RESUMO
The high-specific-activity factor IX (FIX) variant Padua (R338L) is the most promising transgene for hemophilia B (HB) gene therapy. Although R338 is strongly conserved in mammalian evolution, amino acid substitutions at this position are underrepresented in HB databases. We therefore undertook a complete 20 amino acid scan and determined the specific activity of human (h) and canine (c) FIX variants with every amino acid substituted at position 338. Notably, we observe that hFIX-R338L is the most active variant and cFIX-R338L is sevenfold higher than wild-type (WT) cFIX. This is consistent with the previous identification of hFIX-R338L as a cause of a rare X-linked thrombophilia risk factor. Moreover, WT hFIX and cFIX are some of the least active variants. We confirmed the increased specific activity relative to FIX-WT in vivo of a new variant, cFIX-R338I, after gene therapy in an HB dog. Last, we screened 232 pediatric subjects with thromboembolic disease without identifying F9 R338 variants. Together these observations suggest a surprising evolutionary pressure to limit FIX activity with WT FIX rather than maximize FIX activity.
Assuntos
Fator IX , Hemofilia B , Animais , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Criança , Cães , Fator IX/genética , Terapia Genética , Hemofilia B/genética , Hemofilia B/terapia , HumanosRESUMO
OBJECTIVE: To describe the off-label use of recombinant factor VIIa (rFVIIa) in tertiary care pediatric hospitals across the United States and to assess thrombotic events. STUDY DESIGN: A retrospective multi-center cohort study using the Pediatric Health Information System administrative database. Children 18 years of age or younger who received rFVIIa between 2000 and 2007 were included. A label admission was defined as an admission with an International Classification of Diseases diagnostic code for hemophilia or factor VII deficiency; admissions without these codes were classified as off-label. RESULTS: There were 4942 rFVIIa admissions, representing 3764 individual subjects; 74% (3655) of the admissions were off-label. There was a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007 (from 2 to 20.8 per 10 000 hospital admissions, P < .001). The mortality rate in the off-label group was 34% (1258/3655). Thrombotic events occurred in 10.9% (399/3655) of the off-label admissions. CONCLUSIONS: The off-label use of rFVIIa in hospitalized children is increasing rapidly despite the absence of adequate clinical trials demonstrating safety and efficacy. Thrombotic events are common and mortality is high among patients receiving off-label rFVIIa. Further studies are warranted to determine whether these adverse events are attributable to rFVIIa.
Assuntos
Fator VIIa/efeitos adversos , Hemofilia A/tratamento farmacológico , Uso Off-Label , Trombose/epidemiologia , Adolescente , Criança , Pré-Escolar , Fator VIIa/uso terapêutico , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Trombose/induzido quimicamente , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: To review the incidence of postoperative bleeding in children with type 1 von Willebrand disease (VWD) who were treated with a single institution protocol. STUDY DESIGN: We performed a retrospective study to determine the postoperative hemorrhage rate in pediatric patients with type 1 VWD who were treated via the Children's Hospital of Philadelphia institutional protocol. This protocol utilizes intravenous desmopressin (DDAVP), oral aminocaproic acid, and overnight observation. RESULTS: Between the years of 2000 to 2006, 41 children with type 1 VWD underwent an adenotonsillar procedure and were treated with this protocol. Seven patients (17%) experienced delayed (>24 hours after surgery) postoperative hemorrhage requiring intervention. Five of the 7 patients required cautery to control the bleeding, and the remaining 2 patients responded to DDAVP and aminocaproic acid alone. Older age and lower VW antigen levels were associated with postoperative hemorrhage (P = .05). CONCLUSIONS: Despite therapeutic intervention to decrease the risk of postoperative hemorrhage, the incidence of hemorrhage was higher in pretreated patients with type 1 VWD than in children without bleeding disorders. Further prospective studies are necessary to determine the optimal treatment to reduce bleeding complications in these patients.
Assuntos
Adenoidectomia , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/prevenção & controle , Tonsilectomia , Doenças de von Willebrand/epidemiologia , Administração Oral , Adolescente , Fatores Etários , Aminocaproatos/uso terapêutico , Cauterização , Criança , Pré-Escolar , Desamino Arginina Vasopressina/uso terapêutico , Feminino , Hemostáticos/uso terapêutico , Humanos , Infusões Intravenosas , Masculino , Náusea e Vômito Pós-Operatórios/epidemiologia , Estudos Retrospectivos , Doenças de von Willebrand/imunologia , Fator de von Willebrand/análise , Fator de von Willebrand/imunologiaRESUMO
OBJECTIVE: To compare the prevalence of frequent headache in children with sickle cell disease (SCD) to that of black control subjects and to assess factors associated with headache in SCD. STUDY DESIGN: In this cross-sectional study, a headache questionnaire was administered to subjects with SCD and black control subjects. Subjects answered supplementary questions about SCD complications. Clinical and radiographic information were abstracted from medical charts for subjects with SCD. RESULTS: Children (n = 241) with SCD and 141 control subjects were studied; 32.4% (95% CI 26.5%-38.7%) of subjects with SCD reported having headaches at least weekly, similar to control subjects at 27% (95% CI 19.8%-35.1%, P = NS); however, in children <13 years, headache was more common in subjects with SCD than in control subjects (24% vs 9.7%, P = .013). The prevalence of headache was similar among the different SCD genotypes. Factors associated with frequent headaches in subjects with SCD included older age, frequent vaso-occlusive pain episodes, symptoms of obstructive sleep apnea, and cerebral vessel stenosis detected by magnetic resonance angiography. CONCLUSION: The prevalence of headaches in children with SCD is similar to the general population; however, younger children with SCD report headaches more frequently than control subjects. The cause of headache is likely multifactorial, and SCD-specific factors may contribute.
Assuntos
Anemia Falciforme/epidemiologia , Cefaleia/diagnóstico , Cefaleia/epidemiologia , Adolescente , Distribuição por Idade , Análise de Variância , Anemia Falciforme/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Comorbidade , Estudos Transversais , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/epidemiologia , Medição da Dor , Prevalência , Probabilidade , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Distribuição por SexoRESUMO
OBJECTIVE: To evaluate risk factors for recurrent thrombosis in pediatric patients. STUDY DESIGN: This prospective observational cohort study enrolled 120 patients with acute venous thromboembolism from January 2003 to April 2005. Data collection included medical and family history, radiologic and laboratory studies, therapy, and follow-up. RESULTS: The overall prevalence of recurrent thrombosis in our cohort was 19/120 (15.8%). Patients with recurrence were older, with a median age of 14.8 years (range 2 weeks-23.6 years), compared with 10.1 years (range newborn 23.4 years) in patients without recurrence (P = .03). Six of the 19 patients with recurrent thrombosis had cystic fibrosis (CF), compared with 0/101 without recurrence (P < .001). Five of these 6 patients were colonized with Burkholderia cepacia in their sputum. Central venous catheters were associated with most, but not all, of the thromboses in patients with CF. CONCLUSIONS: In this study, patients with CF had a high risk of recurrent venous thrombosis, as well as a high prevalence of colonization with B cepacia. The cause of this risk has not been defined. This observation may have important implications for thromboprophylaxis, particularly in the setting of central venous catheters.