa and/or aPCC. These data suggest that pd-FVIIa/FX significantly improves the impaired coagulant potentials in AHA and is potentially therapeutic.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Coagulantes , Fator VIIa/farmacologia , Fator X/farmacologia , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Fator VIIa/uso terapêutico , Fator X/uso terapêutico , Humanos , Técnicas In Vitro
16.
Ann Biol Clin (Paris) ; 78(1): 35-46, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32108578

RESUMO

Only a few studies on real-world clinical use of recombinant factor VIII -fusionned with Fc (rFVIIIFc, efmoroctocog alpha) have been performed to date, with data on the annual bleeding rate (ABR), the prophylaxis regimen, and FVIII consumption. The aim of our study was to report the real-world clinical application of rFVIIIFc with additional elements, both biological and clinical. A prospective monocentric study has been conducted in the Haemophilia treatment center (HTC) of the Strasbourg university hospital among the severe haemophilia A patients. Thirty male patients were enrolled in the study. After injection of rFVIIIFc, the average time spent above 5%, 2% and 1% of FVIII was respectively almost 3, 4 and 5 days. The average half-life was 15.8 hours. A strong linear correlation between incremental recovery of rFVIIIFc and weight and between rFVIIIFc half-life and basal VWF:Ag level was observed. FVIII activity measurement for rFVIIIFc showed similar results than those previously published. In the follow-up, residual FVIII activity was on average the one of a mild haemophilia patient, corroborated by the results of endogenous thrombin potential of the thrombin generation assay. In clinical practice, rFVIIIFc was well tolerated and patients were mostly satisfied or indifferent of the switch. A single failure was however noticed. No FVIII inhibitor has been detected. Decrease in FVIII consumption was observed, with reduced or unchanged ABR. The switch was an actual success for almost all of the 30 patients, corroborated by satisfactory clinical and biological results.


Assuntos
Substituição de Medicamentos , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adolescente , Adulto , Idoso , Testes de Coagulação Sanguínea , Fator VIII/análise , Fator VIII/farmacocinética , Meia-Vida , Hemofilia A/sangue , Hemofilia A/metabolismo , Hemofilia A/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Proteínas Recombinantes de Fusão/farmacocinética , Índice de Gravidade de Doença , Trombina/metabolismo , Adulto Jovem
17.
Int J Hematol ; 111(4): 544-549, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31939075

RESUMO

Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy for AHA aims to arrest bleeding by eliminating FVIII inhibitors. Factor VIII activity overshoot after complete remission (CR) has been reported anecdotally, but details remain unclear. We retrospectively analyzed data from 17 patients with AHA who achieved CR under immunosuppressive therapy between 2009 and 2019 at Gunma University Hospital. FVIII activity overshoot was defined as ≥ 150%. All 17 patients had low FVIII activity (median 2.1%; range < 1.0-8.9%) due to FVIII inhibition (median 14.7 BU/mL; range 2.0-234.0) and all achieved CR within a median of 39 (range 19-173) days. Overshoot occurred in 11 (64.7%) patients and maximal FVIII activity reached > 200% in six of them. The median duration from CR to overshoot was 13 (range 0-154) days. The FVIII overshoot was transient (72.7%) or persistent (27.3%). Venous thromboembolism developed as a complication of overshoot in one patient due to iliac vein compression by a massive hematoma. Overshoot of FVIII activity after CR occurs more frequently than previously expected in patients with AHA.


Assuntos
Fator VIII/imunologia , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Imunossupressores/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos , Fator VIII/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Raras , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Tromboembolia Venosa/etiologia
18.
Haemophilia ; 26(1): 6-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31846168

RESUMO

Assay discrepancies can occur with laboratory monitoring of FVIII and FIX replacement therapy, particularly for the extended half-life products. This guideline collates current published data and provides advice on appropriate choice of assays for laboratory measurement of replacement therapy for patients with Haemophilia A and B without inhibitors. It is recommended that each haemophilia centre should ensure that appropriate laboratory assays are available for FVIII and FIX products in local clinical use. Patient samples should be assayed against calibrators traceable to WHO Plasma International Standards. Assay discrepancies are common especially for the extended half-life FVIII and FIX products, and assays of these products may need to be verified with the specific CFC being used.


Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Técnicas de Laboratório Clínico , Hemofilia A/tratamento farmacológico , Guias de Prática Clínica como Assunto , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Humanos , Reino Unido
19.
Haemophilia ; 26(1): 151-155, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31859415

RESUMO

INTRODUCTION: The factor VIII mimetic emicizumab (Hemlibra, Hoffman-la Roche, Basel, Switzerland) has a novel mode of action that affects the laboratory monitoring of patients receiving this treatment. AIM: This guideline from the United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO) aims to provide advice for clinical and laboratory staff on appropriate use of laboratory assays in patients with Haemophilia A treated with emicizumab. METHODOLOGY: The guideline was prepared by a review of the available literature and discussion and revision by the authors. RESULTS: The guideline describes the effect of emicizumab on commonly used coagulations tests and provides recommendations on the use of assays for measurement of factor VIII and factor VIII inhibitor in the presence of emicizumab. The guideline also provides recommendations on measurement of emicizumab. CONCLUSION: Knowledge of the effect of emicizumab on coagulation tests and factor assays is required to ensure appropriate testing and monitoring of therapy in patients receiving this drug.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Testes de Coagulação Sanguínea , Hemofilia A/tratamento farmacológico , Guias de Prática Clínica como Assunto , Anticorpos/análise , Anticorpos Biespecíficos/análise , Anticorpos Monoclonais Humanizados/análise , Fator VIII/análise , Fator VIII/antagonistas & inibidores , Fator VIII/uso terapêutico , Humanos , Reino Unido
20.
Haemophilia ; 26(1): 73-78, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31865620

RESUMO

INTRODUCTION: In many countries, there is a shift from standard half-life (SHL) to extended half-life (EHL) clotting factor concentrates (CFCs). AIM: To describe the experience of switching from SHL to an EHL FVIII CFC and the impact of this on frequency of infusions, factor consumption, bleeding rates and HRQoL using the Canadian Hemophilia Kids' Life Assessment Tool (CHO-KLAT). METHODS: A retrospective chart review was conducted at a single haemophilia treatment centre in 2018 that included boys (ages: 4-18 years) with moderate/severe haemophilia A, without inhibitors, who switched from a SHL to an EHL FVIII CFC in the previous 2 years and for whom HRQoL data were available. RESULTS: The study cohort comprised 38 boys [mean (SD) age: 11.0 (3.4) years] with moderate (n = 5)/severe (n = 33) haemophilia A. The switch was associated with a 33% reduction in the number of weekly infusions from a median of 3.5 to 2.3 (P < .0001) and a 17% reduction in median FVIII consumption from 103 IU/kg/wk to 85.5 IU/kg/wk (P = .004). There was no significant change in annualized joint bleed rates or in CHO-KLAT scores. CONCLUSIONS: Despite documenting several benefits of switching to EHL FVIII (less infusions, lower factor consumption with no increase in bleeding), our study did not demonstrate any improvement in HRQoL. We conclude that either the current CHO-KLAT tool is not optimized to measure burden of treatment administration in boys with low bleed rates switching from SHL to EHL FVIII CFCs or that a reduction of 1.2 infusions/week does not result in a meaningful change in HRQoL.


Assuntos
Fator VIII/uso terapêutico , Meia-Vida , Hemofilia A/tratamento farmacológico , Qualidade de Vida/psicologia , Adolescente , Criança , Pré-Escolar , Fator VIII/farmacologia , Humanos , Masculino , Estudos Retrospectivos
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