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BACKGROUND: Once-weekly efanesoctocog alfa provides high sustained factor VIII activity with superior bleeding prevention as compared with prestudy factor VIII prophylaxis in previously treated patients 12 years of age or older with severe hemophilia A. Data on outcomes of efanesoctocog alfa treatment in children younger than 12 years of age with severe hemophilia A are limited. METHODS: We conducted a phase 3, open-label study involving previously treated patients younger than 12 years of age with severe hemophilia A. Patients received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary end point was the occurrence of factor VIII inhibitors (neutralizing antibodies against factor VIII). Secondary end points included annualized rates of treated bleeding episodes, bleeding treatment, safety, and pharmacokinetics. RESULTS: A total of 74 male patients were enrolled (38 with an age of <6 years and 36 with an age of 6 to <12 years). No factor VIII inhibitors developed. Most adverse events were nonserious. No serious adverse events that were assessed by the investigator as being related to efanesoctocog alfa were reported. In the 73 patients treated according to the protocol, the median and model-based mean annualized bleeding rates were 0.00 (interquartile range, 0.00 to 1.02) and 0.61 (95% confidence interval, 0.42 to 0.90), respectively. A total of 47 patients (64%) had no treated bleeding episodes, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints. A total of 41 of 43 bleeding episodes (95%) resolved with one injection of efanesoctocog alfa. Mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours. CONCLUSIONS: In children with severe hemophilia A, once-weekly prophylaxis with efanesoctocog alfa provided high sustained factor VIII activity in the normal to near-normal range (>40 IU per deciliter) for 3 days and more than 10 IU per deciliter for almost 7 days after administration, leading to effective bleeding prevention. Efanesoctocog alfa was associated with mainly nonserious adverse events. (Funded by Sanofi and Sobi; XTEND-Kids ClinicalTrials.gov number, NCT04759131.).
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Fator VIII , Hemofilia A , Hemorragia , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/complicações , Fator VIII/imunologia , Fator VIII/efeitos adversos , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Masculino , Criança , Pré-Escolar , Hemorragia/induzido quimicamente , Lactente , Anticorpos Neutralizantes/sangue , Esquema de MedicaçãoRESUMO
BACKGROUND: Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children. METHODS AND RESULTS: The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events. CONCLUSIONS: Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.
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Dabigatrana , Cardiopatias Congênitas , Tromboembolia Venosa , Criança , Humanos , Anticoagulantes/efeitos adversos , Dabigatrana/efeitos adversos , Cardiopatias Congênitas/complicações , Prevenção Secundária , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Ensaios Clínicos como AssuntoRESUMO
In the phase 2b/3 DIVERSITY trial, 3 months treatment with dabigatran was noninferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm, phase 3, secondary VTE prevention study, up to 12 months dabigatran use was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in the DIVERSITY trial and safety in both studies. Thrombophilia types were similar between the DIVERSITY trial (total population) and secondary prevention studies: factor V Leiden, 42% vs 33%; prothrombin mutation (G20210A), 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; and antiphospholipid antibodies, 18% vs 20% of patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary end point (Mantel-Haenszel-weighted rate difference, -0.135; 95% confidence interval, -0.36 to 0.08; noninferiority P = .0014); comparable to the total DIVERSITY trial population (46% vs 42%) showing dabigatran noninferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia. These trials were registered at www.clinicaltrials.gov as #NCT01895777 and #NCT02197416.
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Dabigatrana , Trombofilia , Tromboembolia Venosa , Criança , Humanos , Dabigatrana/efeitos adversos , Deficiência de Proteína C , Fatores de Risco , Prevenção Secundária , Trombofilia/tratamento farmacológico , Estados Unidos , Tromboembolia Venosa/prevenção & controle , RecidivaRESUMO
BACKGROUND: Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children. OBJECTIVES: This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]). METHODS: Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [N = 358]; dTT 2,348 [N = 324]; ECT 2,929 [N = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements; N = 1,978). Population models were fitted using nonlinear mixed-effects modeling. Covariates (e.g., sex, age) were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure. RESULTS: Overall, relationships between dabigatran, aPTT, dTT, and ECT were similar in children and adults. For children aged <6 months, a higher proportion of baseline samples were outside or close to the upper aPTT and ECT adult ranges. No age-related differences were detected for dTT. With increasing dabigatran concentration, aPTT rose nonlinearly (half the maximum effect at 368 ng/mL dabigatran) while dTT and ECT increased linearly (0.37 and 0.73% change per ng/mL dabigatran, respectively). Mean baseline aPTT (45 vs. 36 seconds) and ECT (40 vs. 36 seconds) were slightly increased for those aged <6 months versus older children. CONCLUSION: The similar relationships of laboratory parameters observed across pediatric age groups suggests that developmental changes in the hemostatic system may have little effect on response to dabigatran.
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Anticoagulantes , Dabigatrana , Adolescente , Antitrombinas , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Criança , Pré-Escolar , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Lactente , Masculino , Tempo de Tromboplastina Parcial , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Venous thromboembolism (VTE) has an increasing rate of significance in pediatric patients. The currently standardized anticoagulants (unfractionated heparin, low molecular weight heparin and vitamin K antagonists) and their dose regimens were not comprehensively trialed in pediatric patients. Recently, several direct oral anticoagulants (DOACs) have been studied in clinical trials in the pediatric population and further trials are ongoing. Dabigatran etexilate and rivaroxaban results show that these DOACs are safe and efficient in the treatment and secondary prevention of pediatric VTE. This review will focus on adverse events (AEs) between specific DOACs reported in the clinical trials in children and compare them to standard of care. This will assist clinicians in decision making of selecting the right anticoagulation for their pediatric patients.
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Inibidores do Fator Xa/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Anticoagulantes/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Dabigatrana/uso terapêutico , Humanos , Fatores de Risco , Rivaroxabana/uso terapêutico , Vitamina K/antagonistas & inibidoresRESUMO
OBJECTIVE: To investigate treatment modalities for children with extremity indwelling catheter (EIC)- or cardiac catheter-related arterial thrombosis. STUDY DESIGN: The treatment of consecutive cases of catheter-related arterial thrombosis (CAT) at our institution between 2002 and 2017 was analyzed retrospectively. RESULTS: A total of 242 CATs developed in 224 children. Of these, 125 (52%) were EIC-related and 117 (48%) were cardiac catheter-related. Treatment included heparin alone in 60 cases (25%), acetylsalicyclic acid (ASA) alone in 6 cases (2%), heparin followed by ASA in 171 cases (71%), heparin followed by vitamin K antagonist (VKA) in 4 cases (1.5%), and VKA alone in 1 case (0.5%). Complete resolution of CAT was observed in 173 cases (71.5%), partial resolution in 13 cases (5.4%), and no resolution in 56 cases (23.1%). No statistical significance in the resolution rate was observed between treatment groups (P = .23). In 66% of cases, complete resolution occurred at a median of 18 days (range, 4-44 days) with heparin alone. A switch from heparin to ASA in children with partial or no resolution of CAT did not increase the resolution rate at follow-up. CONCLUSIONS: Heparin is an efficient treatment modality for CAT in pediatric patients. Long-term, subsequent treatment with ASA does not increase the resolution rate.
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Anticoagulantes/uso terapêutico , Cateterismo Cardíaco/efeitos adversos , Cateteres de Demora/efeitos adversos , Artéria Femoral , Fibrinolíticos/uso terapêutico , Artéria Ilíaca , Trombose/tratamento farmacológico , Adolescente , Aspirina/uso terapêutico , Criança , Pré-Escolar , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Heparina/uso terapêutico , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Trombose/etiologia , Resultado do Tratamento , Vitamina K/antagonistas & inibidoresRESUMO
Background: Following the spread of the coronavirus disease 2019 (COVID-19) pandemic a new disease entity emerged, defined as Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C). In the absence of trials, evidence for treatment remains scarce. Purpose: To develop best practice recommendations for the diagnosis and treatment of children with PIMS-TS in Switzerland. It is acknowledged that the field is changing rapidly, and regular revisions in the coming months are pre-planned as evidence is increasing. Methods: Consensus guidelines for best practice were established by a multidisciplinary group of Swiss pediatric clinicians with expertise in intensive care, immunology/rheumatology, infectious diseases, hematology, and cardiology. Subsequent to literature review, four working groups established draft recommendations which were subsequently adapted in a modified Delphi process. Recommendations had to reach >80% agreement for acceptance. Results: The group achieved agreement on 26 recommendations, which specify diagnostic approaches and interventions across anti-inflammatory, anti-infectious, and support therapies, and follow-up for children with suspected PIMS-TS. A management algorithm was derived to guide treatment depending on the phenotype of presentation, categorized into PIMS-TS with (a) shock, (b) Kawasaki-disease like, and (c) undifferentiated inflammatory presentation. Conclusion: Available literature on PIMS-TS is limited to retrospective or prospective observational studies. Informed by these cohort studies and indirect evidence from other inflammatory conditions in children and adults, as well as guidelines from international health authorities, the Swiss PIMS-TS recommendations represent best practice guidelines based on currently available knowledge to standardize treatment of children with suspected PIMS-TS. Given the absence of high-grade evidence, regular updates of the recommendations will be warranted, and participation of patients in trials should be encouraged.
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INTRODUCTION: Despite adequate medical treatment, many young adults with haemophilia develop joint alterations-especially in ankles and knees. Undetected over years, subtle structural changes cause subclinical symptoms, before problems become obvious. To objectify these silent pressure pains, the pressure pain threshold (PPT) can be measured by algometry. AIM: The aim was to investigate and compare the effect of age on PPTs in asymptomatic ankles and knees between boys and young adults with haemophilia and age-matched controls, in order to gain better knowledge about the alteration of the periarticular structures with increasing age. MATERIAL AND METHODS: Nineteen persons with haemophilia (PwH; severe or moderate; 8-30 years) and 19 age-matched controls with 'healthy' ankles and knees were recruited. Asymptomatic joints with a Haemophilia Joint Health Score = 0 were included. The PPT was measured on four periarticular points per joint, and the data were analysed with a linear mixed model. RESULTS: The PPT of the control group increased with age, whereas the PPT of the PwH decreased. The difference in age effect per year in kPa between PwH and controls was as follows: ß [95%-CI]: -15.41 [-31.63; 0.79]. Although the result was not statistically significant (p = .08), a clear tendency was shown. CONCLUSION: The results suggest that subclinical alterations in the periarticular structures of these joints may evolve unnoticed over time. However, further research is warranted to determine whether this observed trend is confirmed in a larger sample and at what age the PPT begins to decrease in PwH compared to controls.
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Hemofilia A , Tornozelo , Hemofilia A/complicações , Humanos , Joelho , Masculino , Dor/etiologia , Limiar da Dor , Adulto JovemRESUMO
Pediatric thromboembolism is a rare and heterogenous disease. As a result, there is a paucity of knowledge with regard to natural history, management, and outcomes of most types of pediatric venous and arterial thromboembolism. International research collaboration is needed to fill these knowledge gaps. Not only randomized controlled trials, but also representative observational studies are required to answer all research questions. Therefore, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis initiated the International Pediatric Thrombosis Network (IPTN). The aims of the IPTN include (1) development of the Throm-PED registry to facilitate international prospective observational studies, and (2) establishment of a network of pediatric thrombosis centers experienced in effectively conducting clinical trials and observational studies. The IPTN needs dedicated clinicians all over the world and several funding sources to obtain high-quality research data to reach its ultimate goal of improving care in children with thrombosis. The aim of this communication is to call for active participation in the IPTN to all physicians taking care of children with thrombosis worldwide.
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Tromboembolia , Trombose , Criança , Comunicação , Hemostasia , Humanos , Recém-Nascido , Sistema de Registros , Trombose/terapiaRESUMO
The COVID-19 pandemic is an ongoing global healthcare crisis. Based on reports of atypically located thromboses following vaccination with the AstraZeneca COVID-19 vaccine, the Society of Thrombosis and Haemostasis Research (GTH) has issued guidance statements on the recognition, diagnosis, and treatment of this rare complication. It shares pathophysiological features with heparin-induced thrombocytopenia (HIT) and is referred to as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
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Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Trombose/diagnóstico , COVID-19/patologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Guias como Assunto , Heparina/efeitos adversos , Humanos , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/etiologia , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Trombose/etiologiaRESUMO
BACKGROUND: Dabigatran etexilate (DE), a direct oral thrombin inhibitor, has been evaluated in children with venous thromboembolism (VTE) using oral solution, pellets, or capsules. OBJECTIVES: This study evaluated DE pharmacokinetics (PK) in children with VTE and the appropriateness of a DE pediatric age- and weight-based dosing algorithm. PATIENTS/METHODS: A population PK model was fitted to data from four single-arm and one randomized, comparative pediatric VTE studies (358 children aged birth to <18 years; 2748 PK observations) and one healthy-adult study (32 males aged <40 years; 1523 PK observations) using nonlinear mixed-effects modeling. A stepwise, covariate, model-building procedure evaluated the influence of covariates (e.g., age, body weight, body surface area [BSA]-normalized renal function, and sex). The final model was used to evaluate the pediatric dosing algorithm, with simulations comparing pediatric trough exposure with reference exposure defined for the pediatric studies. RESULTS: The population PK of dabigatran was adequately described by a two-compartment model with first-order elimination and absorption. Age, weight, BSA-normalized renal function, and sex were statistically significant covariates (all P < .05). Apparent clearance increased with age (independently of body weight), diminished with decreasing BSA-normalized renal function, and was lower in females than males. All disposition parameters increased with body weight escalation (allometric scaling). Simulations confirmed that for all DE formulations, the final pediatric dosing algorithms achieved reference exposure without dose adjustment. CONCLUSIONS: Using a population PK model of DE for children with VTE, simulations showed that the final dosing algorithms were appropriate for all DE formulations; no dose titration was needed.
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Dabigatrana , Tromboembolia Venosa , Adolescente , Adulto , Antitrombinas , Peso Corporal , Criança , Simulação por Computador , Feminino , Humanos , Masculino , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológicoRESUMO
OBJECTIVES: Unplanned return visits (URVs) to emergency departments (EDs) account internationally for 2.5% to 5.2% of all consultations. ED crowding is an increasing challenge, and URVs seem to contribute to this problem. This study aimed to assess factors for URVs at the ED of a tertiary children's hospital to analyze if they are jointly responsible for the steadily rising amount of treated patients. METHODS: All patients with an URV to a pediatric ED in Switzerland between January and December 2013 were included in the study. Data were taken retrospectively from the electronic patient files, and different variables were defined and analyzed. RESULTS: URVs occurred at an incidence of 4.6%, and mostly concerned infants and toddlers (46%). URVs were independent of weekdays and mostly occurred between 10 am and 10 pm. In 84.2% of the cases, the URVs were judged as unnecessary, and in 15.8%, a hospitalization was indicated, mainly for children with a worsening respiratory illness. CONCLUSIONS: The occurrence of URVs in our ED was within the incidence reported in the literature. While URVs lead to hospitalization in some patients, the majority of URVs were unnecessary from a medical point of view. These results indicate that a correct evaluation of the child's health state by parents is often challenging and requires repeated medical attendance following a first ED visit, especially in infants with airway diseases and infections. Intensive counseling and scheduled short-term follow-up consultation at the pediatrician's office could prevent URVs to the ED.
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Serviço Hospitalar de Emergência , Hospitalização , Criança , Humanos , Incidência , Lactente , Encaminhamento e Consulta , Estudos RetrospectivosRESUMO
BACKGROUND: Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism. METHODS: DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries. Standard of care (low-molecular-weight heparins, unfractionated heparin, vitamin K antagonists or fondaparinux) was compared with a paediatric oral dabigatran dosing regimen (an age-adjusted and weight-adjusted nomogram) in children younger than 18 years with acute venous thromboembolism initially treated (5-21 days) with parenteral anticoagulation, requiring anticoagulation therapy for at least 3 months. Patients were randomised 1:2 (standard of care:dabigatran) and stratified by age (12 to <18 years, 2 to <12 years, and birth to <2 years) via interactive response technology. The primary composite efficacy endpoint (intention-to-treat analysis) was the proportion of children with complete thrombus resolution, and freedom from recurrent venous thromboembolism and venous thromboembolism-related death. A non-inferiority margin of absolute differences of 20% was used. Secondary endpoints included safety (determined by major bleeding events [time-to-event analysis on the treated set]), and pharmacokinetic-pharmacodynamic relationships (descriptive analyses). This trial is registered with ClinicalTrials.gov, NCT01895777 and is completed. FINDINGS: 328 children were enrolled between Feb 18, 2014, and Nov 14, 2019. 267 were randomly assigned (90 [34%] to standard of care and 177 [66%] to dabigatran) and included in the analyses. Median exposure to standard of care was 85·0 days (IQR 80·0-90·0) and to dabigatran was 84·5 days (78·0-89·0). Similar proportions of children treated with standard of care and dabigatran met the composite efficacy endpoint (38 [42%] of 90 vs 81 [46%] of 177; Mantel-Haenszel weighted difference, -0·04; 90% CI -0·14 to 0·07; p<0·0001 for non-inferiority). On-treatment bleeding events were reported in 22 (24%) of 90 children receiving standard of care and 38 (22%) of 176 children receiving dabigatran (hazard ratio [HR] 1·15, 95% CI 0·68 to 1·94; p=0·61); major bleeding events were similar between the groups (two [2%] of 90 and four [2%] of 176; HR 0·94, 95% CI 0·17 to 5·16; p=0·95). Pharmacokinetic-pharmacodynamic curves showed a linear relationship between total dabigatran plasma concentration and diluted thrombin time and ecarin clotting time, and a non-linear relationship with activated partial thromboplastin time; curves were similar to those for adults. Serious adverse events were reported for 18 (20%) of 90 children receiving standard of care and 22 (13%) of 176 children receiving dabigatran. The most common severe adverse events were vascular disorders (standard of care three [3%] of 90, dabigatran two [1%] of 176), and gastrointestinal disorders (standard of care two [2%] of 90 and dabigatran five [3%] of 176). One on-treatment death occurred in the standard of care group (retroperitoneal bleeding, not considered treatment related by the study investigators). INTERPRETATION: An age-adjusted and weight-adjusted dabigatran dosing algorithm was appropriate in children aged birth to less than 18 years with venous thromboembolism. Dabigatran was non-inferior to standard of care in terms of efficacy, with similar pharmacokinetic-pharmacodynamic relationships as those seen in adults, and might be a suitable alternative to standard of care. FUNDING: Boehringer Ingelheim.
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Anticoagulantes/administração & dosagem , Dabigatrana/administração & dosagem , Tromboembolia Venosa , Doença Aguda , Administração Oral , Adolescente , Anticoagulantes/efeitos adversos , Criança , Pré-Escolar , Dabigatrana/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Taxa de Sobrevida , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/mortalidadeRESUMO
INTRODUCTION: Emicizumab (Hemlibra®, Hoffmann-La Roche, Switzerland) is now available for haemophilia A patients with or without factor VIII inhibitors. Management of bleeding events and replacement therapy for invasive procedures have to be adapted. OBJECTIVE: To provide a practical guidance for the management of breakthrough bleeding events and elective or urgent surgery in adult and paediatric patients with haemophilia A without inhibitors treated with emicizumab. METHODS: Based on the available literature and the experiences collected from adult and paediatric patients treated in Switzerland, the Working Party on Haemostasis of the Swiss Society of Haematology and the Swiss Haemophilia Network worked together to reach a consensus on the management of bleeding events and invasive procedures. RESULTS AND CONCLUSION: Minor bleeding events and invasive procedures associated with low bleeding risk can be treated without factor replacement therapy in most cases, whereas major bleeding events and high-risk surgery require additional factor VIII replacement at usual doses, at least for the first days. Emicizumab treatment should be continued throughout the procedure and during the postoperative period. Elective major surgery should be planned according to emicizumab dosing for patients with a once-a-month posology. Of note, so far only few data are available on the management of major bleeds and surgery in patients with haemophilia A treated with emicizumab and this practical guidance will have to be regularly updated with growing experience.  .
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Anticorpos Biespecíficos , Hemofilia A , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Hemofilia A/tratamento farmacológico , Hemorragia/induzido quimicamente , HumanosRESUMO
BACKGROUND: Observational studies indicate that children hospitalized with COVID-19-related illness, like adults, are at increased risk for venous thromboembolism (VTE). A multicenter phase 2 clinical trial of anticoagulant thromboprophylaxis in children hospitalized with COVID-19-related illness has recently been initiated in the United States. To date, there remains a paucity of high-quality evidence to inform clinical practice world-wide. Therefore, the objective of this scientific statement is to provide consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses, and to identify priorities for future research. METHODS: We surveyed 20 pediatric hematologists and pediatric critical care physicians from several continents who were identified by Pediatric/Neonatal Hemostasis and Thrombosis Subcommittee leadership as having experience and expertise in the use of anticoagulant thromboprophylaxis and/or the management of COVID-19-related illness in children. A comprehensive review of the literature on COVID-19 in children was also performed. RESULTS: Response rate was 90%. Based on consensus of expert opinions, we suggest the administration of low-dose low molecular weight heparin subcutaneously twice-daily as anticoagulant thromboprophylaxis (in the absence of contraindications, and in combination with mechanical thromboprophylaxis with sequential compression devices, where feasible) in children hospitalized for COVID-19-related illness (including the multisystem inflammatory syndrome in children [MIS-C]) who have markedly elevated D-dimer levels or superimposed clinical risk factors for hospitalassociated VTE. For children who are clinically unstable or have severe renal impairment, we suggest the use of unfractionated heparin by continuous intravenous infusion as anticoagulant thromboprophylaxis. In addition, continued efforts to characterize VTE risk and risk factors in children with COVID-19, as well as to evaluate the safety and efficacy of anticoagulant thromboprophylaxis strategies in children hospitalized with COVID-19-related illness (including MIS-C) via cooperative multicenter trials, were identified among several key priorities for future research. CONCLUSION: These consensus-based recommendations on the use of anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illnesses and priorities for future research will be updated as high-quality evidence emerges.
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Anticoagulantes/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Medicina Baseada em Evidências/normas , Hospitalização , Pneumonia Viral/tratamento farmacológico , Pesquisa/normas , Tromboembolia Venosa/prevenção & controle , Adolescente , Fatores Etários , Anticoagulantes/efeitos adversos , COVID-19 , Criança , Pré-Escolar , Tomada de Decisão Clínica , Consenso , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Pesquisas sobre Atenção à Saúde , Humanos , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Tromboembolia Venosa/sangue , Tromboembolia Venosa/etiologia , Adulto JovemRESUMO
Hemophilia A (HA) is a serious inherited bleeding disorder resulting from a deficiency of coagulation factor VIII (FVIII). Replacement therapy with intravenous infusion of FVIII can be associated with treatment failure in approximately one-third of patients secondary to the development of neutralizing alloantibodies (inhibitor). Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that binds factor IXa and factor X and mimics FVIII. It has been licensed in many countries for the treatment of patients with HA with and without inhibitors with a favorable efficacy and safety profile. A 7-year-old child with severe HA and FVIII inhibitors, refractory to immune tolerance therapy, developed hematuria with nephrotic-range proteinuria after the first dose of emicizumab and subsequently also after a second dose 6 weeks later, which was associated with mild and transient leukopenia. Renal biopsy revealed a pattern of a full-house lupus nephritis. The patient fully and spontaneously recovered between 2 weeks after symptoms onset. In this report, we provide insights on a new and so far unreported renal complication associated to emicizumab treatment. Although emicizumab offers significant benefits for patient with HA, clinicians should be aware of this rare and potential serious renal adverse effect.
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Anticorpos Biespecíficos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Hemofilia A/terapia , Nefrite Lúpica/etiologia , Criança , Fator VIII/imunologia , Hemofilia A/sangue , Humanos , Leucopenia/etiologia , Nefrite Lúpica/sangue , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , MasculinoRESUMO
Venous thromboembolism has an increasing significance in the pediatric patient population. Due to the lack of well-designed pediatric clinical trials, recommendations for the treatment of venous thromboembolic events in children have low evidence and are mainly extrapolated from adult guidelines. This review summarizes and compares recommendations for the treatment of several venous thromboembolic events in children from CHEST, ASH, and the UK guidelines.