Epidemiology of clinically unsuspected venous thromboembolism in children with cancer: A population-based study from Maritimes, Canada.

Inconsistencies in the definition of clinically unsuspected venous thromboembolism (VTE) in pediatric patients recently led to the recommendation of standardizing this terminology. Clinically unsuspected VTE (cuVTE) is defined as the presence of VTE on diagnostic imaging performed for indications unrelated to VTE in a patient without symptoms or clinical history of VTE. The prevalence of cuVTE in pediatric cancer patients is unclear. Therefore, the main objective of our study was to determine the prevalence of cuVTE in pediatric cancer patients. All patients 0-18 years old, treated at the IWK in Halifax, Nova Scotia, from August 2005 through December 2019 with a known cancer diagnosis and at least one imaging study were eligible (n = 743). All radiology reports available for these patients were reviewed (n = 18,120). The VTE event was labeled a priori as cuVTE event for radiology reports that included descriptive texts indicating a diagnosis of thrombosis including thrombus, central venous catheter-related, thrombosed aneurysm, tumor thrombosis, non-occlusive thrombus, intraluminal filling defect, or small fragment clot for patients without documentation of clinical history and or signs of VTE. A total of 18,120 radiology reports were included in the review. The prevalence of cuVTE was 5.5% (41/743). Echocardiography and computed tomography had the highest rate of cuVTE detection, and the most common terminologies used to diagnose cuVTE were thrombus and non-occlusive thrombus. The diagnosis of cuVTE was not associated with age, sex, and type of cancer. Future efforts should focus on streamlining radiology reports to characterize thrombi. The clinical significance of these cuVTE findings and their application to management, post-thrombotic syndrome, and survival compared to cases with symptomatic VTE and patients without VTE should be further studied.

Hospital-Acquired Venous Thromboembolism and Invasive Mechanical Ventilation: A Report From the Children's Hospital Acquired Thrombosis Consortium.

OBJECTIVES: To determine if the duration of invasive mechanical ventilation (IMV) was associated with hospital-acquired venous thromboembolism (HA-VTE) among critically ill children. DESIGN: A multicenter, matched case-control study as a secondary analysis of Children's Hospital Acquired Thrombosis (CHAT) Consortium registry. SETTING: PICUs within U.S. CHAT Consortium participating centers. PATIENTS: Children younger than 21 years old admitted to a PICU receiving IMV for greater than or equal to 1 day duration from January 2012 to March 2022 were included for study. Cases with HA-VTE were matched 1:2 to controls without HA-VTE by patient age groups: younger than 1, 1-12, and older than 12 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was IMV duration in days. Descriptive data included demographics, anthropometrics, HA-VTE characteristics (i.e., type, location, and timing), central venous catheterization data, thromboprophylaxis practices, and Braden Q mobility scores. Descriptive, comparative, and associative (multivariate conditional logistic regression for HA-VTE) statistics were employed. A total of 152 cases were matched to 304 controls. Cases with HA-VTE were diagnosed at a median of 7 days (interquartile range [IQR], 3-16 d) after IMV. The HA-VTE were limb deep venous thromboses in 130 of 152 (85.5%) and frequently central venous catheterization-related (111/152, 73%). Cases with HA-VTE experienced a longer length of stay (median, 34 d [IQR, 18-62 d] vs. 11.5 d [IQR, 6-21 d]; p < 0.001) and IMV duration (median, 7 d [IQR, 4-15 d] vs. 4 d [IQR, 1-7 d]; p < 0.001) as compared with controls. In a multivariate logistic model, greater IMV duration (adjusted odds ratio, 1.09; 95% CI, 1.01-1.17; p = 0.023) was independently associated with HA-VTE. CONCLUSIONS: Among critically ill children undergoing IMV, HA-VTE was associated with greater IMV duration. If prospectively validated, IMV duration should be included as part of prothrombotic risk stratification and future pediatric thromboprophylaxis trials.

Tenecteplase in Acute Stroke: What About the Children?

Tenecteplase is replacing alteplase as the fibrinolytic agent of choice for the acute management of ischemic stroke in many adult stroke centers due to practical and pharmacokinetic advantages in the setting of similar outcomes. Although thrombolytic use is increasing for acute childhood stroke, there is very limited experience with tenecteplase in children for any indication, and importantly, there are no data on safety, dosing, or efficacy of tenecteplase for childhood stroke. Changes in fibrinolytic capacity over childhood, pediatric pharmacological considerations such as age-specific differences in drug clearance and volume of distribution, and practical aspects of drug delivery such as availability in children's hospitals may impact decisions about transitioning from alteplase to tenecteplase for acute pediatric stroke treatment. Pediatric and adult neurologists should prepare institution-specific guidelines and organize prospective data collection.

Anticoagulation with Intravenous Direct Thrombin Inhibitors in Pediatric Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature.

Although intravenous (IV) direct thrombin inhibitors (DTI) have gained interest in pediatric extracorporeal membrane oxygenation (ECMO), dosing and safety information is limited. The objective of this systematic review was to characterize DTI types, dosing, monitoring, and outcomes (bleeding and thromboembolic) in pediatric ECMO patients managed with IV DTIs. We conducted searches of MEDLINE (Ovid) and Embase (Elsevier) from inception through December 2022. Case reports, retrospective studies, and prospective studies providing per-patients or summary data for patient(s) <18 years of age receiving IV DTI for ECMO anticoagulation were included. Study selection and data extraction were conducted independently by two reviewers. A total of 28 studies: 14 case reports, 13 retrospective studies, and 1 prospective study were included, totaling 329 patients. Bivalirudin was utilized in 318 (96.7%), argatroban in 9 (2.7%), and lepirudin in 2 (0.6%) patients. Infusion dosing included: bivalirudin 0.14 ± 0.37 mg/kg/h, argatroban 0.69 ± 0.73 µg/kg/min, lepirudin 0.14 ± 0.02 mg/kg/h. Laboratory monitoring tests utilized were the activated clotting time, activated partial thromboplastin time (aPTT), diluted thrombin time, and thromboelastography measures. The aPTT was utilized in most patients (95%). Thromboembolism, bleeding, or death were observed in 17%, 17%, and 23% of bivalirudin, argatroban, and lepirudin patients, respectively. Bivalirudin appears to be the most frequently used DTI in pediatric ECMO. Dosing and laboratory monitoring varied, and bleeding and thromboembolic events were reported in 17% of patients. Prospective studies are warranted to establish dosing, monitoring, safety, and efficacy of bivalirudin and other IV DTI in pediatric ECMO.

Dosing, Monitoring, Blood Product Utilization, and Thromboembolic Complications of Four-Factor Prothrombin Complex Concentrate as Part of an Institutional Protocol in Pediatric Cardiac Surgery: A Retrospective Cohort Study.

Pediatric cardiac surgery patients are predisposed to blood loss. Blood product administration can lead to complications. Prothrombin complex concentrates (PCCs) offer potential advantages of factor composition, small volume, decreased immunogenicity/infectious risks, and accessibility. The objective of this study was to describe dosing, monitoring, blood product utilization, and thromboembolic complications of administering four-factor PCC (4F-PCC) in pediatric cardiac surgery. We performed a retrospective review of patients aged <18 years undergoing cardiac surgery from June 2020 to May 2022 (inclusive) who received 4F-PCC. Outcomes of interest included 4F-PCC dosing (units/kg) and number of doses administered, chest tube output, blood product administration, donor exposure, length of stay, and thromboembolic events. Eighty-six patients met eligibility criteria. The median (range) age and weight were 0.37 (0.01-16.3) years and 5.3 (1.6-98) kg, respectively. Median (range) total 4F-PCC dose per patient was 25 (9.2-50) units/kg, with 6 patients (7%) receiving a total of two doses. Median (range) 24-hour postoperative packed red blood cells, platelet, plasma, and cryoprecipitate administration volumes were 0 (0-2.57) mL/kg/24 h, 0 (0-1.09), 0 (0-2.64), and 0 (0-0.28 mL/kg/24 h), respectively. Median (range) length of stay and 24-hour postoperative chest tube output were 10 (6-26) days and 1.1 (0.1-4.2) mL/kg/h, respectively. Two (2%) patients experienced a thromboembolic event within 30 days of 4F-PCC administration. These retrospective findings suggest no worsening of hemostatic parameters, a mild median improvement in fibrinogen, low blood product utilization, and low thromboembolism rates following 4F-PCC use in pediatric cardiac surgery.

Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19-related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a postinfectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and evaluate associated risk factors. We classified patients into 1 of 3 groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (COVID-19, n = 426; MIS-C, n = 138; and asymptomatic SARS-CoV-2, n = 289) in 814 patients, there were 20 patients with thrombotic events (TEs; including 1 stroke). Patients with MIS-C had the highest incidence (9 [6.5%] of 138) vs COVID-19 (9 [2.1%] of 426) or asymptomatic SARS-CoV-2 (2 [0.7%] of 289). In patients with COVID-19 or MIS-C, a majority of TEs (89%) occurred in patients age ≥12 years. Patients age ≥12 years with MIS-C had the highest rate of thrombosis at 19% (9 of 48). Notably, 71% of TEs that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13 of 564), but it was 28% (5 of 18) in patients with TEs. Our findings may help inform pediatric thromboprophylaxis strategies.

Effects of Cumulative Head Impact Exposure in Adolescent Male Contact and Collision Sport Student Athletes.

OBJECTIVE: This prospective cohort study aimed to investigate the association between head impact exposure (HIE) and neuropsychological sequelae in high school football and ice hockey players over 1 year. SETTING: Community sample. PARTICIPANTS: A cohort of 52 adolescent American football and ice hockey players were enrolled in the study, with a final study sample of 35 included in analyses. DESIGN: The study followed a prospective cohort design, with participants undergoing neuropsychological screening and accelerometer-based measurement of HIE over 1 season. MAIN MEASURES: Changes in cognition, emotions, behavior, and reported symptoms were assessed using standardized neuropsychological tests and self-reported questionnaires. RESULTS: Cumulative HIE was not consistently associated with changes in cognition, emotions, behavior, or reported symptoms. However, it was linked to an isolated measure of processing speed, showing inconsistent results based on the type of HIE. History of previous concussion was associated with worsened verbal memory recognition (ImPACT Verbal Memory) but not on a more robust measure of verbal memory (California Verbal Learning Test [CVLT]). Reported attention-deficit/hyperactivity disorder history predicted improved neurocognitive change scores. No associations were found between reported history of anxiety/depression or headaches/migraines and neuropsychological change scores. CONCLUSION: Overall, our findings do not support the hypothesis that greater HIE is associated with an increase in neuropsychological sequelae over time in adolescent football and ice hockey players. The results align with the existing literature, indicating that HIE over 1 season of youth sports is not consistently associated with significant neuropsychological changes. However, the study is limited by a small sample size, attrition over time, and the absence of performance validity testing for neurocognitive measures. Future studies with larger and more diverse samples, longer follow-up, and integration of advanced imaging and biomarkers are needed to comprehensively understand the relationship between HIE and neurobehavioral outcomes. Findings can inform guidelines for safe youth participation in contact sports while promoting the associated health and psychosocial benefits.

Venous Thromboembolism among Noncritically Ill Hospitalized Children: Key Considerations for the Pediatric Hospital Medicine Specialist.

Venous thromboembolism (VTE) is a leading cause of morbidity and preventable harm among noncritically ill hospitalized children. Several clinical factors relevant to the noncritically ill hospitalized child significantly increase the risk of VTE including the presence of central venous catheters, systemic inflammation, and prolonged immobilization. Although risk mitigation strategies have been described, the diagnosis, treatment, and prevention of VTE require standardization of institutional practices combined with multidisciplinary collaboration among pediatric hospitalists, hematologists, and other care providers. In this narrative review, we summarize the epidemiology of VTE, risk models identifying high-risk conditions associated with VTE, and prevention and treatment strategies. We further describe successful quality improvement efforts implementing institutional VTE risk stratification and thromboprophylaxis procedures. Finally, we highlight unique challenges facing pediatric hospital medicine specialists in the era of the COVID-19 pandemic, including caring for adults admitted to pediatric hospital units, and describe future research opportunities for VTE in the noncritically ill hospitalized child.

Venous Thromboembolism in Premature Neonates.

While the incidence of venous thromboembolism (VTE) is lower among children than adults, the newborn period is one of two bimodal peaks (along with adolescence) in VTE incidence in the pediatric population. Most VTE cases in neonates occur among critically ill neonates being managed in the neonatal intensive care unit, and most of these children are born premature. For this reason, the presentation, diagnosis, management, and outcomes of VTE among children born premature deserve special emphasis by pediatric hematologists, neonatologists, pharmacists, and other pediatric health care providers, as well as by the scientific community, and are described in this review.

Defining the Healthy Infant Metabolome: Liquid Chromatography Tandem-Mass Spectrometry Analysis of Dried Blood Spot Extracts from the Prospective Research on Early Determinants of Illness and Children's Health Trajectories Birth Cohort Study.

Newborn screening using dried plasma spots offers preanalytical advantages over conventional cards for plasma-associated targets of interest. Herein we present dried plasma spot-based methods for measuring metabolites using a 250+ compound liquid chromatography tandem mass spectrometry library. Quality assurance reduced this library to 134, and from these, 30 compounds determined the normal newborn reference ranges.

A phase 2 pharmacodynamic dose-finding, safety, and efficacy study of dalteparin for pediatric venous thromboembolism treatment in children with and without cancer.

Data from registrational trials of pediatric venous thromboembolism (VTE) treatment are sparse, especially among cancer patients. We conducted a prospective, multicenter, open-label trial (NCT00952380) on dose-finding, safety, and efficacy (measured by 90-day risks of clinically relevant bleeding [CRB] and symptomatic recurrent VTE [srVTE]) of twice-daily subcutaneous dalteparin for acute VTE treatment in patients ≤18 years old. Among 38 patients (cancer, n = 26; noncancer, n = 12), median dalteparin dose requirements per kilogram varied with age but not cancer status. Risks of CRB and srVTE were <4% in cancer and noncancer subgroups. Dalteparin is an important FDA-approved treatment for pediatric VTE, particularly with cancer.

A New Risk Assessment Model for Hospital-Acquired Venous Thromboembolism in Critically Ill Children: A Report From the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVES: To create a risk model for hospital-acquired venous thromboembolism in critically ill children upon admission to an ICU. DESIGN: Case-control study. SETTING: ICUs from eight children's hospitals throughout the United States. SUBJECTS: Critically ill children with hospital-acquired venous thromboembolism (cases) 0-21 years old and similar children without hospital-acquired venous thromboembolism (controls) from January 2012 to December 2016. Children with a recent cardiac surgery, asymptomatic venous thromboembolism, or a venous thromboembolism diagnosed before ICU admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The multi-institutional Children's Hospital-Acquired Thrombosis registry was used to identify cases and controls. Multivariable logistic regression was used to determine the association between hospital-acquired venous thromboembolism and putative risk factors present at or within 24 hours of ICU admission to develop the final model. A total of 548 hospital-acquired venous thromboembolism cases (median age, 0.8 yr; interquartile range, 0.1-10.2) and 187 controls (median age, 2.4 yr; interquartile range, 0.2-8.3) were analyzed. In the multivariable model, recent central venous catheter placement (odds ratio, 4.4; 95% CI, 2.7-7.1), immobility (odds ratio 3.6, 95% CI, 2.1-6.2), congenital heart disease (odds ratio 2.9, 95% CI, 1.7-4.7), length of hospital stay prior to ICU admission greater than or equal to 3 days (odds ratio, 2.5; 95% CI, 1.1-5.6), and history of autoimmune/inflammatory condition or current infection (odds ratio, 2.1; 95% CI, 1.2-3.4) were each independently associated with hospital-acquired venous thromboembolism. The risk model had an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.73-0.84). CONCLUSIONS: Using the multicenter Children's Hospital-Acquired Thrombosis registry, we identified five independent risk factors for hospital-acquired venous thromboembolism in critically ill children, deriving a new hospital-acquired venous thromboembolism risk assessment model. A prospective validation study is underway to define a high-risk group for risk-stratified interventional trials investigating the efficacy and safety of prophylactic anticoagulation in critically ill children.

A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD.

OBJECTIVES: To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0-18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria. RESULTS: We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common. CONCLUSION: There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.

Community-Onset Venous Thromboembolism in Children: Pediatric Emergency Medicine Perspectives.

Pediatric venous thromboembolism (VTE) is a condition increasingly encountered by emergency medicine physicians. Unfortunately, despite increased incidence, the diagnosis of pediatric VTE relies on a high index of suspicion from clinicians. Delays in diagnosis and initiation of treatment can lead to poor outcomes in children, including an increased risk of mortality from pulmonary embolism, increased risk of VTE recurrence, and the development of the post-thrombotic syndrome. The majority of pediatric VTE events are associated with the presence of at least one underlying prothrombotic risk. Timely recognition of these risk factors in the emergency department (ED) setting is paramount for a prompt diagnosis and treatment initiation. Compared with children with hospital-acquired VTE, children presenting to the ED with new onset VTE tend to be older (>11 years of age), have a lower incidence of co-morbidities, and present more frequently with a deep venous thrombosis of the lower extremity. Currently, there are no validated pediatric-specific VTE clinical pretest probability tools that reliably assist with the accurate and timely diagnosis of pediatric VTE. Compression ultrasound with Doppler is the most common imaging modality used for VTE diagnosis, and low molecular weight heparins are the most common anticoagulants initiated in children presenting with VTE in the ED. Special consideration should be given to patients who present to the ED already on anticoagulation therapy who may require acute management for clinically-significant bleeding or change in antithrombotic therapy approach for progression/recurrence of VTE.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature.

Venous thromboembolism (VTE) in children can lead to significant morbidity and mortality. Traditionally, treatment for thrombotic events in pediatric patients has been limited mainly to unfractionated heparin, low-molecular-weight heparin (LMWH), or vitamin K antagonists. Since the first non-vitamin K antagonist oral anticoagulant (NOAC) was approved for adult use, these agents have gained popularity for a variety of indications. This is largely due to their ease of administration, favorable pharmacokinetic and pharmacodynamic profile, decreased food interactions, and decreased need for therapeutic drug monitoring. Treating and preventing VTE with traditional anticoagulants in pediatric patients presents many challenges. This systematic review evaluated the current literature regarding pediatric NOAC trials. Additionally, based on an up-to-date query of clinicaltrials.gov, we detail current ongoing and as-yet unpublished clinical trials, study outcomes, and projected completion dates. Published pediatric NOAC trials have included 1,007 total children to date and have ranged from phase 1 to 4, with "indications" including both thromboembolism prophylaxis and VTE treatment. Three recent phase 3 trials, specifically involving rivaroxaban and dabigatran, have shown the agents to be at least as effective as traditional anticoagulants for acute and/or extended VTE treatment, with low frequency of recurrent thrombosis and clinically significant bleeding rates. Additionally, specially developed and tested pediatric formulations have allowed for accurate and reliable dosing, oral administration, stable pharmacokinetics and pharmacodynamics, and fewer drug or food interactions. Ongoing trials, anticipated for completion in the next few years, will reveal important information with regard to thromboembolism prophylaxis in special pediatric subpopulations and settings.

A Retrospective Study of Tinea Capitis Management in General Pediatric Clinics and Pediatric Emergency Departments at 2 US Centers.

We examine management practices of tinea capitis at 2 US academic centers. The majority of providers treated tinea capitis with the oral antifungal agent griseofulvin and did not obtain a fungal culture. We recommend newer antifungal treatments such as terbinafine and fluconazole and obtaining a fungal culture for effective treatment.

ENNOBLE-ATE trial: an open-label, randomised, multi-centre, observational study of edoxaban for children with cardiac diseases at risk of thromboembolism.

Children with cardiac diseases suffer from significant morbidity and mortality secondary to thromboembolic complications. Anticoagulant agents currently used for thromboprophylaxis have many limitations, including subcutaneous administration (low molecular weight heparins) and requirement for frequent monitoring via venipuncture (vitamin K antagonists). Edoxaban is an oral direct factor Xa inhibitor without need of monitoring. In the treatment of venous thromboembolism in adults, edoxaban has shown to be effective and safe.This manuscript summarises the rationale and design of a phase 3, open-label, randomised controlled trial to evaluate and compare the safety and efficacy of edoxaban against standard of care (namely, vitamin K antagonist and low molecular weight heparin) in children with cardiac diseases.A goal of 150 children with cardiac diseases at risk of thromboembolic complications who need primary or secondary anticoagulant prophylaxis will be recruited. Eligible children between 6 months and <18 years of age will be randomised in a ratio of 2 to 1 for edoxaban versus standard of care. Randomisation will be stratified based on underlying cardiac disease and concomitant use of aspirin for patients other than Kawasaki disease. The primary outcome will be safety, comprised of major and clinically relevant non-major bleeding in first 3 months of treatment. Bleeding beyond 3 months, symptomatic and asymptomatic thromboembolic events, and pharmacokinetic and pharmacodynamic parameters will be evaluated as secondary outcomes.Randomised controlled anticoagulation trials are challenging in children. This study will evaluate a potentially valuable alternative of oral anticoagulant prophylactic use in children with cardiac diseases.

Plasma Proteomic Analysis Reveals Age-Specific Changes in Platelet- and Endothelial Cell-Derived Proteins and Regulators of Plasma Coagulation and Fibrinolysis.

This post hoc study of a plasma proteomic database investigated hemostatic proteins in the context of developmental hemostasis. Twenty-seven hemostatic proteins changed expression with age, and the hemostatic profile of neonates was unique. Appreciating developmental hemostasis through proteomics may lead to more personalized medicine for hospitalized children.

Group sequential designs for clinical trials with bivariate endpoints.

Although all clinical trials are designed and monitored using more than one endpoint, methods are needed to assure that decision criteria are chosen to reflect the clinically relevant tradeoffs that assure the trial's scientific integrity. This article presents a framework for the design and monitoring clinical trials in a bivariate outcome space. The framework uses a rectangular hyperbola to define a bivariate null curve that divides outcome space into regions of benefit and lack of benefit. The curve is shown to be a flexible mapping of bivariate space that allows a continuous tradeoff between the two endpoints in a manner that captures many previous bivariate designs. The curve is extended to a distance function in bivariate space that allows different decisions in each of the four quadrants that comprise bivariate space. The distance function forms a statistic ( δ ); the distribution of its estimate is derived and used as a basis for trial design and group sequential monitoring plans in bivariate space. A recursive form of the bivariate group sequential density is used to evaluate and control operating characteristics for the proposed design. The bivariate designs are shown to meet or exceed the usual standards for size and power. The proposed design is illustrated in the ongoing NHLBI-sponsored Kids-DOTT multinational randomized controlled trial comparing shortened versus conventional anticoagulation for the treatment of venous thromboembolism in patients less than 21 years of age. The proposed methods are broadly applicable to a wide range of clinical settings and trial designs.