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Pediatric B-acute lymphoblastic leukemia (B-ALL) is a disease of abnormally growing B lymphoblasts. Here we hypothesized that extracellular vesicles (EVs), which are nanosized particles released by all cells (including cancer cells), could be used to monitor B-ALL severity and progression by sampling plasma instead of bone marrow. EVs are especially attractive as they are present throughout the circulation regardless of the location of the originating cell. First, we used nanoparticle tracking analysis to compare EVs between non-cancer donor (NCD) and B-ALL blood plasma; we found that B-ALL plasma contains more EVs than NCD plasma. We then isolated EVs from NCD and pediatric B-ALL peripheral blood plasma using a synthetic peptide-based isolation technique (Vn96), which is clinically amenable and isolates a broad spectrum of EVs. RNA-seq analysis of small RNAs contained within the isolated EVs revealed a signature of differentially packaged and exclusively packaged RNAs that distinguish NCD from B-ALL. The plasma EVs contain a heterogenous mixture of miRNAs and fragments of long non-coding RNA (lncRNA) and messenger RNA (mRNA). Transcripts packaged in B-ALL EVs include those involved in negative cell cycle regulation, potentially suggesting that B-ALL cells may use EVs to discard gene sequences that control growth. In contrast, NCD EVs carry sequences representative of multiple organs, including brain, muscle, and epithelial cells. This signature could potentially be used to monitor B-ALL disease burden in pediatric B-ALL patients via blood draws instead of invasive bone marrow aspirates.
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BACKGROUND: Meta-iodobenzylguanidine(MIBG) scans are used to detect neuroblastoma metastatic lesions at diagnosis and during posttreatment surveillance. MIBG positivity following induction chemotherapy correlates with poor outcome; however, there are reports of patients with progression-free survival despite MIBG positivity at the end of therapy. The factors distinguishing these survivors from patients who progress or relapse are unclear. FDG-positron-emission tomography (PET) scans can also detect metastatic lesions at diagnosis; however, their role in posttherapy surveillance is less well studied. METHODS: We performed a retrospective analysis of International Neuroblastoma Staging System (INSS) stage 4 patients to identify those with residual MIBG-avid metastatic lesions on end-of-therapy scans without prior progression. Data collected included age, disease sites, histopathology, biomarkers, treatment, imaging studies, and response. RESULTS: Eleven of 265 patients met inclusion criteria. At diagnosis three of 11 patients were classified as intermediate and eight of 11 high risk; nine of 11 had documented marrow involvement. Histologic classification was favorable for four of 10 and MYCN amplification was detected in zero of 11 cases. The median time with persistent MIBG positivity following treatment was 1.5 years. Seven patients had at least one PET scan with low or background activity. Biopsies of three of three MIBG-avid residual lesions showed differentiation. All patients remain alive with no disease progression at a median of 4.0 years since end of therapy. CONCLUSION: Persistently MIBG-avid metastatic lesions in subsets of patients following completion of therapy may not represent active disease that will progress. Further studies are needed to determine whether MYCN status or other biomarkers, and/or PET scans, may help identify patients with residual inactive MIBG lesions who require no further therapy.
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Neoplasias Primarias Secundarias , Neuroblastoma , 3-Yodobencilguanidina , Guanidina/uso terapéutico , Humanos , Proteína Proto-Oncogénica N-Myc , Recurrencia Local de Neoplasia , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/terapia , Tomografía de Emisión de Positrones/métodos , Estudios RetrospectivosRESUMEN
Extracellular vesicles (EVs) are nanosized membrane-bound particles released from all living cells examined thus far. EVs can transfer information in the form of proteins, nucleic acids, and lipids from donor cells to recipient cells. Here we summarize recent advances in understanding the role(s) EVs play in hematological malignancies (HM) and outline potential prognostic and diagnostic strategies using EVs. EVs have been shown to promote proliferation and angiogenesis, and alter the bone marrow microenvironment to favour the growth and survival of diverse HM. They also promote evasion of anti-cancer immune responses and increase multi-drug resistance. Using knowledge of EV biology, including HM-specific packaging of cargo, EV based diagnostics and therapeutic approaches show substantial clinical promise. However, while EVs may represent a new paradigm to solve many of the challenges in treating and/or diagnosing HM, much work is needed before they can be used clinically to improve patient outcomes.
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Vesículas Extracelulares/metabolismo , Neoplasias Hematológicas/metabolismo , Transporte Biológico , Biomarcadores , Médula Ósea/metabolismo , Médula Ósea/patología , Comunicación Celular , Resistencia a Antineoplásicos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/etiología , Neoplasias Hematológicas/terapia , Humanos , Neovascularización Patológica/metabolismo , Pronóstico , Microambiente TumoralRESUMEN
We report a newborn with hemolytic disease of the fetus and newborn (HDFN) with rapid resolution of extreme hyperferritinemia without chelation. An infant born at 35+3 weeks with HDFN and a history of 3 intrauterine transfusions developed severe hyperferritinemia (maximum, 8258 mcg/L) without evidence of toxic iron deposition on liver biopsy. Her hyperferritinemia was managed with observation alone, and ferritin levels normalized rapidly. This case supports observation as being the preferred alternative to chelation therapy for significant hyperferritinemia in newborns with HDFN in the absence of demonstrated toxic end-organ iron deposition. We also include a review of the related available literature.
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Terapia por Quelación/métodos , Eritroblastosis Fetal/fisiopatología , Feto/efectos de los fármacos , Hemólisis , Hiperferritinemia/tratamiento farmacológico , Transfusión de Sangre Intrauterina , Tratamiento Conservador , Manejo de la Enfermedad , Femenino , Humanos , Hiperferritinemia/etiología , Hiperferritinemia/patología , Recién Nacido , Embarazo , PronósticoRESUMEN
The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is a major complication of hemophilia A treatment. The sole clinical therapy to restore FVIII tolerance in patients with inhibitors remains immune tolerance induction (ITI) which is expensive, difficult to administer and not always successful. Although not fully understood, the mechanism of ITI is thought to rely on inhibition of FVIII-specific B cells (1). Its efficacy might therefore be improved through more aggressive B cell suppression. FcγRIIB is an inhibitory Fc receptor that down-regulates B cell signaling when cross-linked with the B cell receptor (BCR). We sought to investigate if recombinant FVIII Fc (rFVIIIFc), an Fc fusion molecule composed of FVIII and the Fc region of immunoglobulin G1 (IgG1) (2), is able to inhibit B cell activation more readily than FVIII. rFVIIIFc was able to bind FVIII-exposed and naïve B cells from hemophilia A mice as well as a FVIII-specific murine B cell hybridoma line (413 cells). An anti-FcγRIIB antibody and FVIII inhibited binding, suggesting that rFVIIIFc is able to interact with both FcγRIIB and the BCR. Furthermore, incubation of B cells from FVIII-exposed mice and 413 cells with rFVIIIFc resulted in increased phosphorylation of SH-2 containing inositol 5-phosphatase (SHIP) when compared to FVIII. B cells from FVIII-exposed hemophilia A mice also exhibited decreased extracellular signal-regulated kinase (ERK) phosphorylation when exposed to rFVIIIFc. These differences were absent in B cells from naïve, non-FVIII exposed hemophilic mice suggesting an antigen-dependent effect. Finally, rFVIIIFc was able to inhibit B cell calcium flux induced by anti-Ig F(ab)2. Our results therefore indicate that rFVIIIFc is able to crosslink FcγRIIB and the BCR of FVIII-specific B cells, causing inhibitory signaling in these cells.
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Linfocitos B/inmunología , Factor VIII/inmunología , Activación de Linfocitos/inmunología , Receptores Fc/inmunología , Receptores de IgG/efectos de los fármacos , Proteínas Recombinantes de Fusión/farmacología , Animales , Linfocitos B/efectos de los fármacos , Hemofilia A , Fragmentos Fc de Inmunoglobulinas/inmunología , Activación de Linfocitos/efectos de los fármacos , Ratones , Receptores de IgG/inmunología , Proteínas Recombinantes de Fusión/inmunologíaRESUMEN
BACKGROUND: With significant improvements in the survival rates for most childhood cancers, there is increased pressure to determine how follow-up or aftercare for survivors is best structured. MAIN BODY: Previous work in this area has not been consistent in how it categorizes models of aftercare, which risks confusion between studies and evaluations of different models. The adoption of a standardized method for classifying and describing different models of aftercare is necessary in order to maximize the applicability of the available evidence. We identify some of the different ways models of aftercare have been classified in previous research. We then propose a revised taxonomy which allows for a more consistent classification and description of these models. The proposed model bases the classification of models of aftercare on who is the lead provider, and then collects data on five other key features: which other providers are involved in providing aftercare, where care is provided, how are survivors engaged, which services are provided, and who receives aftercare. CONCLUSION: There is a good deal of interest in the effectiveness of different models of aftercare. Future research in this area would be assisted by the adoption of a shared taxonomy that will allow programs to be identified by their structural type.
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Cuidados Posteriores/clasificación , Supervivientes de Cáncer , Neoplasias/terapia , Cuidados Posteriores/métodos , Cuidados Posteriores/tendencias , Niño , Predicción , Humanos , Modelos Teóricos , Neoplasias/mortalidad , Aceptación de la Atención de Salud , Tasa de SupervivenciaAsunto(s)
Hemofilia A/diagnóstico , Hemofilia B/diagnóstico , Tamizaje Neonatal , Humanos , Recién Nacido , RiesgoRESUMEN
Newborns with hemophilia are at risk of intracranial hemorrhage, extracranial hemorrhage, and other bleeding complications. The safe delivery of a healthy newborn with hemophilia is a complex process that can begin even before conception, and continues throughout pregnancy, birth, and the newborn period. This process involves the expectant parents and a wide variety of health-care professionals: genetic counselors, obstetricians, neonatologists, pediatricians, radiologists, adult and pediatric hematologists, and nurses with expertise in hemophilia. Because of this multidisciplinary complexity, the relative rarity of births of newborns with hemophilia, and the lack of high-quality evidence to inform decisions, there is considerable variation in practice in this area. We present a comprehensive multidisciplinary approach, from preconception counseling to discharge planning after birth, and describe available options for management decisions. We highlight a number of areas of important uncertainty and controversy, including the preferred mode of delivery, the appropriate use and timing of neuroimaging tests, and the appropriate use of clotting factor concentrates in the newborn period. While the approach presented here will aid clinicians in planning and providing care, further research is required to optimize the care of newborns with hemophilia.
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Enfermedades Fetales , Feto , Asesoramiento Genético , Hemofilia A , Enfermedades del Recién Nacido , Femenino , Enfermedades Fetales/diagnóstico , Enfermedades Fetales/genética , Enfermedades Fetales/terapia , Hemofilia A/diagnóstico , Hemofilia A/genética , Hemofilia A/terapia , Humanos , Recién Nacido , Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/terapia , Guías de Práctica Clínica como Asunto , EmbarazoRESUMEN
The Figure 1 used in the originally published version of this article was incorrect.
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Venous thromboembolism (VTE) is a well-recognized complication in pediatric oncology patients. Studies in adult oncology patients have suggested a potential negative association between VTE and survival, but this association has not been examined in pediatric patients yet. The aim of this study was to assess the association of VTE with survival in pediatric oncology patients. Data from all pediatric oncology patients treated at the two tertiary care centers in Atlantic Canada were pooled to create a population-based cohort. The association between VTE and survival was analyzed using a Cox proportional hazards model stratified by diagnosis group (leukemia, lymphoma, and other; sarcoma) and adjusted for age at diagnosis and sex. Out of 939 patients included in this study, 73 had a VTE (8%) and 131 (14%) patients died during the study period. Children in the leukemia/lymphoma/other group with a VTE had significantly poorer survival relative to children in the same group who did not have a VTE. Although children with sarcoma and VTE had poorer survival compared to children with sarcoma with no VTE, this association was not statistically significant. In this population-based study, we found a negative association between VTE and survival in pediatric oncology patients. If future studies confirm this association, this finding may have prognostic implications and potentially offer new avenues for the management of pediatric patients with cancer.
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Neoplasias/mortalidad , Tromboembolia Venosa/epidemiología , Adolescente , Canadá/epidemiología , Niño , Preescolar , Comorbilidad , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Leucemia/mortalidad , Linfoma/mortalidad , Masculino , Modelos de Riesgos Proporcionales , Sarcoma/mortalidad , Centros de Atención Terciaria/estadística & datos numéricosRESUMEN
The development of inhibitory antibodies to factor VIII is the most serious complication of replacement therapy in hemophilia A. Activation of the innate immune system during exposure to this protein contributes to inhibitor development. However, avoidance of factor VIII exposure during innate immune system activation by external stimuli (e.g., vaccines) has not been consistently shown to prevent inhibitors. We hypothesized that dexamethasone, a drug with potent anti-inflammatory effects, could prevent inhibitors by promoting immunologic tolerance to factor VIII in hemophilia A mice. Transient dexamethasone treatment during ainitial factor VIII exposure reduced the incidence of anti-factor VIII immunoglobulin G in both a conventional hemophilia A mouse model (E16KO, 77% vs 100%, P=0.048) and a hemophilia A mouse model with a humanized major histocompatibility complex type II transgene (E17KO/hMHC, 6% vs 33%, P=0.0048). More importantly, among E17KO/hMHC mice that did not develop anti-factor VIII immunoglobulin G after initial exposure, dexamethasone-treated mice were less likely to develop a response after re-exposure six (7% vs 52%, P=0.005) and 16 weeks later (7% vs 50%, P=0.097). Similar results were obtained even when factor VIII re-exposure occurred in the context of lipopolysaccharide (30% vs 100%, P=0.069). The ability of these mice to develop immunoglobulin G to human von Willebrand factor, a structurally unrelated antigen, remained unaffected by treatment. Transient dexamethasone administration therefore promotes antigen-specific immunologic tolerance to factor VIII. This effect is associated with an increase in the percentage of thymic regulatory T cells (12.06% vs 4.73%, P<0.001) and changes in the thymic messenger ribonucleic acid transcription profile.
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Dexametasona/uso terapéutico , Factor VIII/inmunología , Hemofilia A/tratamiento farmacológico , Tolerancia Inmunológica , Animales , Anticuerpos , Modelos Animales de Enfermedad , Inmunidad Innata , Inmunoglobulina G , Ratones , ARN Mensajero/análisis , Linfocitos T Reguladores/inmunología , Timo/inmunología , Factores de Tiempo , Transcripción GenéticaRESUMEN
OBJECTIVE: There are no proven methods to predict the risk of clinically significant bleeding in the PICU. A retrospective study identified platelet count as a risk marker for clinically significant bleeding. We conducted a study to examine any association of platelet count, international normalized ratio, and activated partial thromboplastin time with bleeding risk in PICU patients. DESIGN: Prospective observational cohort study. SETTING: The PICU at the Children's Hospital of Eastern Ontario, a university-affiliated tertiary care pediatric center. PATIENTS: Consecutive patients admitted to the PICU. Exclusion criteria were prior inclusion, admission with bleeding, inherited bleeding disorders, weight less than 3 kg, and age less than 60 days or 18 years or more. INTERVENTIONS: There were no interventions in this observational study. MEASUREMENTS AND MAIN RESULTS: Patients were monitored in real time for clinically significant bleeding, using a broadly inclusive definition of clinically significant bleeding, for up to 72 hours after admission to the PICU, or until death or discharge. All measurements of platelet count, international normalized ratio, and activated partial thromboplastin time obtained during the study period were included as time-varying covariates in Cox proportional hazard models. Two hundred thirty-four patients were eligible, and 25 (11%) had one or more episodes of clinically significant bleeding. Platelet count was associated with increased hazard of clinically significant bleeding (hazard ratio, 0.96 per 10 × 10/L increase in platelet count; 95% CI (0.93-0.997; p = 0.03). Increasing hazard for clinically significant bleeding was seen with decreasing platelet count. Neither international normalized ratio nor activated partial thromboplastin time was significantly associated with clinically significant bleeding. CONCLUSIONS: There is a statistically significant association in PICU patients between decrease in platelet count and clinically significant bleeding, and this association is stronger with lower platelet counts. Further study is required to determine whether platelet transfusion can reduce bleeding risk. International normalized ratio and activated partial thromboplastin time do not predict clinically significant bleeding, and these tests should not be used for this purpose in a general PICU patient population.
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Trastornos de la Coagulación Sanguínea/complicaciones , Hemorragia/etiología , Trombocitopenia/complicaciones , Adolescente , Trastornos de la Coagulación Sanguínea/diagnóstico , Niño , Preescolar , Femenino , Humanos , Lactante , Unidades de Cuidado Intensivo Pediátrico , Relación Normalizada Internacional , Masculino , Tiempo de Tromboplastina Parcial , Recuento de Plaquetas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de Riesgo , Trombocitopenia/diagnósticoRESUMEN
OBJECTIVE: Our objective was to generate, optimize, and validate a self-administered pediatric bleeding questionnaire (Self-PBQ) as a screening tool for von Willebrand disease (VWD) in children referred to the hematology clinic for the first time. STUDY DESIGN: The Self-PBQ was generated by combining the validated expert-administered PBQ and the International Society on Thrombosis and Hemostasis (ISTH) bleeding assessment tool (BAT). Medical terminology was translated into lay language requiring a grade 4 reading level. In Phase 1, the Self-PBQ was optimized and the level of agreement between the Self-PBQ and the expert-administered PBQ was determined. Phase 2 established the normal range of bleeding scores (BSs) of the Self-PBQ. Phase 3 examined the Self-PBQ as a screening tool for first-time referrals to the hematology clinic. RESULTS: The Self-PBQ is a reliable surrogate for the expert-administered PBQ with an excellent intraclass correlation (ICC) of 0.917. The Self-PBQ was scored with the PBQ and the ISTH-BAT scoring systems, for which its normal BS ranges are -1 to 2 or 0 to 2, respectively. A positive Self-PBQ BS (≥3) had a sensitivity of 78%, a specificity of 37%, a positive predictive value of 0.18, and a negative predictive value of 0.91 for identifying VWD in children being investigated by a hematologist for a bleeding disorder. CONCLUSION: The Self-PBQ generates comparable BSs to the expert-administered PBQ and is a reliable, reasonably sensitive screening tool to incorporate into the assessment of children presenting to a hematologist for the investigation of an inherited bleeding disorder.
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Hemorragia , Autoinforme , Encuestas y Cuestionarios , Enfermedades de von Willebrand , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Inflammatory signals such as pathogen- and danger-associated molecular patterns have been hypothesized as risk factors for the initiation of the anti-factor VIII (FVIII) immune response seen in 25% to 30% of patients with severe hemophilia A (HA). In these young patients, vaccines may be coincidentally administered in close proximity with initial exposure to FVIII, thereby providing a source of such stimuli. Here, we investigated the effects of 3 vaccines commonly used in pediatric patients on FVIII immunogenicity in a humanized HA murine model with variable tolerance to recombinant human FVIII (rhFVIII). Mice vaccinated intramuscularly against the influenza vaccine prior to multiple infusions of rhFVIII exhibited a decreased incidence of rhFVIII-specific neutralizing and nonneutralizing antibodies. Similar findings were observed with the addition of an adjuvant. Upon exposure to media from influenza- or FVIII-stimulated lymph node or splenic lymphocytes, naïve CD4(+) lymphocytes preferentially migrated toward media from influenza-stimulated cells, indicating that antigen competition, by means of lymphocyte recruitment to the immunization site, is a potential mechanism for the observed decrease in FVIII immunogenicity. We also observed no differences in incidence or titer of rhFVIII-specific antibodies and inhibitors in mice exposed to the live-attenuated measles-mumps-rubella vaccine regardless of route of administration. Together, our results suggest that concomitant FVIII exposure and vaccination against influenza does not increase the risk of inhibitor formation and may in fact decrease anti-FVIII immune responses.
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Formación de Anticuerpos/efectos de los fármacos , Autoanticuerpos/inmunología , Inhibidores de Factor de Coagulación Sanguínea/inmunología , Factor VIII/antagonistas & inhibidores , Hemofilia A/inmunología , Vacunas contra la Influenza/farmacología , Vacunación , Animales , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Factor VIII/inmunología , Femenino , Humanos , Masculino , Ratones , Ratones NoqueadosRESUMEN
We report an 11-month-old boy with severe hemophilia A who had regular exposure to factor VIII (FVIII) intended to reduce the risk of developing an inhibitor. He developed a high-titer inhibitor (peak titer 19 BU) that disappeared within 6 weeks of starting immune tolerance induction (ITI). Anti-FVIII IgG4 peaked briefly compared with anti-FVIII IgG1 and the Bethesda titer. Neither rapid resolution of an inhibitor after prophylaxis nor this behavior of anti-FVIII IgG4 has been previously reported. Transient anti-FVIII IgG4 may be a marker of an attenuated anti-FVIII response induced by prophylactic FVIII therapy.
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Factor VIII/inmunología , Hemofilia A/inmunología , Tolerancia Inmunológica , Inmunoglobulina G/sangre , Factor VIII/antagonistas & inhibidores , HumanosRESUMEN
OBJECTIVE: To determine the practice patterns of Canadian hematologists and neonatologists/paediatricians who care for newborns with hemophilia, with regard to vitamin K administration, use of empirical clotting factor replacement therapy, neuroimaging and timing of hematology consultation. METHODS: Hematologists and neonatologists/paediatricians, identified from membership lists of Canadian professional organizations, were provided electronic and/or paper versions of the survey instrument. Questions were posed in the context of specific clinical scenarios. Differences in response proportions between groups were compared for selected questions. RESULTS: There were 171 respondents among 616 eligible persons who were sent the survey; 58 respondents had recent experience managing a newborn with hemophilia. There was a consensus not to provide empirical treatment to well newborns after uncomplicated deliveries, to provide empirical treatment to symptomatic newborns and to obtain neuroimaging for symptomatic newborns. Systematic differences between hematologists and neonatologists/paediatricians existed with regard to the timing of hematology consultation when the diagnosis of hemophilia had not been confirmed antenatally, the route of vitamin K administration for newborns with hemophilia and the choice of product to use for empirical treatment of a symptomatic newborn. CONCLUSIONS: The observed lack of consensus regarding important management decisions indicates a need for ongoing research in the care of newborns with hemophilia. Systematic differences between hematologists and neonatologists/paediatricians suggest a role for improved communication and collaboration between these two groups of practitioners.
OBJECTIF: Déterminer les profils de pratique des hématologues et des néonatologistes/pédiatres canadiens qui soignent des nouveau-nés hémophiles à l'égard de l'administration de vitamine K, de l'utilisation empirique du traitement par le facteur de remplacement de coagulation, de la neuro-imagerie et du moment de la consultation en hématologie. MÉTHODOLOGIE: Les hématologues et les néonatologistes/pédiatres, repérés grâce aux listes de membres d'organismes professionnels canadiens, ont reçu une version virtuelle, une version papier ou les deux versions du sondage. Les questions étaient posées dans le contexte de scénarios cliniques précis. Les différences dans les proportions de réponses entre les groupes étaient comparées à l'égard de questions sélectionnées. RÉSULTATS: Sur les 616 personnes admissibles, 171 ont répondu au sondage. De ce nombre, 58 avaient eu une expérience récente de prise en charge d'un nouveau-né hémophile. On observait un consensus de ne pas administrer de traitement empirique aux nouveau-nés en santé après un accouchement sans complication, d'administrer un traitement empirique aux nouveau-nés symptomatiques et d'obtenir une neuroimagerie chez ces nouveau-nés symptomatiques. Il y avait des différences systématiques entre les hématologues et les néonatologistes/pédiatres pour ce qui est du moment de la consultation en hématologie lorsque le diagnostic n'avait pas été confirmé pendant la période anténatale, de la voie d'administration de la vitamine K aux nouveau-nés hémophiles et du choix de produit à utiliser pour administrer un traitement empirique à un nouveau-né symptomatique. CONCLUSIONS: L'absence de consensus observé au sujet d'importantes décisions de prise en charge démontre la nécessité de poursuivre les recherches sur les soins aux nouveau-nés hémophiles. En raison des différences systématiques entre les hématologues et les néonatologistes/pédiatres, il y aurait lieu d'améliorer les communications et la collaboration entre ces deux groupes de praticiens.
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OBJECTIVE: To determine the epidemiology and identify the risk factors for clinically significant bleeding in the pediatric intensive care unit. DESIGN: A retrospective cohort study over 6 months with up to 7 days of observation for each patient. SETTING: The pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Three hundred twenty-six consecutive patients admitted to the pediatric intensive care unit during the study period, with 214 eligible for inclusion. MEASUREMENTS AND MAIN RESULTS: Clinically significant bleeding, defined using a composite of outcomes. Clinically significant bleeding occurred in 19 patients (8.9%). Recursive partitioning identified a platelet count <100 × 10/L as being associated with clinically significant bleeding. Other factors associated with increased risk included mechanical ventilation, antibiotic and antacid medications, the performance of multiple procedures, and cardiac surgery. Episodes of clinically significant bleeding were observed at a median of 9.8 hrs after admission. CONCLUSIONS: Clinically significant bleeding is a more common complication for pediatric intensive care unit patients than has been previously reported. The evidence-based threshold for thrombocytopenia identified as a risk factor should be further investigated in a prospective study.