RESUMO
BACKGROUND: Emicizumab is a monoclonal antibody approved for prophylaxis against bleeds for people with hemophilia A (PwHA). A systematic review was conducted evaluating the efficacy/effectiveness and the safety of emicizumab as prophylaxis for PwHA compared to prophylaxis with factor VIII (FVIII) or bypassing agents (BPA), respectively in patients without and with inhibitors. RESEARCH DESIGN AND METHODS: Database-directed search strategies were performed in Aug/26/2022 and updated in Mar/16/2023. Studies evaluating the prophylaxis with emicizumab versus prophylaxis with FVIII or BPA in PwHA without or with inhibitors, respectively, were selected by two independent reviewers. Data were extracted by two independent reviewers. Annualized bleeding rates for total treated bleeding events (ABR-all) were evaluated by meta-analysis. The quality of studies and certainty of evidence were assessed. RESULTS: A total of 11 studies were included. The standard mean differences for ABR-all were -0.6 (95%CI -1.0 to -0.2, p-value = 0.0002), among PwHA without inhibitors, and -1.7 (95%CI -2.4 to -0.9, p-value <0.00001), among PwHA with inhibitors. However, there was moderate heterogeneity in both meta-analyses. The most frequent adverse event was injection site reaction. CONCLUSIONS: Emicizumab prophylaxis was superior in reducing the ABR-all when compared with prophylaxis with FVIII or BPA.
Assuntos
Anticorpos Biespecíficos , Hemofilia A , Hemostáticos , Humanos , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Fator VIII/efeitos adversos , Hemorragia/etiologia , Hemorragia/prevenção & controle , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Biespecíficos/efeitos adversos , Hemostáticos/uso terapêuticoAssuntos
Fator VIII/efeitos adversos , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemorragia/tratamento farmacológico , Hemorragia/prevenção & controle , Adolescente , Adulto , Criança , Pré-Escolar , Intervalos de Confiança , Hemofilia A/complicações , Hemorragia/etiologia , Hemostáticos/uso terapêutico , Humanos , Lactente , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
In contrast to haemophilia B, allergic manifestations are rare complications in haemophilia A (HA) patients treated with factor VIII (FVIII) concentrates. Nevertheless, it can be serious and hamper replacement therapy in these cases. The aims of this study were to evaluate the frequency of allergic reaction in a cohort of HA patients treated only with plasma-derived FVIII (pdFVIII) concentrates, and assess the possible immune mechanisms involved. History of allergic reaction was retrospectively assessed. Patients with allergic manifestations were followed, and had plasma samples collected in different timepoints in relation to the allergic episode. These samples were analysed for the presence of inhibitor and anti-FVIII immunoglobulins subclasses. Three of 322 HA patients (0.9%) developed allergic reaction after exposure to pdFVIII products during the last 15 years in our centre. The first patient, with severe HA, without inhibitor, had anti-pdFVIII IgE and IgG4, but no anti-recombinant FVIII (rFVIII) IgE. The second patient, with severe HA, and high-responding inhibitor, presented allergic manifestation with both, pdFVIII concentrate and activated prothrombin complex concentrate. Although anti-pdFVIII and anti-rFVIII IgG4 were detected, no anti-FVIII IgE was present. The third patient, with moderate HA without inhibitor, atopic, had no anti-FVIII immunoglobulin detected, and allergic symptoms disappeared after switching to rFVIII concentrate. This study corroborates the low incidence of allergic reactions in HA patients. In the three cases presented, the anti-FVIII immunoglobulin profile demonstrated that the allergic manifestation was triggered by other proteins contained in pdFVIII products, and not directed to FVIII.
Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Adulto , Pré-Escolar , Coagulantes/efeitos adversos , Coagulantes/imunologia , Coagulantes/uso terapêutico , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Fator VIII/efeitos adversos , Fator VIII/imunologia , Hemofilia A/patologia , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/patologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. OBJECTIVES: To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. PATIENTS/METHODS: In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 1265 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. RESULTS: Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. CONCLUSIONS: Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.
Assuntos
Coagulantes/administração & dosagem , Fator VIII/administração & dosagem , Hemofilia A/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Idoso , Ásia , Criança , Coagulantes/efeitos adversos , Estudos Cross-Over , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Europa (Continente) , Fator VIII/efeitos adversos , Hemofilia A/sangue , Hemofilia A/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Proteínas Recombinantes/efeitos adversos , Índice de Gravidade de Doença , África do Sul , América do Sul , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Factor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti-inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high-titre inhibitors or low-titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1-year period, 17 subjects were treated prophylactically (85 ± 15 U kg(-1) every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on-demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms (P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode-free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on-demand therapy than prophylaxis (P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on-demand treatment, and the safety of prophylaxis is comparable to that of on-demand treatment.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Pré-Medicação , Adolescente , Adulto , Inibidores dos Fatores de Coagulação Sanguínea , Fatores de Coagulação Sanguínea/administração & dosagem , Fatores de Coagulação Sanguínea/efeitos adversos , Criança , Fator IX/administração & dosagem , Fator IX/efeitos adversos , Fator VIII/administração & dosagem , Fator VIII/efeitos adversos , Hemofilia A/sangue , Hemofilia A/complicações , Hemofilia B/sangue , Hemofilia B/complicações , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento , Adulto JovemAssuntos
Humanos , Feminino , Gravidez , Antígenos , Fator VIII/efeitos adversos , Tromboembolia Venosa , Fatores de RiscoAssuntos
Humanos , Feminino , Gravidez , Antígenos , Tromboembolia Venosa , Fator VIII/efeitos adversos , Fatores de RiscoRESUMO
El presente estudio es descriptivo, de serie de casos, realizados en Cruz Roja Nicaragüense en el período comprendido del 01 de septiembre al 31 de diciembre del 2000. Siendo la muestra 50 pacientes que pertenecen al Programa de Hemofilia de Cruz Roja Nicaragüense y que cumplierón los críterios de inclusión teniendo como objetivo general determinar la cuantificación del factor VIII en pacientes hemofílicos menores de 17 años en el período de estudio. A estos pacientes se les aplicó un instrumento de recolección de datos, investigándoseles algunas características epidemiológicas, manifestaciones clínicas desde el inicio de su enfermedad así como pruebas de laboratorio para conocer la severidad de la Hemofilia y las enfermedades infecciosas adquiridas por el uso de hemoderivados. Los pacientes estudiados la mayoría residen en la capital, la edad que más predominó fue entre 5 a 9 años. El comportamiento familiar se caracterizópor tener gran cantidad de personas afectadas. La mayoría de los pacientes se clasificaron como Hemofilia moderada teniendo como signo inicial más frecuente el hematoma, y la hemartrosis como la manifestación más frecuente durante toda la enfermedad. La Hepatitis C fue la única enfermedad infecciosa adquiridad por el uso de hemoderivados presentándose con mayor frecuencia a los que se les transfundió más de 3000 unidades...
Assuntos
Coagulação Sanguínea , Transfusão de Sangue , Criança , Dissertações Acadêmicas como Assunto , Fator VIII/efeitos adversos , Hemofilia A , Hemostáticos , NicaráguaRESUMO
Cytomegalovirus (CMV) infection is of major concern in immunocompromised and immunosuppressed patients. Prior to the introduction of HIV-1 antibody screening and efficient virucidal processes to inactivate viruses, individuals with a factor VIII or factor IX deficiency had a high risk of contracting HIV-1 infection through the infusion of contaminated blood products. In addition, blood products were also frequently associated with alterations in immune function. This study investigated the frequency of active CMV infection and its clinical relevance in Brazilian hemophiliacs. One hundred hemophiliacs were screened for the presence of CMV-DNA in their blood using nested PCR. Twenty-five out of 100 patients (25%) were positive for CMV-DNA and 24 of these 100 patients (24%) were HIV-1 positive; 6 of these 24 (25%) were positive for CMV-DNA. A similar frequency was observed among HIV-1-negative patients. In 60 hemophiliacs, the clinical relevance of the CMV infection was assessed. Twenty-one patients were positive for CMV-DNA. Of these, 10 had gastrointestinal bleeding compared to only 9 of 39 patients who were CMV-DNA negative (p = 0.05; chi(2) test). These data indicate a high prevalence of active CMV infection in Brazilian hemophiliac patients, irrespective of whether the patients were or were not infected by HIV-1. There was a possible association between the presence of CMV and the occurrence of gastrointestinal bleeding.
Assuntos
Infecções por Citomegalovirus/complicações , Hemorragia Gastrointestinal/etiologia , Hemofilia A/complicações , Hemofilia B/complicações , Brasil , Comorbidade , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/transmissão , DNA Viral/sangue , Contaminação de Medicamentos , Fator IX/efeitos adversos , Fator VIII/efeitos adversos , Hemorragia Gastrointestinal/epidemiologia , Hemorragia Gastrointestinal/virologia , Soronegatividade para HIV , Soroprevalência de HIV , Hemofilia A/epidemiologia , Hemofilia B/epidemiologia , Humanos , Hospedeiro Imunocomprometido , Reação em Cadeia da Polimerase , Prevalência , Reação Transfusional , Viremia/complicações , Viremia/epidemiologiaRESUMO
Infection with the hepatitis C virus is one of the risks of transfusion therapy. Considering that in Venezuela, there are not enough data that permit one to establish the frequency of hepatitis C in transfused patients, the purpose of this work was to investigate the presence of anti hepatitis C virus (HCV) antibodies in 56 hemophilic patients from Zulia State, Venezuela. Thirty six (64%) had received fresh frozen plasma and/or cryoprecipitate. Another fourteen (25%) also received lyophilized F VIII or prothrombin complex; six patients (10%) were never transfused. The positive samples (EIA 2nd. generation) were reconfirmed by RIBA-2. Twenty two of the patients were positive for HCV. The presence of anti-HCV antibodies was mainly detected in patients that received more than 10.000 U of the deficient factor. Four of the patients with HCV were also positive for the Human Immunodeficiency Virus (HIV). The results suggest that although the transfusion of blood derivatives carries the risk of HCV transmission, our patients show a low prevalence of this disease, probably due to the infrequent use of clotting factors lyophilizates.
Assuntos
Hemofilia A/epidemiologia , Hemofilia B/epidemiologia , Hepatite C/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Comorbidade , Fator VIII/efeitos adversos , Hepacivirus/imunologia , Anticorpos Anti-Hepatite/sangue , Hepatite C/transmissão , Anticorpos Anti-Hepatite C , Humanos , Prevalência , Estudos Soroepidemiológicos , Reação Transfusional , Venezuela/epidemiologiaRESUMO
Results of a HIV prevalence study conducted in hemophiliacs from Belo Horizonte, Brazil are presented. History of exposure to acellular blood components was determined for the five year period prior to entry in the study, which occurred during 1986 and 1987. Patients with coagulations disorders (hemophilia A = 132, hemophilia B = 16 and coagulation disorders other than hemophilia = 16) were transfused with liquid cryoprecipitate, locally produced, lyophilized cryoprecipitate, imported from Säo Paulo (Brazil) and factor VIII and IX, imported from Rio de Janeiro (Brazil), Europe, and United States. Thirty six (22%) tested HIV seropositive. The univariate and multivariate analysis (logistic model) demonstrated that the risk of HIV infection during the study period was associated with the total units of acellular blood components transfused. In addition, the proportional contribution of the individual components to the total acellular units transfused, namely a increase in factor VIII/IX and lyophilized cryoprecipitate proportions, were found to be associated with HIV seropositivity. This analysis suggest that not only the total amount of units was an important determinant of HIV infection, but that the risk was also associated with the specific component of blood transfused
Assuntos
Humanos , Transfusão de Sangue/efeitos adversos , Fator IX/efeitos adversos , Fator VIII/efeitos adversos , Hemofilia A/epidemiologia , Infecções por HIV/epidemiologia , HIV-1 , População Urbana/estatística & dados numéricos , Adolescente , Adulto , Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/epidemiologia , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/terapia , Brasil/epidemiologia , Hemofilia A/complicações , Hemofilia A/imunologia , Hemofilia A/terapia , Anticorpos Anti-HIV/sangue , Infecções por HIV/etiologiaRESUMO
Results of a HIV prevalence study conducted in hemophiliacs from Belo Horizonte, Brazil are presented. History of exposure to acellular blood components was determined for the five year period prior to entry in the study, which occurred during 1986 and 1987. Patients with coagulations disorders (hemophilia A = 132, hemophilia B = 16 and coagulation disorders other than hemophilia = 16) were transfused with liquid cryoprecipitate, locally produced, lyophilized cryoprecipitate, imported from São Paulo (Brazil) and factor VIII and IX, imported from Rio de Janeiro (Brazil), Europe, and United States. Thirty six (22%) tested HIV seropositive. The univariate and multivariate analysis (logistic model) demonstrated that the risk of HIV infection during the study period was associated with the total units of acellular blood components transfused. In addition, the proportional contribution of the individual components to the total acellular units transfused, namely a increase in factor VIII/IX and lyophilized cryoprecipitate proportions, were found to be associated with HIV seropositivity. This analysis suggest that not only the total amount of units was an important determinant of HIV infection, but that the risk was also associated with the specific component of blood transfused.
Assuntos
Fator IX/efeitos adversos , Fator VIII/efeitos adversos , Infecções por HIV/epidemiologia , HIV-1 , Hemofilia A/epidemiologia , Reação Transfusional , População Urbana/estatística & dados numéricos , Adolescente , Adulto , Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/epidemiologia , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/terapia , Brasil/epidemiologia , Anticorpos Anti-HIV/sangue , Infecções por HIV/etiologia , Infecções por HIV/imunologia , Soroprevalência de HIV , Hemofilia A/complicações , Hemofilia A/imunologia , Hemofilia A/terapia , Humanos , Modelos Logísticos , Masculino , Fatores de RiscoRESUMO
The relationship between hemophiliac immunodeficiency and exposures to factor VIII concentrate, LAV/HTLV-III retrovirus, and infection with Epstein-Barr virus and cytomegalovirus was examined. Exposure to factor VIII concentrate was significantly correlated with decreased percentages of T helper/inducer cells, decreased T helper/suppressor cell ratios, and decreased proliferative responses to plant mitogens. LAV/HTLV-III seropositivity was the primary predictor of increased percentages of HLA-DR-bearing mononuclear cells and decreased proliferative responses to pokeweed mitogen. Epstein-Barr virus and cytomegalovirus infections acted in a synergistic manner with LAV/HTLV-III to produce immunoregulatory defects. Increased percentages of T suppressor cells and decreased delayed cutaneous hypersensitivity skin test responses were observed in LAV/HTLV-III seropositive hemophiliacs infected with Epstein-Barr or cytomegalovirus. We conclude that hemophiliacs receiving commercial factor VIII concentrate experience several stepwise incremental insults to the immune system: alloantigens in factor VIII concentrate, LAV/HTLV-III infections, and herpesvirus infections.
Assuntos
Síndrome da Imunodeficiência Adquirida/transmissão , Fator VIII/imunologia , Hemofilia A/imunologia , Infecções por Herpesviridae/transmissão , Tolerância Imunológica , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/transmissão , Deltaretrovirus/imunologia , Contaminação de Medicamentos , Fator VIII/efeitos adversos , Herpesvirus Humano 4/imunologia , Humanos , Hipersensibilidade Tardia/imunologia , Contagem de Leucócitos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Testes Cutâneos , Linfócitos T Auxiliares-Indutores , Linfócitos T ReguladoresAssuntos
Síndrome da Imunodeficiência Adquirida/etiologia , Adulto , Doadores de Sangue , Fator VIII/efeitos adversos , Haiti/etnologia , Homossexualidade , Humanos , Masculino , Nova Zelândia , Pneumonia por Pneumocystis/complicações , Sarcoma de Kaposi/complicações , Linfócitos T/imunologia , Estados UnidosAssuntos
Síndrome da Imunodeficiência Adquirida , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/diagnóstico , Síndrome da Imunodeficiência Adquirida/etiologia , Criança , Fator VIII/efeitos adversos , Feminino , Hemofilia A/terapia , Humanos , Recém-Nascido , MasculinoAssuntos
Linfoma de Burkitt/etiologia , Fator VIII/efeitos adversos , Hemofilia A/terapia , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/transmissão , Criança , Diagnóstico Diferencial , Fator VIII/administração & dosagem , Humanos , Masculino , Neoplasias Mandibulares/diagnóstico , Neoplasias Mandibulares/etiologiaRESUMO
Two patients with hemophilia A had generalized lymphadenopathy, lymphopenia, elevated IgG values, depressed T4 (helper) lymphocytes, elevated T8 (suppressor) lymphocytes, and abnormally low T4/T8 ratios. One of the patients, who also had hepatosplenomegaly, underwent cervical lymph node biopsy; the node contained 43% T8-lymphocytes, a marked elevation over the small fraction of T8 cells usually found in lymph nodes. These patients may have a form of the acquired immune deficiency syndrome described in male homosexuals, Haitians, intravenous drug abusers, and recently, in patients with hemophilia. We studied T cell phenotypes in 43 patients with hemophilia. Fourteen of 28 patients given commercial factor VIII concentrates had abnormal T4/T8 ratios; none of nine patients who used cryoprecipitate had abnormal values. T4 helper cells were significantly lower, T8 suppressor cells significantly elevated, and T4/T8 ratios significantly lower in the lyophilized concentrate users and in patients with hemophilia as a total group. The type of therapeutic factor VIII replacement may alter the risk of developing T4/T8 abnormalities or AIDS.