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1.
J Assoc Physicians India ; 67(11): 52-55, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31793269

RESUMO

Aim: To assess effect of low dose prophylaxis in hemophilics in terms of bleeding, joint function, QoL and cost-effectiveness. Methods: Analytic study done during one year among 70 adult hemophilics. In observation period (12 weeks), on-demand factor and during prophylaxis (12 weeks), low dose factor was given (Factor VIII 10 IU/KgBW biweekly for haemophilia A and Factor IX 20 IU/KgBW weekly for haemophilia B). Clinical joint assessment was done by Gilbert score and improvement by WFH definitions. Results: Bleed reduced by 68.99% in moderate hemophilics (40 v/s 129) and 64.86% in severe hemophilics (26 v/s74) (p<0.05). During observation in moderate hemophilics, joint, soft tissue and mucosal bleeds occurred in frequency of 120, 1 and 8. This was reduced to 39 joint bleeds, 1 soft tissue bleed and no mucosal bleed during prophylaxis. In severe hemophilics, 70 joint, 2 soft tissue bleeds and 2 mucosal bleeds occurred during observation which reduced to 26 joint bleeds without soft tissue/mucosal bleed in prophylaxis. Bleeding episodes decreased by 65.79% in joints, 66.67% in soft tissues, 100% mucosal bleeds. After prophylaxis one joints (0.61 %) showed good improvement in joint function, thirty (18.18 %) joints showed moderate improvement and ninety two joints (55.76 %) showed mild improvement in joint function. Hospitalization reduced by 60.34% (163 v/s 411) and absenteeism by 53.73% (279 v/s 603). Factors consumption reduced by 12.33 % during prophylaxis period. Conclusion: The low dose prophylaxis strategy significantly decreased the subsequent episodes of total bleeds including joint bleeds and improved the joint function as well as quality of life.


Assuntos
Coagulantes , Hemartrose , Hemofilia A , Adulto , Coagulantes/economia , Coagulantes/uso terapêutico , Análise Custo-Benefício , Fator IX/economia , Fator IX/uso terapêutico , Fator VIII/economia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia A/etiologia , Hemofilia A/prevenção & controle , Humanos , Qualidade de Vida , Resultado do Tratamento
2.
Blood Coagul Fibrinolysis ; 30(1S Suppl 1): S14-S18, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517711

RESUMO

: The development of inhibitors continues to be the most important complication in severe hemophilia A. The management of inhibitor patients revolves around two basic principles: eradication of the inhibitor and management and prevention of bleeding. In this paper, we review the prophylactic treatments carried out in the last two decades with the two available bypassing agents and the results of the clinical trials carried out with the new molecules under investigation or already licensed for the prevention of hemorrhagic episodes in hemophilia, like emicizumab.


Assuntos
Hemofilia A/terapia , Hemorragia/prevenção & controle , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Fator VIIa/uso terapêutico , Humanos , Proteínas Recombinantes/uso terapêutico
3.
Rinsho Ketsueki ; 60(6): 647-658, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281158

RESUMO

Hemophilia is the most common congenital coagulation disorder, characterized by a tendency to bleed severely. Treatment is based on the replacement of defective FVIII or FIX. Following the introduction of recombinant FVIII and FIX, the treatment paradigm of the disease is shifting from episodic to prophylactic treatment with regular the infusion of factor concentrates. Since 2000, several new recombinant FVIII and FIX products with longer half-life have been developed by pegylation protein modification and other technologies, resulting in improved quality of life for patients with hemophilia. Recently, therapeutics with novel hemostatic mechanisms have been developed to overcome several unmet needs. FVIII (a), mimicking bispecific antibody recognizing FIX (a) /FX, has been approved in Japan. The product has several advantages, including a much longer half-life spanning 30 days, subcutaneous injectability, and effectiveness irrespective of the presence of FVIII inhibitor. The paradigm of hemophilia treatment is now shifting towards intact joint function and higher activity.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/terapia , Humanos , Japão , Qualidade de Vida
4.
J Thromb Thrombolysis ; 48(2): 299-302, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152365

RESUMO

Antithrombotic treatment and perioperative management in patients with hemophilia remains a challenge. As life expectancy in these patients is increasing, a concern about cardiovascular diseases is emerging. Herein we present the case of a 68 year-old patient with mild hemophilia B and multivessel coronary disease who underwent coronary artery bypass grafting (CABG) surgery. Off-pump surgery with continuous infusion FIX treatment was performed successfully with stable factor IX levels, and no bleeding or thrombotic complications. There is a paucity of cases reported regarding management of CABG in this population. To our knowledge, this is the first patient with mild hemophilia B that underwent CABG surgery with off-pump technique, that seems to be a secure and effective procedure.


Assuntos
Ponte de Artéria Coronária/métodos , Hemofilia B/cirurgia , Idoso , Doença da Artéria Coronariana/cirurgia , Fator IX/uso terapêutico , Humanos , Resultado do Tratamento
5.
Haemophilia ; 25(4): e247-e256, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168882

RESUMO

INTRODUCTION: In 2010, nonacog alfa became the first recombinant factor IX (rFIX) available in Japan for patients with haemophilia B. AIM: To determine real-world safety (adverse events, incidence of inhibitors) and effectiveness of nonacog alfa in Japan. METHODS: This multicentre, prospective, observational, postmarketing surveillance study enrolled previously treated and untreated patients (PTPs and PUPs, respectively) who were observed for 1 and 2 years, respectively, after initiating nonacog alfa therapy. Safety and effectiveness were assessed for each treatment type. Annualized bleeding rate (ABR) and incremental recovery of rFIX were also evaluated. RESULTS: Overall, 312 of 314 patients enrolled from 173 sites were eligible for the safety analysis set (PTPs, 281; PUPs, 28; other, 3). Mean age was 25.4 (PTPs) and 14.8 (PUPs) years. Haemophilic severity ranged from mild to severe, and 133 (42.6%) patients had haemophilic arthropathy. Of 285 patients (PTPs, 257; PUPs, 28) in the effectiveness set, 112 received on-demand treatment for 1161 bleeding episodes (effectiveness rate, 93.7%) and 185 received routine prophylaxis (effectiveness rate, 95.5%). No spontaneous bleeding was observed in 52.4% of patients during prophylactic treatment. Median ABR was lower during routine prophylaxis (2.0) vs the rest of the observation period (8.3). A weak negative correlation was found between body weight and the reciprocal of rFIX recovery. Eleven adverse drug reactions occurred in 7 PTPs (2.2% [7/312]); recurrence of inhibitor was observed in 1 patient, but no new inhibitor developed in PTPs or PUPs. CONCLUSION: Nonacog alfa therapy is safe and effective in the real-world scenario in Japan.


Assuntos
Fator IX/efeitos adversos , Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Vigilância de Produtos Comercializados , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Segurança , Adolescente , Adulto , Idoso , Feminino , Hemofilia B/complicações , Hemorragia/complicações , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Int J Hematol ; 110(1): 59-68, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31006077

RESUMO

Bleeding into the joints represents the major morbidity of severe hemophilia and predisposes it to hemophilic arthropathy (HA). In a reproducible hemarthrosis mouse model, we found distinct changes in thrombin activity in joint tissue homogenate following exposure of the joint to blood in wide type (WT) and hemophilic B mice. Specifically, at early time points (4 h and 24 h) after hemarthrosis, thrombin activity in WT mice quickly peaked at 4 h, and returned to baseline after 1 week. In hemophilia B mice, there was no/minimal thrombin activity in joint tissues at 4 h and 24 h, whereas at 72 h and thereafter, thrombin activity kept rising, and persisted at a higher level. Nevertheless, prothrombin had not decreased in both WT and hemophilia. The pattern was also confirmed by Western blotting and immunostaining. To optimize the protection against development of HA, we tested different treatment regimens by administration of clotting factor IX into hemophilia B mouse after hemarthrosis induction, including a total of 600 IU/kg FIX within the first 24 h or the whole 2-week period. We concluded that timely (in the first 24 h) and sufficient hemostasis correction is critical for a better protection against the development of hemophilic arthropathy.


Assuntos
Fator IX/uso terapêutico , Hemartrose/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hemofilia B/complicações , Hemofilia B/patologia , Hemorragia/tratamento farmacológico , Articulações/patologia , Camundongos , Trombina/metabolismo , Fatores de Tempo
8.
Haemophilia ; 25(4): 668-675, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30993845

RESUMO

BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague. AIM: To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs. METHODS: Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months. RESULTS: Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%). CONCLUSION: Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.


Assuntos
Custos e Análise de Custo , Fator IX/economia , Fator IX/uso terapêutico , Fator VIII/economia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Criança , Prescrições de Medicamentos/economia , Prescrições de Medicamentos/estatística & dados numéricos , Fator IX/farmacocinética , Fator VIII/farmacocinética , Feminino , Geografia , Meia-Vida , Hemofilia A/metabolismo , Hemofilia B/metabolismo , Humanos , Estudos Longitudinais , Masculino , Estados Unidos , Adulto Jovem
12.
Haemophilia ; 25(1): 154-161, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30664825

RESUMO

N9-GP (nonacog beta pegol; Refixia® ; Rebinyn® , Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated extended half-life recombinant factor IX (rFIX) that exhibits efficacy and potency comparable to unmodified FIX molecules in non-clinical models. Phase 3 clinical trials have confirmed the efficacy and tolerability of N9-GP for the prevention and on-demand treatment of bleeding episodes in patients with haemophilia B. Recent studies have shown that PEGylation affects clotting times in activated partial thromboplastin time (aPTT)-based one-stage activity assays due to interaction between the FIX molecule and certain aPTT reagents. In recognition of the challenges surrounding FIX activity assessment, the identification of consistent, reproducible and accurate assays to measure FIX activity has been a priority for Novo Nordisk, running in parallel to the clinical development program for N9-GP. N9-GP activity can be reliably measured using chromogenic substrate assays and specific aPTT reagents. The conjugation of the PEG moiety to the FIX molecule may affect one-stage aPTT-based clotting assays in a reagent-dependent manner. Many aPTT reagents that use silica as the contact activator dramatically overestimate N9-GP activity due to premature activation. On the other hand, the contact activator in some other aPTT reagents negatively affects the enzymatic activity of FXIa, causing the underestimation of N9-GP activity. While N9-GP activity cannot be measured consistently with all available aPTT reagents, accurate N9-GP measurements can be achieved with certain aPTT reagents. Here, we review the studies that led to these findings and summarize the current options for accurate measurement of N9-GP in patient samples.


Assuntos
Testes de Coagulação Sanguínea/métodos , Fator IX/análise , Polietilenoglicóis/análise , Monitoramento de Medicamentos , Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Humanos , Tempo de Tromboplastina Parcial , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/análise , Proteínas Recombinantes/uso terapêutico
15.
Haemophilia ; 25(1): 45-53, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30427091

RESUMO

INTRODUCTION: Frequent infusions and bleeds can impact on the health-related quality of life (HRQoL) of paediatric haemophilia B patients. rIX-FP (IDELVION® ) is a fusion protein linking recombinant factor IX with recombinant albumin, and is associated with low bleeding rates with a weekly regimen, which could improve HRQoL. AIMS: To measure the effect of rIX-FP prophylaxis on the HRQoL of paediatric patients and treatment satisfaction in their caregivers using the Haemo-QoL and Hemo-SATP questionnaires, respectively. METHODS: At baseline and end-of-study (EOS), patients 4-11 years old participating in the PROLONG-9FP program answered the Haemo-QoL questionnaire and gave information on their socio-demographic data and physical activity. Caregivers completed the Hemo-SatP . Minimal important differences (MID) (|Cohen's d| > 0.5) between baseline and EOS and the number of responders (patients with meaningful subject-level improvements over time) at EOS were calculated. RESULTS: Twenty patients (age group I: 4-7 years old [n = 12]; age group II: 8-12 years old [n = 8]) completed the Haemo-QoL questionnaire at baseline. MIDs were found in age group I representing improvement for "physical health" (d = -0.547) domain; 60% of patients were responders for "physical health." In age group II, MIDs were seen in most domains; 71.4% patients were responders in "total score." In caregivers, improvements were seen for most domains of the Hemo-SatP with a small effect size. Fewer patients missed school when treated with rIX-FP and 94.1% patients maintained their physical activity level. CONCLUSION: Prophylaxis with rIX-FP led to substantial improvements in HRQoL in paediatric patients and treatment satisfaction in caregivers.


Assuntos
Coagulantes/uso terapêutico , Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Qualidade de Vida , Proteínas Recombinantes de Fusão/uso terapêutico , Albumina Sérica/uso terapêutico , Cuidadores/psicologia , Criança , Pré-Escolar , Esquema de Medicação , Exercício , Humanos , Masculino , Inquéritos e Questionários
16.
Eur J Haematol ; 102(2): 111-122, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30411401

RESUMO

The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment-related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult-to-treat patients. Some alternative, non-ITI approaches for inhibitor management, are also proposed.


Assuntos
Inibidores dos Fatores de Coagulação Sanguínea/imunologia , Hemofilia A/imunologia , Hemofilia B/imunologia , Isoanticorpos/imunologia , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Dessensibilização Imunológica , Gerenciamento Clínico , Resistência a Medicamentos , Fator IX/efeitos adversos , Fator IX/uso terapêutico , Fator VIII/efeitos adversos , Fator VIII/uso terapêutico , Hemofilia A/sangue , Hemofilia A/complicações , Hemofilia A/terapia , Hemofilia B/sangue , Hemofilia B/complicações , Hemofilia B/terapia , Hemorragia/diagnóstico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Hemorragia/terapia , Humanos , Tolerância Imunológica , Isoanticorpos/sangue , Pré-Medicação/métodos , Resultado do Tratamento
17.
Blood ; 133(5): 389-398, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30559264

RESUMO

Hemophilia A (HA) and hemophilia B (HB) are the most common severe bleeding disorders. Replacement therapy, providing the missing coagulation factor, has been the mainstay of treatment both prophylactically and to treat bleeding. Despite widespread availability of safe and effective replacement therapy, patients with HA and HB continue to experience a tremendous burden of treatment, breakthrough bleeding, and progressive joint disease, as well as high rates of inhibitor development. These remaining challenges are now being addressed by incredible advances in bioengineering. Recombinant bioengineering has led to replacement therapies with easier modes of administration, decreased immunogenicity, increased efficacy, and extended half-lives. Emicizumab, a bispecific antibody that acts as a substitutive therapy for HA, has been approved for patients with and without inhibitors. Novel compounds are in development to exploit the natural balance of hemostasis by targeting the natural anticoagulants protein C, protein S, tissue factor pathway inhibitor, and antithrombin. The substitution and rebalancing therapies provide an opportunity for steady-state hemostatic control without exposure to immunogenic clotting factor proteins. As such, they may have broader applications outside those being investigated in the clinical trial programs.


Assuntos
Hemofilia A/terapia , Hemofilia B/terapia , Animais , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Coagulantes/uso terapêutico , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Hemostasia/efeitos dos fármacos , Humanos , Proteínas Recombinantes/uso terapêutico
18.
Drug Des Devel Ther ; 12: 2933-2943, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30254423

RESUMO

Decisions over hemophilia treatment selection and switching involve balancing many clinical and patient-related factors. The current standard of care for patients with hemophilia B is prophylaxis with plasma-derived or recombinant factor IX (rFIX) concentrates. However, several extended half-life (EHL) rFIX products have recently been developed to improve treatment convenience and clinical outcomes for these patients. Nonacog beta pegol, an rFIX product that combines the FIX protein with a 40 kDa polyethylene glycol moiety, has been evaluated in 115 previously treated patients with hemophilia B (including 25 children) in the paradigm clinical trial program. FIX activity levels and pharmacokinetics were monitored throughout these trials and showed that nonacog beta pegol offers significant pharmacological improvements over standard FIX products. Once-weekly prophylaxis with nonacog beta pegol 40 IU/kg resulted in fewer bleeds in all patients (median annualized bleeding rate of 1.0 across all ages), resolved 90% of target joints, and improved health-related quality of life. No patients developed FIX inhibitors, and there were no thromboembolic events or unexpected safety concerns. Nonacog beta pegol was also safe and effective in the perioperative setting. These findings show that nonacog beta pegol is highly effective, while also offering more convenient dosing than standard FIX products. Nonacog beta pegol represents a significant advance in the current context of treatment for hemophilia B, offering effective management across several treatment modalities and settings, and potentially easing the treatment burden for patients of all ages. Meanwhile, the development of novel treatment strategies, such as gene therapy, anti-tissue factor pathway inhibitor antibodies, and RNA interference therapy, may provide patients with additional therapeutic options, which would require reassessment of the role of EHL products in the future.


Assuntos
Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Humanos , Proteínas Recombinantes/uso terapêutico
20.
Paediatr Drugs ; 20(5): 455-464, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30128815

RESUMO

Regular prophylactic treatment with factor VIII (FVIII) and factor IX (FIX) concentrates in hemophilia A and B, respectively, is introduced in early infancy and has resulted in dramatic improvement of the conditions. Recombinant FVIII and FIX concentrates have been available for > 25 years and have been modified and refined through the years; however, unfortunately frequent intravenous administrations are still necessary. The half-lives of these products have now been extended (EHL) by fusion with albumin, the Fc-portion of IgG, or by being PEGylated. This has been very successful for EHL-FIX, with 3-5 times longer half-life, and to a lesser degree for EHL-FVIII with a half-life extension of only 1.5 times the conventional products. New treatment principles using FVIII mimetics or monoclonal antibodies that rebalance the pro- and anti-coagulation system by interfering with production of anti-thrombin or tissue factor pathway inhibitor have the benefits of long-lasting activity, subcutaneous administration, and being useful in patients both with and without neutralizing antibodies. As the ultimate treatment, recent progress has also been made with gene therapy of both hemophilia A and B.


Assuntos
Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/prevenção & controle , Hemofilia B/prevenção & controle , Criança , Fator IX/farmacocinética , Fator VIII/farmacocinética , Terapia Genética , Meia-Vida , Humanos
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