Publications by authors named "Leonardo R Brandão"

82 Publications

Characterization of physical literacy in children with chronic medical conditions compared to healthy controls: a cross-sectional study.

Appl Physiol Nutr Metab 2021 Mar 9. Epub 2021 Mar 9.

Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.

To determine the physical literacy, defined as the capability for a physically active lifestyle, of children with medical conditions compared with healthy peers, this multicenter cross-sectional study recruited children with medical conditions from cardiology, neurology (including concussion), rheumatology, mental health, respirology, oncology, hematology, and rehabilitation (including cerebral palsy) clinics. Participants aged 8-12 years (N=130; mean age: 10.0±1.44 years; 44% female) were randomly matched to three healthy peers from a normative database, based on age, sex, and month of testing. Total physical literacy was assessed by the Canadian Assessment of Physical Literacy, a validated assessment of physical literacy measuring physical competence, daily behavior, knowledge/understanding, and motivation/confidence. Total physical literacy mean scores(/100) did not differ (t(498)=-0.67; p=0.44) between participants (61.0±14.2) and matched healthy peers (62.0±10.7). Children with medical conditions had lower mean physical competence scores (/30; -6.5 [-7.44, -5.51]; p<0.001) but higher mean motivation/confidence scores (/30; 2.6 [1.67, 3.63]; p<0.001). Mean daily behavior and knowledge/understanding scores did not differ from matches (/30; 1.8 [0.26, 3.33]; p=0.02; /10; -0.04 [-0.38, 0.30]; p=0.81; respectively). Children with medical conditions are motivated to be physically active but demonstrate impaired movement skills and fitness, suggesting the need for targeted interventions to improve their physical competence. Novelty bullets: • Physical literacy in children with diverse chronic medical conditions is similar to healthy peers • Children with medical conditions have lower physical competence than healthy peers, but higher motivation and confidence • Physical competence (motor skill, fitness) interventions, rather than motivation or education, are needed for these youth.
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http://dx.doi.org/10.1139/apnm-2020-0957DOI Listing
March 2021

Pediatric May-Thurner Syndrome-Systematic review and individual patient data meta-analysis.

J Thromb Haemost 2021 Mar 2. Epub 2021 Mar 2.

The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: The outcomes of deep vein thrombosis (DVT) in children with May-Thurner Syndrome (MTS) remain unclear.

Objectives: This systematic review and patient-level meta-analysis aims to describe the outcomes of children with MTS presenting with DVT.

Methods: A systematic review of the published literature was performed. Data related to patients <18 years diagnosed with MTS and DVT was extracted. Risk of bias was assessed using the Murad criteria. Outcomes included vessel patency post-treatment, DVT recurrence, and post-thrombotic syndrome (PTS). Predictive and explanatory models were developed for these outcomes.

Results: In total, 109 cases were identified (age range 4-17 years; 77 females) in 28 studies; 75% of patients had ≥1 additional risk factor for DVT. PTS was seen in 61% of patients, DVT recurrence in 38%, and complete vessel patency post-treatment in 65%. The models developed to predict and explain PTS performed poorly overall. Recurrent thrombosis (adjusted for age and patency) predicted PTS (odds ratio [OR] 3.36, 95% confidence interval [CI] 1.28-8.82). DVT management strategies (adjusted for age and DVT characteristics) predicted vessel patency (OR 2.10, 95% CI 1.43-3.08). Lack of complete vessel patency (adjusted for age and thrombophilia) predicted recurrent DVT (OR 2.70, 95% CI 1.09-6.67). Sensitivity analyses showed the same direction of effects for all outcomes.

Conclusions: PTS and DVT recurrence occur frequently in pediatric MTS. PTS prediction is complex and it was not possible to identify early predictors to guide clinical practice. Use of imaging-guided therapy and thrombus burden predicted venous patency, and lack of patency predicted DVT recurrence.
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http://dx.doi.org/10.1111/jth.15284DOI Listing
March 2021

Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism.

J Thromb Haemost 2021 Feb 26. Epub 2021 Feb 26.

Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

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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http://dx.doi.org/10.1111/jth.15277DOI Listing
February 2021

Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

Lancet Haematol 2021 Jan 5;8(1):e22-e33. Epub 2020 Dec 5.

Hematology Department, University Children's Hospital, Zurich, Switzerland. Electronic address:

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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http://dx.doi.org/10.1016/S2352-3026(20)30368-9DOI Listing
January 2021

Coagulation issues in vascular anomalies.

Semin Pediatr Surg 2020 Oct 16;29(5):150966. Epub 2020 Sep 16.

The Hospital for Sick Children, Division of Haematology-Oncology, Toronto, Ontario, Canada.

Vascular anomalies, comprised of vascular tumors and malformations, are frequently associated with coagulopathy. Recognition of and familiarity with these vascular anomaly-associated hematologic abnormalities prior to surgery or interventional procedures is essential for pre-operative pre-operative planning. Complicated coagulopathies present within the framework of either Kasabach-Merritt phenomenon (KMP) or localized intravascular coagulopathy (LIC), and their management benefits from the expertise of a hematologist for optimal intra- and peri‑operative care. Furthermore, with the recent broadening of understanding of vascular anomalies and the addition of new classification sub-groups, distinctions of these two classic coagulopathy phenotypes have been recognized. This review summarizes the main features of these coagulopathies, described according to their vascular anomaly type, highlighting clinical aspects relevant to surgical management.
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http://dx.doi.org/10.1016/j.sempedsurg.2020.150966DOI Listing
October 2020

Cancer and Tumor-Associated Childhood Stroke: Results From the International Pediatric Stroke Study.

Pediatr Neurol 2020 10 10;111:59-65. Epub 2020 Jun 10.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: The prevalence of cancer among children with stroke is unknown. This study sought to evaluate cancer- and tumor-associated childhood ischemic stroke in a multinational pediatric stroke registry.

Methods: Children aged 29 days to less than 19 years with arterial ischemic stroke or cerebral sinovenous thrombosis enrolled in the International Pediatric Stroke Study between January 2003 and June 2019 were included. Data including stroke treatment and recurrence were compared between subjects with and without cancer using Wilcoxon rank sum and chi-square tests.

Results: Cancer or tumor was present in 99 of 2968 children (3.3%) with arterial ischemic stroke and 64 of 596 children (10.7%) with cerebral sinovenous thrombosis. Among children in whom cancer type was identified, 42 of 88 arterial ischemic stroke cases (48%) had brain tumors and 35 (40%) had hematologic malignancies; 45 of 58 cerebral sinovenous thrombosis cases (78%) had hematologic malignancies and eight (14%) had brain tumors. Of 54 cancer-associated arterial ischemic stroke cases with a known cause, 34 (63%) were due to arteriopathy and nine (17%) were due to cardioembolism. Of 46 cancer-associated cerebral sinovenous thrombosis cases with a known cause, 41 (89%) were related to chemotherapy-induced or other prothrombotic states. Children with cancer were less likely than children without cancer to receive antithrombotic therapy for arterial ischemic stroke (58% vs 80%, P = 0.007) and anticoagulation for cerebral sinovenous thrombosis (71% vs 87%, P = 0.046). Recurrent arterial ischemic stroke (5% vs 2%, P = 0.04) and cerebral sinovenous thrombosis (5% vs 1%, P = 0.006) were more common among children with cancer.

Conclusions: Cancer is an important risk factor for incident and recurrent childhood stroke. Stroke prevention strategies for children with cancer are needed.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.06.002DOI Listing
October 2020

Bleeding risk associated with combination thromboprophylaxis therapy is low for patients with coronary artery aneurysms after Kawasaki disease.

Int J Cardiol 2020 Dec 19;321:6-11. Epub 2020 Jul 19.

Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Cardiology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address:

Background: Kawasaki disease (KD) may lead to coronary artery aneurysms (CAA) with potential for thrombosis. We aimed to determine the bleeding risk during thromboprophylaxis regimens with dual and triple therapy.

Methods: KD patients with medium to large CAAs receiving combination thromboprophylaxis therapy (dual or triple therapy with acetylsalicylic acid (ASA), clopidogrel, low molecular weight heparin (LMWH) or warfarin) were reviewed (1979-2017). Treatment periods <30 days were excluded. Bleeding events were classified using the Bleeding Academic Research Consortium (BARC) Score. The incidence of bleeding events per patient year of exposure was determined for each regimen.

Results: n = 98 of 3022 KD (23 females:75 males) were included. Median age at diagnosis was 2.6 years (IQR: 0.6-6.2), median maximum CAA z-score was 18.0 (range: 5-65.5, IQR: 10.8-28.0, m = 6) and median follow-up duration was 6.5 years (IQR: 2.5-20.2). The incidence of type ≥2 bleeds per patient-year for each regimen was 0 (ASA + clopidogrel+LMWH), 0.03 (ASA + clopidogrel), 0.06 (ASA + warfarin), 0.06 (ASA + clopidogrel+warfarin), and 0.1 (ASA + LMWH) in ascending order. 31 bleeding events requiring medical attention (type ≥2) occurred in 30 patients (median age 7.8 years). Of the 17 type ≥2 bleeds on warfarin with an International Normalised Ratio (INR) available, 13 occurred with an INR >3. For patients receiving triple therapy (dual antiplatelet with anticoagulant), there were 57 bleeding events over 20 treatment periods.

Conclusions: The overall bleeding risk was low in KD patients receiving combination thromboprophylaxis, and not significantly different across all regimens. Type ≥2 bleeding events that occurred on warfarin were most frequently associated with high INR values.
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http://dx.doi.org/10.1016/j.ijcard.2020.07.022DOI Listing
December 2020

Heparin-Induced Thrombocytopenia in a Pediatric Population: Implications for Clinical Probability Scores and Testing.

J Pediatr 2020 Jul 5. Epub 2020 Jul 5.

Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address:

Objectives: To determine the applicability of the 4Ts score and the Heparin-Induced Thrombocytopenia (HIT) Expert Probability (HEP) score in children with suspected HIT and to estimate the number of children potentially at risk of HIT.

Study Design: We retrospectively estimated 4Ts and HEP scores in a cohort of 50 children referred for laboratory screening with enzyme immunoassay. In addition, minor modifications were introduced to the 4Ts score (modified 4Ts score) to adapt it for use in the pediatric setting. All patients with positive enzyme immunoassays were tested with serotonin release assay. We also extracted the number of patients started on heparins in a similar period of time.

Results: The median age at the time of testing was 4 years (25th-75th percentile, 8.7 months to 13.5 years); 78% of patients had low and 22% had intermediate risk pretest probability scores using the original 4Ts score; 86% had low risk and 14% had intermediate risk scores using the modified 4Ts score; 54% of children had a HEP score of ≥2. Six patients (12%) had a positive (≥0.40 optical density units) enzyme immunoassay, but none had a positive serotonin release assay. Based on anticoagulation dose, there were 1-2 new daily potentially high-risk exposures to heparinoids at our institution.

Conclusions: The modified 4Ts and original 4Ts scores may be more adequate than the HEP score to determine HIT pretest probability in children. Despite the number of patients potentially at risk, HIT is rare in pediatrics.
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http://dx.doi.org/10.1016/j.jpeds.2020.06.081DOI Listing
July 2020

Predictors of postthrombotic syndrome in pediatric thrombosis: A systematic review and meta-analysis of the literature.

J Thromb Haemost 2020 10 26;18(10):2601-2612. Epub 2020 Aug 26.

Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Postthrombotic syndrome (PTS) is a significant complication of pediatric deep venous thrombosis (DVT). There is a gap in the understanding of the risk factors associated with the development of pediatric PTS preventing the early identification of those patients at greatest risk, and the development of risk-stratified interventions.

Objectives: To conduct a systematic review and meta-analysis of the literature on prognostic factors for PTS development in pediatric patients.

Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library from 1960 to December 2018 was performed. Eligible studies reported at least one prognostic factor for PTS development in patients < 21 years of age with a radiographically confirmed DVT. To be included in the meta-analysis, prognostic factors had to be reported in at least three published studies.

Results And Conclusions: Twelve studies (n = 1160 patients) met criteria for inclusion. Ninety-three percent of patients with an extremity DVT (n = 1076) were assessed for PTS. PTS developed in 40% (n = 434) of these patients. Central venous catheter-associated DVT (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.08-2.98), complete veno-occlusion (OR, 1.89; 95% CI, 1.04-3.46), and incomplete DVT resolution (OR, 2.07; 95% CI, 1.4-3.07) were identified as candidate prognostic factors for pediatric PTS. These findings should be interpreted in the context of the heterogeneity of the included studies and the limitations of current pediatric PTS assessment tools. Further, the predictive value of these prognostic factors will need to be validated in future collaborative prospective multicenter studies that maximize the homogeneity of pediatric DVT patients.
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http://dx.doi.org/10.1111/jth.14984DOI Listing
October 2020

Low molecular weight heparin for prevention of central venous catheter-related thrombosis in children.

Cochrane Database Syst Rev 2020 06 18;6:CD005982. Epub 2020 Jun 18.

Division of Haematology-Oncology, The Hospital for Sick Children, Toronto, Canada.

Background: The prevalence of children diagnosed with thrombotic events has been increasing in the last decades. The most common thrombosis risk factor in neonates, infants and children is the placement of a central venous catheter (CVC). It is unknown if anticoagulation prophylaxis with low molecular weight heparin (LMWH) decreases CVC-related thrombosis in children. This is an update of the Cochrane Review published in 2014.

Objectives: To determine the effect of LMWH prophylaxis on the incidence of CVC-related thrombosis and major and minor bleeding complications in children. Further objectives were to determine the effect of LMWH on occlusion of CVCs, number of days of CVC patency, episodes of catheter-related bloodstream infection (CRBSI), other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis) and mortality during therapy.

Search Methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 7 May 2019. We undertook reference checking of identified trials to identify additional studies.

Selection Criteria: We included randomised controlled trials (RCTs) and quasi-randomised trials comparing LMWH to no prophylaxis (placebo or no treatment), or low-dose unfractionated heparin (UFH) either as continuous infusion or flushes (low-dose UFH aims to ensure the patency of the central line but has no systemic anticoagulation activity), given to prevent CVC-related thrombotic events in children. We selected studies conducted in children aged 0 to 18 years.

Data Collection And Analysis: Two review authors independently identified eligible studies, which were assessed for study methodology including bias, and extracted unadjusted data where available. In the data analysis step, all outcomes were analysed as binary or dichotomous outcomes. The effects of interventions were summarised with risk ratios (RR) and their respective 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach.

Main Results: One additional study was included for this update bringing the total to two included studies (with 1135 participants). Both studies were open-label RCTs comparing LMWH with low-dose UFH to prevent CVC-related thrombosis in children. We identified no studies comparing LMWH with placebo or no treatment. Meta-analysis found insufficient evidence of an effect of LMWH prophylaxis in reducing the incidence of CVC-related thrombosis in children with CVC, compared to low-dose UFH (RR 0.68, 95% CI 0.27 to 1.75; 2 studies; 787 participants; low-certainty evidence). One study (158 participants) reported symptomatic and asymptomatic CVC-related thrombosis separately and detected no evidence of a difference between LMWH and low-dose UFH (RR 1.03, 95% CI 0.21 to 4.93; low-certainty evidence; RR 1.17, 95% CI 0.45 to 3.08; low-certainty evidence; for symptomatic and asymptomatic participants respectively). There was insufficient evidence to determine whether LMWH impacts the risk of major bleeding (RR 0.27, 95% CI 0.05 to 1.67; 2 studies; 813 participants; low-certainty evidence); or minor bleeding. One study reported minor bleeding in 53.3% of participants in the LMWH arm and in 44.7% of participants in the low-dose UFH arm (RR 1.20, 95% CI 0.91 to 1.58; 1 study; 158 participants; very low-certainty evidence), and the other study reported no minor bleeding in either group (RR: not estimable). Mortality during the study period was reported in one study, where two deaths occurred during the study period. Both were unrelated to thrombotic events and occurred in the low-dose UFH arm. The second study did not report mortality during therapy per arm but showed similar 5-year overall survival (low-certainty evidence). No additional adverse effects were reported. Other pre-specified outcomes (including CVC occlusion, patency and CRBSI) were not reported.

Authors' Conclusions: Pooling data from two RCTs did not provide evidence to support the use of prophylactic LWMH for preventing CVC-related thrombosis in children (low-certainty evidence). Evidence was also insufficient to confirm or exclude a difference in the incidence of major and minor bleeding complications in the LMWH prophylaxis group compared to low-dose UFH (low and very low certainty respectively). No evidence of a clear difference in overall mortality was seen. Studies did not report on the outcomes catheter occlusion, days of catheter patency, episodes of CRBSI and other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis). The certainty of the evidence was downgraded due to risk of bias of the included studies, imprecision and inconsistency, preventing conclusions in regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombosis in children.
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http://dx.doi.org/10.1002/14651858.CD005982.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390480PMC
June 2020

Different unfractionated heparin doses for preventing arterial thrombosis in children undergoing cardiac catheterization.

Cochrane Database Syst Rev 2020 02 17;2:CD010196. Epub 2020 Feb 17.

The Hospital for Sick Children, Division of Haematology-Oncology, 555 University Avenue, Toronto, ON, Canada, M5G 1X8.

Background: The role of cardiac catheterization in pediatrics has progressed significantly over the last two decades, evolving from a primary diagnostic tool to a primary treatment modality in children with congenital heart disease. Vascular complications, particularly arterial thrombosis, are among the most common unwanted post-cardiac catheterization events. In 1974, unfractionated heparin proved to be superior to placebo in decreasing the incidence of arterial thrombosis in pediatric patients. However, the optimal dose of unfractionated heparin to be utilized in this setting remains a matter of controversy. This is an update of the review first published in 2014.

Objectives: To evaluate the use of low-dose (< 100 units/kg) versus high-dose (≥ 100 units/kg) unfractionated heparin administered as an intravenous bolus at the time of initiation of cardiac catheterization (that is, immediately after arterial puncture), with or without subsequent heparin maintenance doses, for the prevention of post-procedural arterial thrombosis in children.

Search Methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 15 October 2019. We planned to undertake reference checking of identified trials to identify additional studies. No language restrictions were applied.

Selection Criteria: We included randomized or quasi-randomized trials that compared low dose to high dose unfractionated heparin administered prior to cardiac catheterization. We selected studies conducted in children aged 0 to 18 years.

Data Collection And Analysis: The first screening of potentially eligible studies was conducted by one of the authors (MLA). The second screening, risk of bias assessment and data extraction were independently conducted by two authors (MLA, LRB). Outcomes (thrombotic events, bleeding complications, other complications) were treated as dichotomous variables. The effect measures used were risk ratio (RR), risk difference (RD) and number needed to treat (NNT), with 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach.

Main Results: We identified no new studies for inclusion in this review. In total, two studies with a total of 492 participants were included. We had concerns about risk of bias for one of the two studies. The certainty of the evidence for our key outcomes was downgraded to moderate due to risk of bias concerns and imprecision. The confidence interval for the risk of arterial thrombotic events was compatible with benefits of either high or low unfractionated heparin dose regimens (RR low-dose versus high-dose 1.06, 95% CI 0.58 to 1.92). Only one of the studies reported the frequency of bleeding events and found no clear difference in the incidence of major or minor bleeding events between arms (RR low-dose versus high-dose 2.96, 95% CI 0.12 to 71.34 for major bleeding events; RR low-dose versus high-dose 1.38, 95% CI 0.46 to 4.13 for minor bleeding). This study also reported on the incidence of deep vein thrombosis when comparing the high versus low dose of heparin and reported a non-significant difference (RR low-dose versus high-dose 0.34, 95% CI 0.01 to 8.28). The other study lacked information about bleeding. Additional side effects of heparin other than bleeding events were not reported in either of the studies.

Authors' Conclusions: Due to the limitations of the current evidence, small number of included studies, and lack of details reported in one study, we are unable to determine the effects of different dosing regimens of unfractionated heparin for the prevention of vascular thrombosis during cardiac catheterization in children. Further adequately powered, randomized clinical trials are needed.
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http://dx.doi.org/10.1002/14651858.CD010196.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025780PMC
February 2020

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

Blood 2020 02;135(7):491-504

Pediatric Hematology/Oncology Department, Pediatric Hospital Bambino Gesù, Rome, Italy.

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to <18 years (age stratum 1), 2 to <12 years (stratum 2), and >3 months to <2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from >3 months to <18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.
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http://dx.doi.org/10.1182/blood.2019000998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019192PMC
February 2020

CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.

Pharmacogenomics J 2020 04 1;20(2):306-319. Epub 2019 Nov 1.

Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.
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http://dx.doi.org/10.1038/s41397-019-0117-xDOI Listing
April 2020

Post-thrombotic syndrome in children: Measurement properties of CAPTSure, a new diagnostic tool.

Res Pract Thromb Haemost 2019 Oct 28;3(4):652-657. Epub 2019 Aug 28.

Department of Pediatrics The Hospital for Sick Children Toronto ON Canada.

Background: CAPTsure (Clinical Assessment of PTS) is a new tool for diagnosis and severity rating of pediatric postthrombotic syndrome (PTS). Our objective was to test the reliability, measurement error, and minimal detectable change of CAPTSure.

Methods: Children aged newborn to 18 years who sustained upper extremity or lower extremity deep vein thrombosis (DVT) were enrolled ≥ 6 months after DVT diagnosis. Patients were assessed by 2 raters to determine the reliability of the clinician assessment component (CC) of CAPTSure. Patients/proxies completed CAPTSure at baseline and approximately 2 weeks later to assess test-retest reliability of the symptoms component (SC).

Results: Of 148 patients enrolled in the study; 30 had sustained either bilateral or both upper and lower extremity DVT. Hence, 178 extremities were assessed for PTS signs (86 upper extremity, 92 lower extremity). Intraclass correlation coefficient (ICC) for the CC was 0.89 (95% confidence interval [CI], 0.84-0.93) for upper extremity and 0.88 (95% CI, 0.83-0.92) for lower extremity. Nonclinicians performed 59% of measurements. Ninety-eight patients completed the SC at baseline and follow-up, for a total of 60 upper extremity and 61 lower extremity assessments. ICC for the SC was 0.89 (95% CI, 0.84-0.93) for upper extremity and 0.92 (0.87-0.95) for lower extremity. ICC for CAPTSure was 0.92 (95% CI, 0.87-0.95) for upper extremity and 0.93 (95% CI, 0.88-0.95) for lower extremity assessment. Measurement error ranged between 1.7 and 4.3 of 100 points. A change of approximately 11 of 100 points in CAPTSure score would be required to be confident that there was a change in PTS severity.

Conclusion: CAPTSure has excellent reliability and a small measurement error, even when applied by nonhematologists.
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http://dx.doi.org/10.1002/rth2.12251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781925PMC
October 2019

Abnormal hemostasis in children with vascular anomalies, part I: Thrombocytopenias among different vascular anomalies.

Thromb Res 2020 12 13;196:626-634. Epub 2019 Jun 13.

Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address:

Long before the classification of vascular anomalies from the International Society for the Study of Vascular Anomalies (ISSVA) provided a framework to differentiate vascular anomalies, otherwise known as vascular birthmarks, it was recognized that patients with such lesions can present with acute life-threatening hemostatic and/or thrombotic complications, as well as chronic long-standing bleeding or thrombotic issues. Scenarios such as a rapidly growing vascular lesion with severe acute thrombocytopenia, a visceral hemorrhagic lesion, a lesion associated with repetitive and painful superficial thrombosis, and cases of unprovoked or post-procedural fatal pulmonary embolism highlight the wide spectrum of manifestations of abnormal coagulation in patients with vascular anomalies. The separation of vascular anomalies into two distinct groups, vascular tumors and vascular malformations, was followed by the characterization that their respective coagulopathies were due to either a derangement of platelets or to a disequilibrium of the patient's coagulation/fibrinolytic process. This configuration of coagulopathies will be the foundation for this two-chapter review series. In the initial review, coagulopathies where thrombocytopenia is the main feature will be characterized, whereas the second review will focus on vascular malformations that have a coagulation disorder secondary to some degree of coagulation consumption and/or fibrinolytic pathway derangement.
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http://dx.doi.org/10.1016/j.thromres.2019.06.004DOI Listing
December 2020

Clinical Impact of Chronic Venous Changes Induced by Central Lines in Children: A Cohort with Abnormal Venograms.

J Vasc Interv Radiol 2019 May 27;30(5):715-723. Epub 2019 Mar 27.

Image Guided Therapy, Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8, Canada.

Purpose: To explore the hypothesis that central venous stenosis/obstructions (CVS/O) in children are influenced by prior central venous access devices (CVADs) and are associated with future risk for thromboses.

Material And Methods: A convenience sample of 100 patients with abnormal venography (stenosis, collaterals, occlusions) documented during peripherally inserted central catheter (PICC) placements were identified from consecutive PICC placements (January 2008 to November 2012). The patients (41 males, 59 females, median age 2.7 years, median weight 11 kg) were categorized based on venographic presence (Group A, n = 53) or absence (Group B, n = 47) of visible connection to the superior vena cava. Each patient's CVAD history, before and after venography, was analyzed (until October 2016).

Results: Before venogram, Group B patients were associated with a higher number of previous CVADs, larger diameter devices, greater incidence of malposition, and more use of polyurethane catheters than Group A patients (P < .001). An ipsilateral PICC was successfully placed in 98% of Group A, compared to 32% of Group B (P < .001). After venogram, significantly more Doppler ultrasounds (DUS) were performed and thromboses diagnosed in Group B (57% and 36%) compared to Group A (21% and 8%) (P < .003; P = .001), respectively.

Conclusions: Previous catheter characteristics influenced the severity of venographic changes of CVS/O (Group B). Group B was associated with more subsequent symptomatic thromboses. This information may assist parents and referring physicians to anticipate potential adverse sequelae from CVS/O on the child's venous health.
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http://dx.doi.org/10.1016/j.jvir.2018.08.034DOI Listing
May 2019

Outcomes and risk factors of massive and submassive pulmonary embolism in children: a retrospective cohort study.

Lancet Haematol 2019 Mar 13;6(3):e144-e153. Epub 2019 Feb 13.

Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address:

Background: Little is known about severe pulmonary embolism in children. We aimed to report pulmonary embolism outcomes, identify risk factors for unfavourable outcomes, and evaluate the discriminative ability of two clinical-severity indices in children.

Methods: In this retrospective cohort study, we included consecutive patients aged 18 years or younger with acute pulmonary embolism, objectively diagnosed radiologically or pathologically, between Jan 1, 2000, and Dec 31, 2016, from two Canadian paediatric hospitals (The Hospital for Sick Children, Toronto, ON, and the Children's Hospital of Eastern Ontario, Ottawa, ON). Exclusion criteria were sudden death without radiological or pathological pulmonary embolism confirmation and non-thromboembolic pulmonary embolism. The primary outcome was a composite of unfavourable outcomes of pulmonary embolism-related death and pulmonary embolism recurrence or progression. Potential predictors of the composite unfavourable outcome (ie, age at pulmonary embolism diagnosis, sex, underlying cardiac disease, severity of the pulmonary embolism, presence of a central venous catheter, associated venous thromboembolism, family history of thrombosis, treatment modalities, thrombophilia, obesity, and recent surgery) were explored with logistic regression. We calculated pulmonary embolism severity index (PESI) and simplified PESI (sPESI) using age-adjusted parameters; we estimated the ability of PESI and sPESI to predict mortality using receiver-operating characteristic (ROC) curve analysis.

Findings: Of the 170 patients included, 37 (22%) had massive, 12 (7%) submassive, and 121 (71%) non-massive pulmonary embolism. Patients with massive or submassive pulmonary embolism were younger (median age 12·5 years [IQR 0·6-15·1] vs 14·4 years [9·3-16·1], p<0·0001), more likely to have a cardiac condition (16 [33%] vs 17 [14%] patients, p=0·009), and had more central venous catheters (29 [59%] vs 48 [40%] patients, p=0·027) than patients with non-massive pulmonary embolism. Aggressive treatment modalities were more commonly used in massive or submassive pulmonary embolism (22 [45%] vs 7 [6%] patients, p<0·0001). Of the predictors tested, only pulmonary embolism severity was associated with the composite unfavourable outcome in the multivariable analysis (odds ratio 3·53, 95% CI 1·69-7·36; p=0·011). The area under the ROC curve for PESI to predict 30-day mortality was 0·76 (95% CI 0·64-0·87). Sensitivity of sPESI was 100% and specificity was 30%.

Interpretation: Massive or submassive pulmonary embolism led to higher rates of unfavourable outcomes than non-massive pulmonary embolism in children. Further adaptations of PESI and sPESI are required to improve their clinical usefulness in paediatric patients.

Funding: Trainee Start-Up Fund (The Hospital for Sick Children).
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http://dx.doi.org/10.1016/S2352-3026(18)30224-2DOI Listing
March 2019

Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study.

Thromb J 2018 4;16:31. Epub 2018 Dec 4.

11Clinical Development, Bayer AG, Pharmaceuticals, Wuppertal, Germany.

Background: The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.

Methods: This was a multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5-18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5-2 years, 2-6 years, 6-12 years and 12-18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.

Results: Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.

Conclusions: Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.

Trial Registration: ClinicalTrials.gov number, NCT01145859.
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http://dx.doi.org/10.1186/s12959-018-0186-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278122PMC
December 2018

Characterization of Post-Thrombotic Syndrome in Children with Cardiac Disease.

J Pediatr 2019 04 7;207:42-48. Epub 2018 Dec 7.

Division of Haematology/Oncology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.

Objective: To assess the validity of existing clinical scales assessing the presence of physical and functional abnormalities for diagnosing post-thrombotic syndrome (PTS) in children, including specific evaluation of use in children with congenital heart disease (CHD).

Study Design: One hundred children aged >2 years (average age, 6 years), including 33 with CHD and previously proven extremity deep vein thrombosis (DVT), 37 with CHD and no previous DVT, and 30 healthy siblings, were blindly assessed for PTS using the modified Villalta Scale (MVS). All patients aged <6 years underwent neurodevelopmental testing and an age-appropriate quality of life assessment.

Results: The MVS identified mild PTS in 20 children and moderate PTS in 1 child (including 14 of 33 [42%] in the CHD/DVT group, 5 of 37 [14%] in the CHD/no DVT group, and 2 of 30 controls [7%]). The diagnosis of PTS was confirmed clinically in 14 patients, all of whom had previous thrombosis and 1 of whom was MVS-negative. MVS had an accuracy of 91% and performed reasonably well as a screening tool but poorly as a diagnostic tool. MVS reliability was acceptable. Children with PTS had similar quality of life as those without PTS but had higher rates of neurodevelopmental delays in gross motor skills (70% vs 24%; P = .02) and problem-solving indicators (60% vs 15%; P = .008).

Conclusions: Using the MVS scale for PTS screening in children with CHD is feasible and reliable, and the scale has good correlation with a clinical diagnosis of PTS despite a high prevalence of false-positive findings. Further research is needed to determine the clinical relevance of PTS in this population.
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http://dx.doi.org/10.1016/j.jpeds.2018.10.064DOI Listing
April 2019

American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism.

Blood Adv 2018 11;2(22):3292-3316

Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Background: Despite an increasing incidence of venous thromboembolism (VTE) in pediatric patients in tertiary care settings, relatively few pediatric physicians have experience with antithrombotic interventions.

Objective: These guidelines of the American Society of Hematology (ASH), based on the best available evidence, are intended to support patients, clinicians, and other health care professionals in their decisions about management of pediatric VTE.

Methods: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews (up to April of 2017). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

Results: The panel agreed on 30 recommendations, covering symptomatic and asymptomatic deep vein thrombosis, with specific focus on management of central venous access device-associated VTE. The panel also addressed renal and portal vein thrombosis, cerebral sino venous thrombosis, and homozygous protein C deficiency.

Conclusions: Although the panel offered many recommendations, additional research is required. Priorities include understanding the natural history of asymptomatic thrombosis, determining subgroup boundaries that enable risk stratification of children for escalation of treatment, and appropriate study of newer anticoagulant agents in children.
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http://dx.doi.org/10.1182/bloodadvances.2018024786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258911PMC
November 2018

Thromboembolism Incidence and Risk Factors in Children with Cancer: A Population-Based Cohort Study.

Thromb Haemost 2018 Sep 13;118(9):1646-1655. Epub 2018 Aug 13.

Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

There is conflicting information about the epidemiology of thromboembolism (TE) in paediatric oncology. Objectives were to describe the incidence and risk factors of TE in children with cancer. We included all children with cancer less than 15 years of age diagnosed from 2001 to 2016, treated at one of the 12 Canadian paediatric centres outside of Ontario and entered into the Cancer in Young People-Canada database. Potential risk factors for TE were evaluated using Cox proportional hazards regression stratified by haematological malignancies versus solid tumours. Factors associated with vascular access- and non-vascular access-related TE were compared using chi-square or Fisher's exact tests. Of the 7,471 children included, 283 experienced TE requiring medical intervention; cumulative incidence of TE at 5 years was 3.8 ± 0.2% and 0.36% ± 0.07% for life-threatening or fatal TE. For haematological malignancies, the following factors were associated with TE in multivariable regression: age < 1 year, 5 to 9.99 years and 10 to 14.99 years (relative to age 1-4.99 years), haematopoietic stem cell transplant (hazard ratio [HR] = 1.49, 95% confidence interval [CI], 1.00-2.32), anthracyclines (HR = 2.21, 95% CI, 1.12-4.37) and asparaginase (HR = 1.68, 95% CI, 1.15-2.44). For solid tumours, obesity (HR = 1.92, 95% CI, 1.01-3.68), surgery (HR = 2.70, 95% CI, 1.44-5.08), radiation (HR = 47.51, 95% CI, 24.01-94.01), anthracyclines (HR = 2.74, 95% CI, 1.29-5.82) and platinum agents (HR = 2.26, 95% CI, 1.19-4.28) were associated with TE. Life-threatening and fatal TEs were more common among non-vascular access TEs (14.5% vs. 3.3%  = 0.001). In a population-based cohort, 4% of children with cancer developed a clinically significant TE. Accurate risk stratification tools are needed specific to malignancy type.
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http://dx.doi.org/10.1055/s-0038-1668543DOI Listing
September 2018

Assessment of limb edema in pediatric post-thrombotic syndrome.

Res Pract Thromb Haemost 2018 Jul 17;2(3):591-595. Epub 2018 Apr 17.

Department of Pediatrics The Hospital for Sick Children Toronto ON Canada.

Background: Pediatric tools for diagnosis of post-thrombotic syndrome (PTS) include the assessment of limb edema as a symptom (patient/proxy-reported) and as a sign. However, it is unclear whether these two approaches refer to the same clinical aspect of PTS. This could result in overestimation of disease severity. We sought to evaluate the correlation among different techniques to assess limb edema as a sign and as a symptom in children who sustained upper extremity (UE) or lower extremity (LE) deep vein thrombosis (DVT) and were, therefore, at risk of PTS.

Methods: Limb edema was cross-sectionally measured as a symptom (ie, patient- or proxy-reported) and as a sign (ie, clinician-assessed limb circumference difference, limb volume ratio, bioimpedance spectroscopy ratio (BIS), and durometry ratio) in 140 children at risk of PTS (n = 70 UE-DVT, n = 70 LE-DVT). Item-item correlations were estimated using Pearson or Spearman correlation coefficients, as appropriate, and separately for the UE and LE groups.

Results: In the UE-DVT group, proxy-reported swelling correlated weakly to moderately with circumference difference and with volume ratio, but not with BIS ratio. In the LE-DVT group, proxy-reported swelling correlated moderately with thigh circumference difference and volume ratio, and patient-reported swelling correlated moderately with BIS ratio.

Conclusion: Our findings suggest that patient/proxy-reported and clinician-assessed limb edema measure slightly different aspects of PTS, justifying their inclusion in pediatric PTS tools. In addition, proxy-reported swelling was in closer agreement with clinician-assessed total limb size (ie, observed edema), and patient-reported swelling in the LE seemed to reflect limb fluid content (ie, perceived edema).
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http://dx.doi.org/10.1002/rth2.12082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046586PMC
July 2018

Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design.

Res Pract Thromb Haemost 2018 Jul 24;2(3):580-590. Epub 2018 Apr 24.

Department of Pediatrics Division of Hematology/Oncology The Hospital for Sick Children University of Toronto Toronto ON Canada.

Background: Anticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy.

Objectives: To address these concerns, a study was designed to evaluate the safety of dabigatran etexilate in children requiring secondary thrombus prevention in whom an initial VTE was associated with an identified risk factor that persisted after the acute VTE treatment period. We report herein the rationale and design of the study.

Patients/methods: This phase 3, open-label, single-arm, multicenter, multinational, prospective cohort study will be conducted in ≥100 children aged 0 to <18 years at ~100 specialist sites worldwide. Children will be treated with dabigatran etexilate for 12 months, or for a shorter duration if their identified VTE risk factor resolves, as per current American College of Chest Physicians recommendations. A nomogram will be used to determine starting doses for each patient.

Results: The primary outcomes of the study will be VTE recurrence, bleeding events, overall mortality, and VTE-related mortality. Secondary outcomes will include occurrence of post-thrombotic syndrome, the pharmacokinetics of dabigatran, and the need for dose adjustments during treatment. Data on adverse events during the study will also be collected.

Conclusion: This study will evaluate the safety of dabigatran etexilate for the secondary prevention of VTE in children, in addition to providing further data to guide pediatric dosing with dabigatran.
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http://dx.doi.org/10.1002/rth2.12093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046601PMC
July 2018

Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism.

Res Pract Thromb Haemost 2018 Apr 25;2(2):347-356. Epub 2018 Mar 25.

Children's Hospital of Eastern Ontario University of Ottawa Ottawa ON Canada.

Background: The current standard of care (SOC) for pediatric venous thromboembolism (VTE) comprises unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH) followed by LMWH or vitamin K antagonists, all of which have limitations. Dabigatran etexilate (DE) has demonstrated efficacy and safety for adult VTE and has the potential to overcome some of the limitations of the current SOC. Pediatric trials are needed to establish dosing in children and to confirm that results obtained in adults are applicable in the pediatric setting.

Objectives: To describe the design and rationale of a planned phase IIb/III trial that will evaluate a proposed dosing algorithm for DE and assess the safety and efficacy of DE versus SOC for pediatric VTE treatment.

Patients/methods: An open-label, randomized, parallel-group noninferiority study will be conducted in approximately 180 patients aged 0 to <18 years with VTE, who have received initial UFH or LMWH treatment and who are expected to require ≥3 months of anticoagulation therapy. Patients will receive DE or SOC for 3 months. DE will be administered twice daily as capsules, pellets, or an oral liquid formulation according to patient age. Initial doses will be calculated using a proposed dosing algorithm.

Results: There will be two coprimary endpoints: a composite efficacy endpoint comprising the proportion of patients with complete thrombus resolution, freedom from recurrent VTE and VTE-related mortality, and a safety endpoint: freedom from major bleeding events.

Conclusion: Findings will provide valuable information regarding the efficacy and safety of DE for the treatment of pediatric VTE. ClinicalTrials.gov registration number: NCT01895777.
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http://dx.doi.org/10.1002/rth2.12086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055566PMC
April 2018

Characteristics of pain, other symptoms and function in pediatric post-thrombotic syndrome.

Res Pract Thromb Haemost 2018 Apr 15;2(2):334-338. Epub 2018 Apr 15.

Department of Pediatrics The Hospital for Sick Children Toronto ON Canada.

Essentials:

Background: Symptoms and function in pediatric post-thrombotic syndrome (PTS) remain poorly characterized.

Methods: The present cross-sectional study describes the characteristics of pain, other symptoms, and impaired function in pediatric PTS in a cohort of children with history of upper or lower limb deep vein thrombosis and PTS diagnosis. The frequency of clinical findings was compared between patients with and without pain, and between patients with upper and lower extremity PTS.

Results: Seventy-eight children were included in the study. The most common PTS symptoms were pain, tired limb and heaviness. Symptoms were usually reported to occur at mid-day or later and were typically triggered by exercise. Half the patients reported impaired endurance. Pain was reported by 45% of patients and was usually mild-moderate. Heaviness, tightness, tired limb, paresthesia, self-reported limb edema, and impaired endurance were most common in patients with than in patients without pain. Conversely, activity and participation scores, skin redness, and clinician-assessed limb edema did not differ between patients with and without pain. Lastly, there was no difference in pain intensity or frequency of paresthesia, swelling, heaviness, or impaired endurance when comparing the upper and lower extremities.

Conclusion: Tired limb, heaviness, pain, and impaired endurance were the most frequent clinical findings in pediatric PTS. Frequency of symptoms and pain intensity did not differ between upper and lower extremities. Pain was associated with the presence of other symptoms and impaired function, but not with activity limitation and participation restriction. Better tools are needed to measure these two latter aspects of health.
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http://dx.doi.org/10.1002/rth2.12099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055484PMC
April 2018

Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism.

Res Pract Thromb Haemost 2018 Jan 17;2(1):69-76. Epub 2017 Nov 17.

Clinical Development Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield CT USA.

Background: The incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life-threatening. Idarucizumab is a fragment antigen-binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults.

Objective And Methods: This phase III, open-label, single-arm, multicenter, multinational trial will assess the safety of idarucizumab in children participating in two ongoing trials investigating dabigatran etexilate. Eligible patients will be children with VTE (aged 0-≤18 years; n = ~5) with life-threatening or uncontrolled bleeding (group A), and children who require emergency surgery/urgent procedures for a condition other than bleeding (group B). Patients will receive idarucizumab up to 5 g as two consecutive intravenous infusions over 5-10 minutes each, as two 10-15-minute drips or as two bolus injections (15 minutes apart) and will be monitored for 30 days. The primary endpoint will be the safety of idarucizumab assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality. Secondary endpoints will be the reversal of dabigatran anticoagulant effects assessed by changes in diluted thrombin time and ecarin clotting time, time to achieve complete reversal and the duration of the reversal and bleeding severity (group A). The formation of antidrug antibodies at 30 days post-dose and cessation of bleeding will also be assessed.

Conclusion: This study will report the safety of idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran. Clinical trial registration: NCT02815670.
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http://dx.doi.org/10.1002/rth2.12053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868044PMC
January 2018

Can thrombophilia predict recurrent catheter-related deep vein thrombosis in children?

Blood 2018 06 3;131(24):2712-2719. Epub 2018 May 3.

Division of Hematology/Oncology, Department of Pediatrics, and.

The role of thrombophilia testing in predicting catheter-related deep vein thrombosis (DVT) after an incident (ie, first) catheter-related DVT in children remains unclear. The present study investigated the association between thrombophilia and recurrent catheter-related DVT. Children with thrombophilia testing, performed according to the clinician's judgment and the family's preference, and a history of objectively confirmed catheter-related DVT were included in the study. Recurrent catheter-related DVT after placement of a new catheter was the main outcome. Thrombophilia was classified as minor, major, or none. Analysis was conducted using mixed effect logistic regression. A total of 245 patients had 1,365 catheters inserted; 941 of these catheters were placed after the incident catheter-related DVT. Anticoagulants as treatment or prophylaxis were administered in 78.1% of inserted catheters for at least 50% of the time they were in place. Minor thrombophilia was found in 12.7% of patients, whereas major thrombophilia was seen in 8.2% of children. The incidence rate of recurrent events was 0.23/100 catheter-days (95% confidence interval, 0.19-0.28 catheter-days); 34.3% (95% confidence interval, 28.6%-40.0%) of patients requiring a new catheter after their incident thrombotic event had at least 1 recurrent event. The incidence proportion of bleeding complications was 4.6/100 patients receiving anticoagulation. Young age of the patient at the time of catheter insertion and lack of administration of treatment or prophylactic doses of anticoagulant were predictive of recurrent events. In contrast, thrombophilia was not predictive of recurrent catheter-related DVT during subsequent catheter insertions among tested patients. Our findings suggest that thrombophilia testing to predict recurrence in these patients may be unnecessary.
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http://dx.doi.org/10.1182/blood-2017-10-811216DOI Listing
June 2018

Increased risk of symptomatic upper-extremity venous thrombosis with multiple peripherally inserted central catheter insertions in pediatric patients.

Pediatr Radiol 2018 07 27;48(7):1013-1020. Epub 2018 Feb 27.

Image Guided Therapy, Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Background: Peripherally inserted central catheters (PICCs) are associated with superficial and deep venous thrombosis of the arm.

Objective: The purpose of this study was to analyze the sequelae of repeated upper limb PICC insertions in children, in terms of the frequency of upper limb thrombosis in this patient group.

Materials And Methods: The study population included all children who underwent their first successful arm PICC insertion between January 2010 and December 2015. We included subsequent ipsilateral arm PICCs in the analysis. Patients were followed until March 2016 or until any alternative central venous line insertion. For each PICC insertion, we collected demographic variables and line characteristics. We correlated all symptomatic deep and superficial thromboses of the arm with the PICC database.

Results: Applying inclusion and exclusion criteria, 2,180 PICCs remained for analysis. We identified first, second, third and fourth PICC insertions in the same arm in 1,955, 181, 38 and 6 patients, respectively. In total there were 57 upper body deep symptomatic thrombotic events. An increasing odds ratio was seen with higher numbers of PICC insertions, which was significant when comparing the first with the third and fourth PICC insertions in the same arm (odds ratio [OR] 6.00, 95% confidence interval [CI] 2.25-16.04, P=0.0004). Double-lumen PICCs were associated with a significantly higher risk of thrombosis than single lumen (OR 2.77, 95% CI 1.72-4.47, P=0.0003).

Conclusion: Repetitive PICC insertions in the same arm are associated with an increased risk of symptomatic thrombosis. Double-lumen PICCs are associated with a higher risk of thrombosis compared to single-lumen lines.
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http://dx.doi.org/10.1007/s00247-018-4096-xDOI Listing
July 2018

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Dabigatran Etexilate Oral Liquid Formulation in Infants with Venous Thromboembolism.

Thromb Haemost 2017 11 30;117(11):2168-2175. Epub 2017 Nov 30.

Hematology Department, University Children's Hospital, Zürich, Switzerland.

Venous thromboembolism (VTE) is more frequent in infants than in older children. Treatment guidelines in children are adapted from adult VTE data, but do not currently include direct oral anticoagulant use. Dabigatran etexilate (DE) use in the paediatric population with VTE therefore requires verification. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship, safety and tolerability of DE oral liquid formulation (OLF) in infants with VTE (aged < 12 months) who had completed standard anticoagulant treatment in an open-label, phase IIa study. Patients received a single-dose of DE OLF (based on an age- and weight-adjusted nomogram) yielding an exposure comparable to 150 mg in adults. The PK end point was plasma concentration of total dabigatran; PD end points included activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and diluted thrombin time (dTT). Safety end points included incidence of all bleeding and other adverse events (AEs). Ten patients were screened; eight entered the study (age range, 41-169 days). The geometric mean (gMean) total dabigatran plasma concentrations 2 hours post-dose (around peak concentrations) were 120 ng/mL with a geometric coefficient of variation (gCV) of 62.1%. The gMean at 12 hours post-dosing was 60.4 ng/mL (gCV 30%). PK/PD relationship was linear for ECT and dTT ( = 0.858 and 0.920, respectively), while total dabigatran concentration and aPTT showed a non-linear correlation. There were no deaths, treatment discontinuations or treatment-related AEs. In conclusion, DE was well tolerated without any treatment-related AEs in infants. The observed PK/PD relationships were comparable with the established profile in older patients with VTE.
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http://dx.doi.org/10.1160/TH17-06-0429DOI Listing
November 2017

Variants in chondroitin sulfate metabolism genes in thrombotic storm.

Thromb Res 2018 01 21;161:43-51. Epub 2017 Nov 21.

University of Miami, John P. Hussman Institute for Human Genomics, Miller School of Medicine, Biomedical Research Building, 1501 NW 10th Ave, Miami, FL 33136, United States. Electronic address:

Introduction: Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders.

Material And Methods: We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (<5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality.

Results: We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden).

Conclusions: As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.
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http://dx.doi.org/10.1016/j.thromres.2017.11.016DOI Listing
January 2018