RESUMO
AIM: To describe the prevalence and complications in babies ≤2 years with haemophilia. METHODS: We used a standardized collection tool to obtain consented data on eligible babies aged ≤2 years with haemophilia enrolled in the Centers for Disease Control and Prevention Universal Data Collection System surveillance project at US Hemophilia Treatment Centers (HTCs). RESULTS: Of 547 babies, 82% had haemophilia A, and 70% were diagnosed within one month of birth. Diagnosis was prompted by known maternal carrier status (40%), positive family history (23%), bleeding (35%) and unknown 2%; 81% bled during the first two years. The most common events were bleeding (circumcision, soft tissue, oral bleeding) and head injury. There were 46 episodes of intracranial haemorrhage (ICH) in 37 babies (7%): 18 spontaneous, 14 delivery related, 11 traumatic, 2 procedure related and 1 unknown cause. Of the 176 central venous access devices (CVADs) in 148 (27%) babies, there were 137 ports, 22 surgically inserted central catheters and 20 peripherally inserted central catheters. Ports had the lowest complication rates. Inhibitors occurred in 109 (20%) babies who experienced higher rates of ICH (14% vs. 5%; P = 0.002), CVAD placement (61% vs. 19%; P < 0.001) and CVAD complications (44% vs. 26%; P < 0.001). The most common replacement therapy was recombinant clotting factor concentrates. CONCLUSION: Bleeding events in haemophilic babies ≤2 years were common; no detectable difference in the rates of ICH by the mode of delivery was noted. Neonatal factor exposure did not affect the inhibitor rates. Minor head trauma, soft tissue and oropharyngeal bleeding were the leading indications for treatment.
Assuntos
Hemofilia A/complicações , Centers for Disease Control and Prevention, U.S. , Pré-Escolar , Coleta de Dados , Feminino , Hemofilia A/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Estados UnidosRESUMO
BACKGROUND: Inhibitor formation complicates haemophilia treatment and requires immune tolerance induction to rid inhibitors over 5 BU. In the prospective, randomized International Immune Tolerance Study, immune tolerance induction was equally effective with high-dose (HD) (200 IU kg-1 day-1 ) and low-dose (LD) (50 IU kg-1 3× per week) factor VIII, but haemorrhages were twofold higher in the LD arm. This finding was unexpected as inhibitors neutralize FVIII activity. We hypothesized that the thrombin generation assay (TGA), a global measure of clot formation, might predict bleeding better than FVIII levels. METHODS: We evaluated TGA using relipidated tissue factor (TF) on 83 thawed, recalcified corn trypsin inhibitor/citrate plasma samples from 31 subjects (17 HD, 14 LD) who participated on the ITI study, and who had sufficient sample available and appropriate informed consent. RESULTS: There were no significant differences in peak thrombin, estimated thrombin potential, maximum rate or lag time between HD and LD arms; between pre-, during and post-ITI time points, or after FVIII spiking. In 19 subjects (12 HD, 7 LD) with anti-FVIII<1.0 BU, the prevalence of non-neutralizing antibody (NNA) and neutralizing antibody (NA) was 89.5% (17/19), and the latter strongly correlated with anti-VIII titer, r = 0.73 [95% CI: 0.55, 0.88]. CONCLUSION: In haemophilia inhibitor patients, thrombin generation is present, but does not predict bleeding risk. Following tolerance induction, NNA remains detectable in the majority.
RESUMO
INTRODUCTION: Central venous access devices (CVADs) are frequently required as stable long-lasting venous access in children with haemophilia, especially those requiring immune tolerance induction (ITI) for inhibitors. CVAD infection is one of the most frequently reported catheter-related complications in this patient population. AIM: Detailed review of CVAD complications from the International ITI (I-ITI) study and analysis of potential risk factors for such complications. METHODS: Retrospective analysis of prospectively obtained data from the I-ITI study primarily focused on CVAD-related complications. RESULTS: A total of 115 children were recruited and 183 CVADs were placed in 99 subjects resulting in 121,206 CVAD-days observed on-study. A total of 124 CVAD infections were reported in 41 of 99 (41%) subjects with an overall infection rate of 0.94 per 1000 CVAD-days (interquartile ranges 0-1.7). A similar number of infections were observed in the two treatment arms (median: 2 and 3 in high dose and low dose respectively). Infections occurred more frequently in the presence of external catheters than with fully implanted catheters (P = 0.026). Infected patients were significantly younger at the time of CVAD insertion (median age: 22 vs. 25 months, P = 0.020). Patients with Gram-positive infections were also significantly younger than those with Gram-negative infections (median age: 17 vs. 25 months, P < 0.0001). CONCLUSION: CVAD infection was the most common complication observed in children with severe haemophilia and inhibitors in the frame of the I-ITI study. Younger age at CVAD insertion and external CVAD were associated with higher risk for infection. ITI outcome was unaffected by CVAD infections.
Assuntos
Anticorpos/imunologia , Cateterismo Venoso Central , Hemofilia A/imunologia , Tolerância Imunológica , Internacionalidade , Cateterismo Venoso Central/efeitos adversos , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Infecções Relacionadas à Prótese/etiologia , Fatores de Risco , Fatores de TempoRESUMO
Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII ≥ 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII ≥ 1 IU dL(-1) . Among subjects with FVII ≥ 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored.
Assuntos
Deficiência do Fator VII/diagnóstico , Hemorragia/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Deficiência do Fator VII/sangue , Deficiência do Fator VII/genética , Feminino , Fibrinólise , Hemorragia/sangue , Hemorragia/etiologia , Hemorragia/genética , Humanos , Masculino , Fenótipo , Estudos Prospectivos , Adulto JovemRESUMO
Clinical hip abnormalities, secondary to recurrent joint and/or muscle bleeding in persons with haemophilia, have not been well characterized and have the potential for significant morbidity. We aimed to examine the prevalence of clinical hip abnormalities in the US haemophilia population and to explore associations between these findings and putative risk factors. We conducted a study of hip abnormalities of 8192 subjects aged 2-69 years with haemophilia A and haemophilia B (54% of haemophilia A and haemophilia B are severe) currently enrolled in the Universal Data Collection (UDC) database. Associations between hip abnormality and type/severity of haemophilia A/B, current age, history of high-titre (≥ 5 BU) inhibitor (HTinh), concomitant ankle (AA) and knee arthropathy (KA), overweight and obesity and prophylaxis were examined using logistic regression. Overall prevalence of hip abnormality at the last recorded UDC visit for all subjects was 16.7%. Haemophilia A (aOR = 1.3, 1.0-1.4), severe haemophilia (aOR = 1.3, 1.0-1.5), a history of HTinh (aOR = 1.4, 1.1-1.7), and concomitant AA (aOR = 1.7, 1.4-1.9) were each independently associated with hip abnormality. Older age (45-69 years) was significantly associated with hip abnormality prevalence only in subjects with KA (aOR = 3.4, 1.9-5.9). The presence of overweight (aOR = 1.4, 1.1-1.8) and obesity (aOR = 2.1, 1.6-2.8) was associated with hip abnormality only among subjects without KA. Hip abnormality prevalence was not influenced by prophylaxis (aOR = 0.9, 0.8-1.1). These data suggest that hip abnormalities in US patients with haemophilia are associated with haemophilia severity and type, HTinh, concomitant AA and, depending on the presence or absence of KA, advancing age and obesity.
Assuntos
Hemofilia A/epidemiologia , Hemofilia B/epidemiologia , Quadril/anormalidades , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Bases de Dados Factuais , Humanos , Artropatias/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Índice de Gravidade de Doença , Adulto JovemRESUMO
Progress in the evidence-based care of haemophilia A and B worldwide has been historically challenged by the dearth of evaluable outcome data, including but not limited to the safety and effectiveness of therapeutic interventions. These challenges are partially rooted in the inherent difficulty of conducting prospective clinical trials and observational studies with statistically meaningful endpoints in a rare disease such as haemophilia. Despite the logistical barriers, the need for outcome data has never been more critical than in this time of expansive therapeutic advance tempered by the shrinking economic capacity to fund the rapidly increasing cost of treatment. Given that systematic analyses of published literature have been largely unsuccessful in compensating for the lack of rigorous and purposeful data collection, new approaches to clinical study design and statistical modelling are urgently needed. However, even as these are considered, the lack of broadly accepted and well-defined clinical outcome endpoints poses an additional barrier to progress. The three presentations encompassed by this paper highlight the timely need for quality data from the perspectives of the clinicians, regulatory agencies and health care funders, and describe the ongoing coordinated efforts by the international haemophilia community to further understand and dismantle the barriers to harmonized and standardized data collection on a global scale using well-defined clinical outcome endpoints.
Assuntos
Ensaios Clínicos como Assunto/métodos , Coagulantes/uso terapêutico , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Humanos , Cooperação Internacional , Avaliação de Resultados em Cuidados de Saúde/normasRESUMO
In patients with confirmed or suspected type 1 von Willebrand disease (VWD), adenotonsillectomy has been reported to be associated with a rate of peri-operative hemorrhage between 8 and 23%. Desmopressin acetate (DDAVP, 1-deamino 8-D arginine- vasopressin) is the treatment of choice for type 1 patients with baseline von Willebrand factor levels of 10 IU/dL or greater. DDAVP is generally well tolerated; however, severe hyponatremia and seizures have been reported in young children less than 2 years of age, limiting its use in this age group. Antifibrinolytic therapy plays an important adjunctive role in the effective treatment of mucocutaneous bleeding, particularly in the oropharynx where the salivary concentration of fibrinolytic enzymes is high. During the past 10 years, we treated 6 pediatric patients with mild/moderate type 1 VWD undergoing an adenotonsillar procedure at our institution with the same hemostatic regimen consisting of one single dose of DDAVP and an extended use of EACA. In this small case series, the above mentioned prophylactic treatment regimen was both well tolerated and efficacious in controlling hemorrhage. Furthermore, DDAVP-related complications were avoided in a pediatric population with a higher risk of developing them.
Assuntos
Adenoidectomia , Ácido Aminocaproico/administração & dosagem , Antifibrinolíticos/administração & dosagem , Desamino Arginina Vasopressina/administração & dosagem , Hemostáticos/administração & dosagem , Hemorragia Pós-Operatória/prevenção & controle , Tonsilectomia , Doença de von Willebrand Tipo 1/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Preparações de Ação Retardada/administração & dosagem , Feminino , Humanos , Lactente , Infusões Intravenosas , Masculino , Estudos RetrospectivosRESUMO
Severe factor XI (sFXI) deficiency is a rare bleeding disorder (RBD). FXI replacement is most often required for surgical hemostasis. Plasma, the sole US treatment option, is often complicated by life-threatening allergic reactions. In such circumstances, the FDA offers a mechanism for institution-industry collaboration to facilitate limited use of replacement products licensed abroad. A 58 years old man with sFXI deficiency, required hip replacement. In the past, he received prophylactic plasma for thyroidectomy and experienced a severe allergic reaction. A single use institutional IND FDA application was initiated in collaboration with LFB (Les Ulis, France) to access Hemoleven®, a plasma-derived FXI concentrate. The application required an investigator-initiated IRB-approved protocol for treatment and safety/efficacy monitoring that included: preoperative thrombophilia, FXI inhibitor and pharmacokinetic (PK) evaluations; peri- postoperative administration of ≤ 4 doses of 10-15 U/kg Hemoleven® ; DIC monitoring; postoperative thromboprophylaxis; observation for product efficacy and potential complications. PK study demonstrated the expected 1.8% FXI recovery per U/kg with half-life of 62 hours. Mild D-Dimer elevation was noted 6-9 hours post-infusion. The initial dose (15 U/kg) was administered 15 hours before surgery; subsequently, 3 doses (10 U/kg) were infused every 72 hours. Hemostasis was excellent. No complications were observed. Collaboration allowed for successful patient access to Hemoleven® with excellent PK, safety, and efficacy. This case underscores the need for additional efforts to ensure safe and effective licensed replacement therapies for RBD patients.
Assuntos
Anticoagulantes/uso terapêutico , Artroplastia de Quadril , Deficiência do Fator XI/tratamento farmacológico , Fator XI/uso terapêutico , Artroplastia de Quadril/métodos , Perda Sanguínea Cirúrgica/prevenção & controle , Hemostasia Cirúrgica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Cranial haemorrhage (CH) is a potentially serious complication in patients with severe congenital haemophilia with inhibitors (CHwI). Treatment includes bypassing agents, such as recombinant activated factor VII (rFVIIa). To examine the US experience in treating CH with rFVIIa, a retrospective review of the Hemophilia and Thrombosis Research Society 2004-2008 database was conducted. Among 29 patients with CHwI, 56 of the reported haemorrhages met the study criteria. Of these, 75% were traumatic and 80% were extracranial (ECH). The majority (8/11, 73%) of intracranial haemorrhages (ICHs) developed spontaneously. Conversely, most ECHs (39/45, 87%) followed trauma. ICHs were treated with a median/mean of 23/58 rFVIIa infusions over a median/mean of 7/9 days while ECHs were treated with a median/mean of 1/3 infusions (P = 0.011) over a median/mean of 1/1 day. The median/mean initial rFVIIa doses for all CHs were 106/137 microg kg(-1), and were similar for ICHs and ECHs. All ECHs were effectively controlled with rFVIIa; 44/45 bleeds were controlled within 24 h, one bleed was successfully treated perioperatively, and 27 ECHs required only a single dose. Nine out of 11 ICHs were effectively treated with rFVIIa; six ICHs were controlled within 24 h, one within 72 h and in two cases haemostasis was achieved during the perioperative period. No serious treatment-associated adverse events were reported. One patient died as a result of ICH despite the reported control of bleeding. In conclusion, standard dosing of rFVIIa was found to be safe and effective in treating CH with an efficacy rate of 100% for ECH and 82% for ICH.
Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Fator VIIa/uso terapêutico , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemofilia B/complicações , Hemofilia B/tratamento farmacológico , Hemorragia/tratamento farmacológico , Adolescente , Adulto , Inibidores dos Fatores de Coagulação Sanguínea/análise , Criança , Pré-Escolar , Humanos , Lactente , Hemorragias Intracranianas/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Sistema de Registros , Adulto JovemRESUMO
BACKGROUND: Although fibrinogen concentrate has been available for the treatment of congenital fibrinogen deficiency for years, knowledge of its pharmacokinetics comes from only two small studies. OBJECTIVES: To assess the pharmacokinetic (PK) profile, clot integrity and safety of fibrinogen concentrate (human) (FCH) in patients with afibrinogenemia. PATIENTS AND METHODS: A multinational, prospective, open-label, uncontrolled study of patients with afibrinogenemia > or = 6 years of age was conducted in the USA and Italy. Plasma was collected before and after infusion for PK analyses and evaluation by rotational thromboelastometry of maximum clot firmness (MCF) to assess clot integrity. Safety was assessed on the basis of adverse events and laboratory parameters. RESULTS: After a single dose of 70 mg kg(-1) body weight (b.w.) FCH in 14 patients, median incremental in vivo recovery was a 1.7 mg dL(-1) increase per mg kg(-1) b.w., and median levels were 1.3 g L(-1) for fibrinogen activity and antigen 1 h after infusion. Median half-life (t(1/2)) was 77.1 h for fibrinogen activity and 88.0 h for antigen. Plasma recovery in children < 16 years old was similar to that in adults aged 16 to < 65 years, but the t(1/2) and area under the curve were decreased, with an increased steady-state volume and clearance. MCF increased by a mean of 8.9 mm from baseline to 1 h after infusion of FCH (P < 0.0001). All four adverse events reported were mild, and none was serious or related to study drug. CONCLUSIONS: These PK findings confirm a rapid increase in plasma fibrinogen levels after infusion with FCH. Together with the clot integrity and safety data and published data on efficacy, the results support the idea that FCH substitution can restore hemostasis with a good safety profile.
Assuntos
Afibrinogenemia/tratamento farmacológico , Fibrinogênio/farmacocinética , Adolescente , Adulto , Fatores Etários , Testes de Coagulação Sanguínea , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Fibrinogênio/efeitos adversos , Fibrinogênio/uso terapêutico , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Farmacocinética , Tromboelastografia , Estados Unidos , Adulto JovemRESUMO
Lack of detailed natural history and outcomes data for neonates and toddlers with haemophilia hampers the provision of optimal management of the disorder. We report an analysis of prospective data collected from 580 neonates and toddlers aged 0-2 years with haemophilia enrolled in the Universal Data Collection (UDC) surveillance project of the Centers for Disease Control and Prevention (CDC). This study focuses on a cohort of babies with haemophilia whose diagnosis was established before the age of two. The mode of delivery, type and severity of haemophilia, onset and timing of haemorrhages, site(s) of bleeding, provision of prophylaxis with coagulation factor replacement therapy, and the role played by the federally funded Haemophilia Treatment Centers (HTC) in the management of these infants with haemophilia were evaluated. Seventy-five per cent of haemophilic infants were diagnosed early, in the first month of life, especially those with a family history or whose mothers were known carriers; infants of maternal carriers were more likely to be delivered by C-section. Involvement of an HTC prior to delivery resulted in avoidance of the use of assisted deliveries with vacuum and forceps. Bleeding from the circumcision site was the most common haemorrhagic complication, followed by intra- and extra-cranial haemorrhages and bleeding from heel stick blood sampling. Eight per cent of the infants were administered factor concentrate within 24 h of birth; more than half were treated to prevent bleeding. This study highlights the significant rate and the sites of initial bleeding unique to very young children with haemophilia and underscores the need for research to identify optimal evidence-based recommendations for their management.
Assuntos
Parto Obstétrico , Hemofilia A/diagnóstico , Hemorragias Intracranianas/epidemiologia , Idade de Início , Pré-Escolar , Medicina Baseada em Evidências , Feminino , Hemofilia A/epidemiologia , Humanos , Lactente , Recém-Nascido , Hemorragias Intracranianas/prevenção & controle , Masculino , Gravidez , Estudos Prospectivos , Estados Unidos/epidemiologiaRESUMO
The North American Immune Tolerance Registry (NAITR) began in 1992 as a project of the ISTH Factor VIII/IX Subcommittee with the goal of further determining immune tolerance induction (ITI) practices in Canada and the United States. This retrospective registry study, published in 2002, was limited in its capacity to provide definitive answers to many unresolved ITI practice issues. Nonetheless, it played a role in developing guidelines for current ITI practice and in generating hypotheses that must now be examined through rigorous prospective data collection efforts. For haemophilia A, the logical next step has been the initiation of international prospective randomized studies of ITI outcome relative to factor VIII (FVIII) dose and purity for subjects with high titre inhibitors. Both trials will additionally provide platforms for translational study of the immunology of tolerance, a prelude to the next generation of safe and effective tolerizing strategies. For the less common problem of FIX inhibitor eradication, prospective randomized studies will not be a feasible way to confirm the NAITR observations. Coordinated international efforts will still be required to prospectively collect data on ITI outcome to document new potentially effective therapeutic strategies for inhibitor eradication. These registries will hopefully also serve to identify potential subjects for scientific studies of immunology of haemophilia B-related allergic phenomena, a devastating complication of FIX antibody development.
Assuntos
Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Sistema de Registros , Fator IX/imunologia , Fator VIII/imunologia , Hemofilia A/imunologia , Hemofilia B/imunologia , Humanos , Isoanticorpos/sangue , Masculino , América do Norte , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: Recurrent hemarthroses in hemophilia results in synovitis and joint arthropathy. Primary prophylaxis when universally instituted at current doses can prevent joint deterioration but is expensive. Alternatively, the selective implementation of prophylaxis would require a more sensitive tool for detecting synovitis than possible with clinical surveillance or plain radiographs. Magnetic resonance imaging (MRI) is such a tool and is utilized for the evaluation of hemophilic joint disease (HJD). However, it is expensive, and requires sedation in younger children precluding its utility for monitoring of synovitis. Ultrasonography (USG) with power Doppler (USG-PDS) has been utilized to detect and quantitate synovial vascularity in other arthritides and could provide an equally effective but less costly tool for HJD, particularly in children who would not require sedation. OBJECTIVES: To determine whether USG-PDS is comparable to MRI in the evaluation of hemophilic synovitis. PATIENTS: A prospective cohort of 31 subjects including 33 joints (knees, elbows, ankles) underwent dynamic contrast enhanced (DCE)-MRI and USG-PDS. RESULTS: USG-PDS measurements of synovial thickness(r = 0.70, P < 0.0001) and synovial vascularity (r = 0.73, P < 0.0001) correlated strongly with those obtained with DCE-MRI. A cutoff of PDS intensity of 1.3 decibels (dB) per mm(2) was found to yield a sensitivity of 100% and a specificity of 94.1% in 17 joints with/without a history of hemarthroses. Pettersson radiographic scores correlated significantly with synovial thickness in adults but not children. CONCLUSIONS: Our data suggest that USG-PDS may be an inexpensive and easily implemented imaging tool for detecting hemophilic synovitis and could be useful in tailoring effective prophylaxis.
Assuntos
Hemartrose/complicações , Hemofilia A/complicações , Sinovite/diagnóstico por imagem , Ultrassonografia Doppler/métodos , Adolescente , Adulto , Criança , Diagnóstico por Imagem/métodos , Diagnóstico por Imagem/normas , Humanos , Articulações/diagnóstico por imagem , Articulações/patologia , Imageamento por Ressonância Magnética , Sinovite/diagnóstico , Ultrassonografia Doppler/economia , Ultrassonografia Doppler/normas , Adulto JovemRESUMO
Painful controversy has so far been largely absent from the history of haemophilia-related clinical research. However, the investigative methods now needed to realize evidence-based clinical practice, therapeutic advance, and a progressive standard of care for patients worldwide will be accompanied by the potential for ethical dilemma and transgression. From the current vantage point, three primary ethical issues merit special consideration: (i) the therapeutic misconception inherent to all clinical research and the randomized trial in particular; (ii) high risk and potentially non-beneficial novel technology research in children; and (iii) a collaborative partnership approach to research in the developing world. This study will focus on a discussion of each of these, drawing from the research ethics literature to offer a potential template for future deliberations in clinical trial design.
Assuntos
Pesquisa Biomédica/ética , Técnicas de Transferência de Genes/ética , Hemofilia A/terapia , Experimentação Humana/ética , Consentimento Livre e Esclarecido/ética , Temas Bioéticos , Pesquisa Biomédica/tendências , Criança , Medicina Baseada em Evidências , Técnicas de Transferência de Genes/tendências , Terapia Genética/ética , Hemofilia A/complicações , Humanos , Consentimento Livre e Esclarecido/legislação & jurisprudência , Seleção de Pacientes/ética , Ensaios Clínicos Controlados Aleatórios como Assunto/normasRESUMO
Surgery in infants and young children with haemophilia, when preceded by accurate diagnosis and accompanied by safe and effective factor prophylaxis, is not associated with a significant risk of haemorrhage. Haemophilic newborns undergoing circumcision or major surgery prior to diagnosis and in the absence of appropriate haemostatic prophylaxis remain as a concern. Inhibitor development has replaced haemorrhage as the major surgical complication in the developed world, largely because of the intensity of treatment used to secure haemostasis. For that reason only, essential surgery should be performed. Intracranial haemorrhage (ICH) during the neonatal period affects 3.5-4.0% of all haemophilia boys in countries with a good standard of health care, which is considerably (40-80 times) higher than expected in the normal population. Because of the high frequency of sporadic cases, ICH in the neonatal period can only be partially prevented by improved carrier diagnosis and counselling. Infections and thrombosis are the major serious complications of central venous lines. Large differences are seen in the frequency of these complications, the most plausible explanations are probably related to the protocol used for device care, the quality of education and the compliance of the users, an issue addressed in an on-going study.
Assuntos
Hemartrose/complicações , Hemofilia A/complicações , Hemorragias Intracranianas/prevenção & controle , Trombose/prevenção & controle , Cateterismo Venoso Central/métodos , Pré-Escolar , Circuncisão Masculina/efeitos adversos , Fator IX/uso terapêutico , Fator VIII/uso terapêutico , Testes Genéticos , Hemartrose/tratamento farmacológico , Hemartrose/cirurgia , Hemofilia A/tratamento farmacológico , Hemofilia A/cirurgia , Humanos , Lactente , Recém-Nascido , Hemorragias Intracranianas/epidemiologia , Masculino , Fatores de RiscoRESUMO
Factor VIII (FVIII) inhibitors remain a serious complication of treatment for patients with haemophilia A. Immune tolerance induction (ITI) can eliminate inhibitors in the majority of patients, but there are major concerns related with this therapy. Investigators have raised the possibility that the use of FVIII/von Willebrand factor (FVIII/VWF) concentrates may improve the success rate of ITI and may shorten the duration of therapy necessary to attain tolerance. This retrospective study describes 25 patients at five institutions in the USA, who were treated with FVIII/VWF concentrate as part of their ITI. These were all patients who were considered poor prognosis because of clinical and laboratory characteristics, which made ITI less likely to be successful or because of a poor response to initial ITI with a monoclonal/recombinant FVIII concentrate. Overall success (complete tolerization) was 32% with another 40% attaining partial tolerization, but not complete tolerization. Of those patients attaining only partial tolerization, two patients ultimately discontinued ITI and had return of their high titre inhibitors. Eight percent of patients failed to attain either partial or complete tolerization and discontinued ITI. Another 24% are continuing with ITI but have titres of >10 BU. This study adds further retrospective data to the information regarding the use of FVIII/VWF concentrate in ITI.
Assuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Fator de von Willebrand/uso terapêutico , Anticorpos/sangue , Criança , Pré-Escolar , Hemofilia A/imunologia , Humanos , Lactente , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Fibrinogen, a hexameric glycoprotein encoded by three genes - FGA, FGB, FGG - clustered on chromosome 4q is involved in the final steps of coagulation as a precursor of fibrin monomers required for the formation of the haemostatic plug. Inherited disorders of fibrinogen abnormalities are rare and not as well clinically characterized as some other inherited bleeding disorders. To characterize the clinical manifestations, molecular defects and treatment modalities of these rare disorders, a Medline search from January 1966 to September 2007 for these disorders reported in large studies and registries was undertaken. Inherited fibrinogen disorders can manifest as quantitative defects (afibrinogenemia and hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Quantitative fibrinogen deficiencies may result from mutations affecting fibrinogen synthesis, or processing while qualitative defects are caused by mutations causing abnormal polymerization, defective cross-linking or defective assembly of the fibrinolytic system. Clinical manifestations vary from being asymptomatic to developing catastrophic life-threatening bleeds or thromboembolic events. Management of bleeds includes use of purified plasma-derived concentrates, cryoprecipitate or fresh frozen plasma. Use of some of these products carries risks of viral transmission, antibody development and thromboembolic events. Establishment of registries in Iran, Italy and North America has fostered a better understanding of these disorders with an attempt to explore molecular defects. Rare Bleeding Disorder Registries developed through the United States and international efforts hopefully will encourage development and licensure of safer, effective products.
Assuntos
Afibrinogenemia/genética , Fibrinogênio/genética , Mutação , Complicações Hematológicas na Gravidez/genética , Adulto , Afibrinogenemia/sangue , Afibrinogenemia/diagnóstico , Afibrinogenemia/tratamento farmacológico , Afibrinogenemia/epidemiologia , Coagulação Sanguínea/genética , Coagulantes/administração & dosagem , Fator VIII/administração & dosagem , Feminino , Fibrinogênio/administração & dosagem , Fibrinogênio/química , Fibrinogênio/metabolismo , Genótipo , Hemorragia/tratamento farmacológico , Hemorragia/genética , Humanos , Recém-Nascido , Irã (Geográfico)/epidemiologia , Itália/epidemiologia , MEDLINE , Masculino , América do Norte/epidemiologia , Fenótipo , Gravidez , Complicações Hematológicas na Gravidez/terapia , Diagnóstico Pré-Natal , Doenças Raras/genéticaRESUMO
A retrospective chart review of 11 subjects with severe haemophilia A and high-titre inhibitors who received a von Willebrand factor-containing FVIII concentrate (VWF/FVIII) for immune tolerance induction (ITI) was accompanied by B cell inhibitor epitope mapping during 10/11 treatment courses. ITI was successful or partially successful in all seven subjects who received VWF/FVIII for initial ITI, and failed in all four subjects whose ITI with this product was initiated following treatment failure using recombinant factor VIII. Variables including age at inhibitor development and age at ITI initiation, interval between inhibitor detection and ITI initiation, titre at start of ITI, and peak historical titres prior to and during ITI were not statistically significant outcome predictors in this cohort. However, the B cell epitope specificity in all four successful and in one of two partially successful ITI subjects for whom information was available included the C2 and excluded the A2 domains. Conversely, FVIII B cell epitopes in one partially successful ITI and in all three failed ITI subjects for whom data were available mapped to both the C2 and the A2 domains. The FVIII B cell epitope profile was associated with ITI outcome in this VWF/FVIII-treated cohort. Its role in predicting ITI outcome and guiding choice of FVIII product for ITI requires further study.
Assuntos
Autoanticorpos/sangue , Fator VIII/imunologia , Hemofilia A/tratamento farmacológico , Hemofilia A/imunologia , Hemostáticos/uso terapêutico , Fator de von Willebrand/uso terapêutico , Adolescente , Adulto , Linfócitos B/imunologia , Criança , Pré-Escolar , Combinação de Medicamentos , Mapeamento de Epitopos , Epitopos/análise , Fator VIII/uso terapêutico , Genótipo , Hemofilia A/genética , Humanos , Tolerância Imunológica , Lactente , Recém-Nascido , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Although immune tolerance induction (ITI) has been used for 30 years to eliminate inhibitors and restore normal factor pharmacokinetics in patients with hemophilia, there is a paucity of scientific evidence to guide therapeutic decision-making. In an effort to provide direction for physicians and hemophilia treatment center staff members, an international panel of hemophilia opinion leaders met to develop consensus recommendations for ITI in patients with severe and mild hemophilia A and hemophilia B. These recommendations draw on the available published literature and the collective clinical experience of the group and are rated based on the level of supporting evidence.