RESUMO
The development of inhibitors is the main complication of haemophilia A (HA) treatment. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. We describe the methodology of the Brazilian Immune Tolerance Induction (BrazIT) Study, aimed to identify clinical, genetic, and immune biomarkers associated with response to ITI and inhibitor recurrence. This cohort study includes people with HA (PwHA) and inhibitors (a) who require bypassing agents to treat and/or prevent bleeding, and (b) who are at any stage of ITI treatment. Patients are included in each haemophilia treatment centre (HTC). Factor VIII (FVIII) and inhibitor assessments are performed at local laboratories of each HTC. The ITI regimen followed the national protocol of the Brazilian Ministry of Health. All PwHA starts with low-dose ITI (50 IU/kg three times weekly); high-dose regimen (100 IU/kg daily) is used if there is lack of response to the low-dose ITI. Outcomes are classified as total or partial success, and failure. Standardized case report forms with clinical, laboratory, and treatment data are collected from medical files and interviews. Blood samples are collected for genetic and immune biomarkers at the time of inclusion in the study and at the end of ITI. The study is ongoing and, currently, 202/250 (80.8%) PwHA from 15 HTCs have been included. BrazIT Study is the largest cohort of PwHA and inhibitor under treatment with the same ITI regimen reported to date. This study is likely to contribute with novel predictors of ITI response.
Assuntos
Anticorpos Biespecíficos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Fator VIII/genética , Hemofilia A/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Biomarcadores/sangue , Brasil/epidemiologia , Fator VIII/imunologia , Feminino , Hemofilia A/sangue , Hemofilia A/genética , Hemofilia A/imunologia , Humanos , Tolerância Imunológica/imunologia , Masculino , Fatores de RiscoRESUMO
Up to 35% of patients with hemophilia A and 5% with hemophilia B develop neutralizing antibodies which can inhibit the therapeutic activity of factor replacement (inhibitors). Despite the clinical relevance of antifactor VIII and IX neutralizing antibodies, there is still a major gap on the knowledge of risk factors for their development. Furthermore, most of the studies on risk factors for inhibitor development come from Caucasian and Afro-American populations. The HEMFIL is a Brazilian prospective cohort study of previously untreated children with hemophilia, which primary aim is to identify new risk factors related to inhibitor development. This manuscript aims at describing the study design and its methodology. After the diagnosis, children are followed up to 75 exposure days or to inhibitor development. Standardized forms and blood samples are collected to describe clinical characteristics and to perform the measurement of immunological and genetic biomarkers at three time points; Inclusion time (T0), at inhibitor development or at 75 exposure days without inhibitors (T1) and after immune tolerance induction for patients in whom it is indicated and performed (T2). Currently, 120 children have been included, of whom, 95 have completed the follow-up. For severe/moderately severe hemophilia A, the cumulative incidence of inhibitors at 75 exposure days was 35% (95% confidence interval, 26-46%). The inclusion of additional patients and a longer follow-up will allow the analysis of risk factors for inhibitor development.
Assuntos
Anticorpos Neutralizantes/imunologia , Formação de Anticorpos , Fator VIII/imunologia , Hemofilia A/imunologia , Brasil/epidemiologia , Fator VIII/uso terapêutico , Feminino , Hemofilia A/epidemiologia , Hemofilia A/terapia , Hemofilia B/epidemiologia , Hemofilia B/imunologia , Hemofilia B/terapia , Humanos , Tolerância Imunológica , Lactente , Masculino , Estudos Prospectivos , Fatores de RiscoAssuntos
Consenso , Hemofilia A , Hemofilia B , Fatores de Coagulação Sanguínea/efeitos adversos , Fatores de Coagulação Sanguínea/uso terapêutico , Diagnóstico Diferencial , Fator IX/análise , Fator IX/imunologia , Fator VIII/análise , Fator VIII/imunologia , Feminino , Testes Genéticos , Hemartrose/diagnóstico , Hemartrose/etiologia , Hemartrose/terapia , Hemofilia A/complicações , Hemofilia A/diagnóstico , Hemofilia A/genética , Hemofilia A/terapia , Hemofilia B/complicações , Hemofilia B/diagnóstico , Hemofilia B/genética , Hemofilia B/terapia , Hemostasia/genética , Humanos , Isoanticorpos/análise , Estilo de Vida , Masculino , México , Cuidados Pré-Operatórios/métodosRESUMO
INTRODUCTION: The development of anti-factor VIII neutralizing antibodies in hemophilia A is the most severe com plication related to treatment. Immune tolerance induction (ITI) is the only known treatment for eradicating inhibitors. A successful ITI allows using factor VIII (FVIII) again for the treatment or prophylaxis of hemorrhagic events. OBJECTIVE: To report the experience of pediatric patients who underwent ITI in the country's public health care network. PATIENTS AND METHOD: Retrospective and descriptive analysis of 13 pediatric patients with severe Hemophilia A and high-titer inhibitors persis tence who underwent ITI and complete follow-up. Plasma-derived FVIII concentrate was used at 70 180 IU/kg/day doses. The success of the treatment is defined by achieving a negative titer and a half life recovery of the FVIII. The results were expressed in median (range). RESULTS: In 13 patients, the inhibitor was identified at an average age of 17.6 months, after 35.2 days of exposure to the FVIII. 11 patients (84.6%) recovered the half-life of FVIII after 49.6 months of treatment. In the patients who responded to treatment, the inhibitor titer was negative at 6 months on average. CONCLUSIONS: ITI is the treatment of choice for patients with hemophilia A and inhibitors persistence. ITI must be perso nalized since the time response is variable in each patient.
Assuntos
Fator VIII/uso terapêutico , Hemofilia A/terapia , Tolerância Imunológica/imunologia , Imunoterapia/métodos , Isoanticorpos/imunologia , Criança , Pré-Escolar , Fator VIII/imunologia , Feminino , Seguimentos , Hemofilia A/imunologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Resumen: Introducción: El desarrollo de aloanticuerpos neutralizantes anti-factor VIII en hemofilia A es la complicación más seria relacionada al tratamiento. La inducción de tolerancia inmune (ITI) o inmunotolerancia es el único tratamiento que erradica inhibidores, permitiendo utilizar nuevamente factor VIII para el tratamiento o profilaxis de eventos hemorrágicos. Objetivo: reportar la experiencia en niños sometidos a inmunotolerancia en la red pública del país. Pacientes y Método: Análisis retrospectivo y descriptivo de 13 niños con Hemofilia A severa e inhibidores persistentes de alto título, que recibieron ITI y seguimiento completo. Se utilizó concentrado de FVIII plasmático en dosis de 70-180 UI/Kg/diarias, definiendo éxito como la negativización del inhibidor y recu peración de la vida media del FVIII. Resultados expresados en media (rango). Resultados: En 13 pacientes se identificó el inhibidor, a una edad de 17,6 meses (2-48), tras 35,2 días (9-112) de exposición a FVIII. Once pacientes (84,6%) recuperaron la vida media del FVIII, tras 49,6 meses (26-70) de tratamiento. En los pacientes que respondieron, el título del inhibidor se negativizó en 7,3 meses (1-20). Conclusiones: En niños con hemofilia A e inhibidores persistentes de alto título, la ITI tiene un elevado éxito. Dado que el tiempo de respuesta es variable, la inmunotolerancia debe ser personalizada.
Abstract: Introduction: The development of anti-factor VIII neutralizing antibodies in hemophilia A is the most severe com plication related to treatment. Immune tolerance induction (ITI) is the only known treatment for eradicating inhibitors. A successful ITI allows using factor VIII (FVIII) again for the treatment or prophylaxis of hemorrhagic events. Objective: To report the experience of pediatric patients who underwent ITI in the country's public health care network. Patients and Method: Retrospective and descriptive analysis of 13 pediatric patients with severe Hemophilia A and high-titer inhibitors persis tence who underwent ITI and complete follow-up. Plasma-derived FVIII concentrate was used at 70 180 IU/kg/day doses. The success of the treatment is defined by achieving a negative titer and a half life recovery of the FVIII. The results were expressed in median (range). Results: In 13 patients, the inhibitor was identified at an average age of 17.6 months, after 35.2 days of exposure to the FVIII. 11 patients (84.6%) recovered the half-life of FVIII after 49.6 months of treatment. In the patients who responded to treatment, the inhibitor titer was negative at 6 months on average. Conclusions: ITI is the treatment of choice for patients with hemophilia A and inhibitors persistence. ITI must be perso nalized since the time response is variable in each patient.
Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Fator VIII/uso terapêutico , Hemofilia A/terapia , Tolerância Imunológica/imunologia , Imunoterapia/métodos , Isoanticorpos/imunologia , Fator VIII/imunologia , Estudos Retrospectivos , Seguimentos , Resultado do Tratamento , Hemofilia A/imunologiaRESUMO
Acquired hemophilia (AH) is an autoimmune hemostatic disorder mediated by autoantibodies directed against factor VIII: C. In 52% of cases, the cause is unknown or is not associated with other pathological entities; in the rest, there are concomitant factors: lupus, rheumatoid arthritis, cancer, pregnancy, and medications. In Mexico, there is not a registry of AH, and awareness of the disease among health personnel is low. The groups with the highest incidence are women of childbearing age and individuals older than 70 years. It is characterized by severe bleeding, especially after trauma and normal childbirth or cesarean delivery, and large ecchymoses in the trunk and extremities. The suspicion is simple, it just takes for sudden, severe hemorrhage and a prolonged activated partial thromboplastin time that is not corrected with plasma to concur in an individual. Treatment involves achieving hemostasis and eradicating the antibody. The former is achieved with recombinant activated factor VII or activated prothrombin complex concentrate. Cyclophosphamide, prednisone or rituximab are used to eradicate the antibody. Most cases of AH are not diagnosed, which translates into a high mortality rate. Given that awareness about the disease among physicians is low, it is not suspected, neither diagnosed, and nor is it treated. This document reviews the most recent data on AH and expands on its diagnosis and treatment.
La hemofilia adquirida (HA) es un trastorno hemostático autoinmune ocasionado por autoanticuerpos dirigidos contra el factor VIII: C. En 52 % de los casos, la causa se desconoce o no se asocia con otra entidad patológica; en el resto, existen factores concomitantes: lupus, artritis reumatoide, cáncer, embarazo y medicamentos. En México no existe registro ni conciencia de la enfermedad entre el personal de salud. Los grupos de mayor incidencia son las mujeres en edad reproductiva y los individuos mayores de 70 años. Se caracteriza por hemorragia grave, sobre todo posterior a traumatismos y parto o cesárea, y equimosis grandes en tronco y extremidades. La sospecha es simple, basta que concurran hemorragia súbita, grave y un TTPa prolongado que no se corrige con plasma. El tratamiento consiste en lograr la hemostasia y erradicar el anticuerpo; lo primero se logra con el factor VII activado recombinante o concentrado del complejo de protrombínico activado. La ciclofosfamida, prednisona o rituximab sirven para erradicar el anticuerpo. La mayoría de los casos no son diagnosticados y la mortalidad es alta. Ya que los médicos desconocen el problema, no se sospecha, no se diagnostica y no se trata. Este documento revisa los datos más recientes de la HA y abunda en el diagnóstico y tratamiento.
Assuntos
Autoanticorpos/imunologia , Fator VIII/imunologia , Hemofilia A/imunologia , Adulto , Idoso , Equimose/etiologia , Feminino , Hemofilia A/complicações , Hemofilia A/epidemiologia , Hemofilia A/terapia , Hemorragia/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações Hematológicas na Gravidez/etiologia , Prognóstico , Adulto JovemRESUMO
Resumen La hemofilia adquirida (HA) es un trastorno hemostático autoinmune ocasionado por autoanticuerpos dirigidos contra el factor VIII: C. En 52 % de los casos, la causa se desconoce o no se asocia con otra entidad patológica; en el resto, existen factores concomitantes: lupus, artritis reumatoide, cáncer, embarazo y medicamentos. En México no existe registro ni conciencia de la enfermedad entre el personal de salud. Los grupos de mayor incidencia son las mujeres en edad reproductiva y los individuos mayores de 70 años. Se caracteriza por hemorragia grave, sobre todo posterior a traumatismos y parto o cesárea, y equimosis grandes en tronco y extremidades. La sospecha es simple, basta que concurran hemorragia súbita, grave y un TTPa prolongado que no se corrige con plasma. El tratamiento consiste en lograr la hemostasia y erradicar el anticuerpo; lo primero se logra con el factor VII activado recombinante o concentrado del complejo de protrombínico activado. La ciclofosfamida, prednisona o rituximab sirven para erradicar el anticuerpo. La mayoría de los casos no son diagnosticados y la mortalidad es alta. Ya que los médicos desconocen el problema, no se sospecha, no se diagnostica y no se trata. Este documento revisa los datos más recientes de la HA y abunda en el diagnóstico y tratamiento.
Abstract Acquired hemophilia (AH) is an autoimmune hemostatic disorder mediated by autoantibodies directed against factor VIII: C. In 52% of cases, the cause is unknown or is not associated with other pathological entities; in the rest, there are concomitant factors: lupus, rheumatoid arthritis, cancer, pregnancy, and medications. In Mexico, there is not a registry of AH, and awareness of the disease among health personnel is low. The groups with the highest incidence are women of childbearing age and individuals older than 70 years. It is characterized by severe bleeding, especially after trauma and normal childbirth or cesarean delivery, and large ecchymoses in the trunk and extremities. The suspicion is simple, it just takes for sudden, severe hemorrhage and a prolonged activated partial thromboplastin time that is not corrected with plasma to concur in an individual. Treatment involves achieving hemostasis and eradicating the antibody. The former is achieved with recombinant activated factor VII or activated prothrombin complex concentrate. Cyclophosphamide, prednisone or rituximab are used to eradicate the antibody. Most cases of AH are not diagnosed, which translates into a high mortality rate. Given that awareness about the disease among physicians is low, it is not suspected, neither diagnosed, and nor is it treated. This document reviews the most recent data on AH and expands on its diagnosis and treatment.
Assuntos
Humanos , Masculino , Feminino , Gravidez , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Autoanticorpos/imunologia , Fator VIII/imunologia , Hemofilia A/imunologia , Complicações Hematológicas na Gravidez/etiologia , Prognóstico , Equimose/etiologia , Hemofilia A/complicações , Hemofilia A/terapia , Hemofilia A/epidemiologia , Hemorragia/etiologia , Imunossupressores/uso terapêuticoRESUMO
Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found. SUMMARY: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type-inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84-5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89-14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.