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    [Anticoagulant treatment for cerebral venous thromboses in children and newborns. French Society of Pediatric Neurology guidelines]. Lebas A,Chabrier S,Tardieu M,Kossorotoff M, Archives de pediatrie : organe officiel de la Societe francaise de pediatrie Anticoagulation is recommended in the acute phase of cerebral venous thrombosis in adults, then for 3-12 months. In children, 2 consensus reports published in 2008 also recommend use of anticoagulants, whereas conclusions diverge for newborns. These consensus reports are based on observational studies, authors' experience, and comparisons with adult pathology. In view of the original studies published since then, the French Society of Pediatric Neurology (Société française de neurologie pédiatrique [SFNP]) wished to update the level of evidence and the knowledge in this domain. The results from the analysis of the literature show that anticoagulation is widely used in pediatrics. It is well-tolerated in children (class I, level of evidence B) and probably in the newborn (class IIa, level of evidence B). In the acute phase of cerebral venous thrombosis, anticoagulation is probably effective in reducing the risk of death in children (class IIa, level of evidence B). It is not possible to draw a conclusion on newborns (class IIb). Over the longer term, anticoagulation is effective in reducing the risk of recurrence (class I, level of evidence B). Since this risk is highly dependent on a number of individual factors (the main ones being the child's age, the cause of the thrombosis, and the kinetics of the sinus recanalization), the duration of anticoagulation should be analyzed individually (class I, level of evidence B). All in all, the convergence of the results, the physiopathologic arguments, and the concordance with the data on adult patients has led to the following recommendations: in the absence of a contra-indication, it is reasonable to propose anticoagulation in the acute phase of cerebral venous thrombosis in children. Prolonging this treatment for 3-6 months is indicated depending on the number of individual factors. In the absence of a contra-indication, anticoagulation may be considered individually in the acute phase of cerebral venous thrombosis in newborns for 6-12 weeks. 10.1016/j.arcped.2011.01.017
    Bleeding Risk of Warfarin and Direct Oral Anticoagulants in Younger Population: A Historical Cohort Study Using a Japanese Claims Database. Yokoyama Satoshi,Tanaka Yuki,Nakagita Kazuki,Hosomi Kouichi,Takada Mitsutaka International journal of medical sciences A historical cohort analysis of the Japan medical data center (JMDC) claims databases was performed to compare the incidence rates of bleeding events with warfarin (WF) versus direct oral anticoagulant (DOAC) treatment in patients with non-valvular atrial fibrillation. The aim of this study is to clarify the risk factors for bleeding events in younger patients newly treated with WF or DOAC in clinical practice setting. Patients who newly initiated WF or DOAC treatment from April 2012 to March 2015 were selected from the JMDC claims database. A 1:1 propensity score matching analysis was used for new users of WF or DOAC. Kaplan-Meier curves were generated to depict the time to bleeding event (total bleeding events, gastrointestinal hemorrhage, and intracranial hemorrhage) during the follow-up period. Cox proportional regression models were used to estimate the hazard ratios for total bleeding events caused by oral anticoagulants. Overall, 2,046 patients (503 WF and 1,543 DOAC) were included. After applying propensity score matching, Kaplan-Meier analysis of the WF and DOAC groups displayed comparable incidences of total bleeding events, gastrointestinal hemorrhage, and intracranial hemorrhage. Cox proportional hazards modeling showed that the use of WF was not associated with total bleeding events compared with DOAC (hazard ratio: 1.21, 95% confidence interval: 0.93-1.54, = 0.15). This historical cohort study using a claims database indicates that the bleeding risk of DOAC was comparable to that of WF in Japanese younger population. 10.7150/ijms.28877
    Anticoagulation Therapy in Children. Radulescu Vlad Calin Seminars in thrombosis and hemostasis Venous thromboembolism (VTE) is very uncommon in children and adolescents compared with older adults, though its incidence has significantly increased over the past two decades. Given the rarity of the condition, the data on pediatric VTE lag behind the adult experience and consequently the management of VTE in children is, in large part, modeled on the adult strategies. This approach has certain limitations, given that young children have developmental particularities of the hemostatic system and differences in the pharmacokinetics and pharmacodynamics of various anticoagulant agents. The most commonly used anticoagulants in children continue to be the heparins and the vitamin K antagonists. Direct intravenous thrombin inhibitors, argatroban, bivalirudin, have very limited pediatric use. The non-vitamin K antagonist oral anticoagulant drugs (novel oral anticoagulants) present potential advantages in terms of efficacy, safety, and convenience, though pediatric data are limited to preclinical and small phase I trials. There are several ongoing phase I, II, and III trials for dabigatran rivaroxaban, apixaban, and edoxaban, the results of which are likely to change the future management of pediatric thromboses. 10.1055/s-0036-1598004
    Catheter-Related Venous Thrombosis in Hospitalized Pediatric Patients with Inflammatory Bowel Disease: Incidence, Characteristics, and Role of Anticoagulant Thromboprophylaxis with Enoxaparin. Diamond Carrie E,Hennessey Carole,Meldau Jennifer,Guelcher Christine J,Guerrera Michael F,Conklin Laurie S,Sharma Karun V,Diab Yaser A The Journal of pediatrics OBJECTIVE:To describe the incidence and characteristics of central venous catheter (CVC)-related thrombosis in hospitalized pediatric patients with active inflammatory bowel disease (IBD) and report the potential usefulness of anticoagulant thromboprophylaxis (AT). STUDY DESIGN:We conducted a retrospective study of patients who were admitted to our children's hospital in the last 2 years with active IBD and required a CVC and identified all patients with an objectively confirmed symptomatic CVC-related thrombosis. To assess the usefulness of a recently implemented institutional AT protocol, we compared the frequency of CVC-related thrombosis, nadir hemoglobin, and red blood cell transfusion requirements in patients who received AT with those who did not during the study period. RESULTS:A total of 40 patients with IBD who required 47 consecutive hospitalizations were included. AT was administered during 24 of 47 hospitalizations (51%). Patients who received AT were similar to those who did not receive AT with regard to demographics, IBD phenotypes, extent of colonic involvement, and thrombotic risk factors. CVC-related thrombosis occurred in 5 of 23 hospitalizations (22%) in which AT was withheld compared with 0 of 24 hospitalizations (0%) in which patients received AT (P = .02). The red blood cell transfusion requirements and nadir hemoglobin were not significantly different between the 2 groups. CONCLUSIONS:We observed a high incidence of CVC-related thrombosis in hospitalized children with IBD. Administration of AT in our population was associated with significant reduction in CVC-related thrombosis without evidence of increased bleeding. 10.1016/j.jpeds.2018.02.039
    Direct thrombin and factor Xa inhibitors in children: a quest for new anticoagulants for children. Streif Werner,Ageno Walter Wiener medizinische Wochenschrift (1946) Venous thrombosis and pulmonary embolism rarely occur in children but are associated with significant morbidity and mortality. Venous thromboembolism (VTE) mostly affects children with severe underlying conditions and multiple risk factors. Newborns and adolescents are at the highest risk. Standard and low molecular weight heparins and vitamin K antagonists are routinely used for the prevention and treatment of VTE. The new anticoagulants, both parenteral such as argatroban, bivalirudin and fondaparinux and oral such as dabigatran and rivaroxaban, have favourable pharmacological properties, all are approved for clinical use in adults and are currently being investigated in children. Argatroban is the only new anticoagulant licensed for use in children so far. The role of these new anticoagulants as alternative anticoagulants for children remains to be defined. This review focuses on the characteristics of VTE in children and reviews current knowledge on the use of the new thrombin and factor Xa inhibitors in this population. 10.1007/s10354-011-0879-5
    Enoxaparin Thromboprophylaxis in Children Hospitalized for COVID-19: A Phase 2 Trial. Pediatrics BACKGROUND:Evidence regarding the safety and efficacy of anticoagulant thromboprophylaxis among pediatric patients hospitalized for coronavirus disease 2019 (COVID-19) is limited. We sought to evaluate safety, dose-finding, and preliminary efficacy of twice-daily enoxaparin as primary thromboprophylaxis among children hospitalized for symptomatic COVID-19, including primary respiratory infection and multisystem inflammatory syndrome in children (MISC). METHODS:We performed a phase 2, multicenter, prospective, open-label, single-arm clinical trial of twice-daily enoxaparin (initial dose: 0.5mg/kg per dose; max: 60mg; target anti-Xa activity: 0.20-0.49IU/mL) as primary thromboprophylaxis for children <18 years of age hospitalized for symptomatic COVID-19. Study endpoints included: cumulative incidence of International Society of Thrombosis and Haemostasis-defined clinically relevant bleeding; enoxaparin dose-requirements; and cumulative incidence of venous thromboembolism within 30-days of hospital discharge. Descriptive statistics summarized endpoint estimates that were further evaluated by participant age (±12 years) and clinical presentation. RESULTS:Forty children were enrolled and 38 met analyses criteria. None experienced clinically relevant bleeding. Median (interquartile range) dose to achieve target anti-Xa levels was 0.5 mg/kg (0.48-0.54). Dose-requirement did not differ by age (0.5 [0.46-0.52] mg/kg for age ≥12 years versus 0.52 [0.49-0.55] mg/kg for age <12 years, P = .51) but was greater for participants with MISC (0.52 [0.5-0.61] mg/kg) as compared with primary COVID-19 (0.48 [0.39-0.51] mg/kg, P = .010). Two children (5.3%) developed central-venous catheter-related venous thromboembolism. No serious adverse events were related to trial intervention. CONCLUSIONS:Among children hospitalized for COVID-19, thromboprophylaxis with twice-daily enoxaparin appears safe and warrants further investigation to assess efficacy. 10.1542/peds.2022-056726
    Clinical Progress Note: Direct Oral Anticoagulants for Treatment of Venous Thromboembolism in Children. Caldwell Alicia,Moss Stephanie,Jenkins Ashley,Herbst Brian Journal of hospital medicine 10.12788/jhm.3517
    Activity levels of natural anticoagulant proteins in childhood acute lymphoblastic leukemia: relation to thromboembolic complications and treatment. Ismail Manal M,Hamed Gehan M Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis Thromboembolism is a well recognized life-threatening complication in childhood acute lymphoblastic leukemia (ALL). Proper and early diagnosis of thromboembolism is of paramount importance to reduce mortality and morbidity. We evaluated antithrombin III (ATIII), protein C, protein S, and D-dimer in 60 children with ALL compared with 30 healthy controls, and patients were followed up for 12 months for detection of thrombotic complications. The relation between these natural anticoagulants and the development of thrombotic complications, as well as therapy was assessed to identify patients at risk of thromboembolism. ATIII, protein C, and protein S were significantly reduced (P < 0.001) with elevated D-dimer (P < 0.001) in patients with ALL compared with those in the control group. The incidence of thrombotic complications was 16.7%. Patients with thrombotic complications had significantly lower ATIII, protein C, protein S, and platelet count, whereas age, total leukocyte count, and D-dimer were increased compared with those without thrombosis (P < 0.05). Patients under chemotherapy had lower ATIII, protein C, and protein S levels with higher D-dimer compared with the newly diagnosed untreated patients (P < 0.05). ATIII and protein C were positively correlated (r = 0.573, P = 0.002), whereas both were negatively correlated with D-dimer (P < 0.001). ALL is associated with a state of hypercoagulability, which may be attributed to hemostatic derangement because of increased thrombin generation indicated by elevated D-dimer in association with decreased natural anticoagulants ATIII, protein C, and protein S. ALL children during induction/consolidation phase of chemotherapy are at high risk of developing thromboembolism complications and the prophylactic use of anticoagulant should be considered. 10.1097/MBC.0000000000000521
    The in vitro anticoagulant effect of rivaroxaban in children. Attard C,Monagle P,Kubitza D,Ignjatovic V Thrombosis research INTRODUCTION:Current anticoagulation therapy in children is less than ideal, requiring regular venous monitoring and dosing adjustments. Limitations associated with conventional anticoagulants have prompted the development of novel drugs that specifically target key proteins in the coagulation system. Rivaroxaban is the first oral, direct Factor Xa inhibitor available for the prevention of venous thromboembolism in adults. Its predictable pharmacokinetic profile, high oral bioavailability and once-daily dosing make rivaroxaban an optimal anticoagulant that warrants investigation in children. The aim of this study was to investigate the age-related anticoagulant effect of rivaroxaban in vitro. MATERIALS AND METHODS:Age-specific plasma pools were created (i.e. 28 days-23 months, 2-6, 7-11, 12-16 years and adults) and spiked with increasing concentrations of rivaroxaban (0-500 ng/ml). Commercially available PT, APTT and anti-Factor Xa assays, as well as sub-sampling thrombin generation assays, were used to measure rivaroxaban effect. RESULTS:The results of this study indicate that there are no significant differences in rivaroxaban effect across the age groups in vitro. CONCLUSION:In vivo studies are required to confirm the consistency of dose-response across the paediatric age groups. 10.1016/j.thromres.2012.07.009
    Retrospective pharmacogenetic analysis of a pediatric patient under anticoagulant treatment: Clinical case Cavieres Mirta,Suárez Marcelo,Verón Gabriel,Quiñones Luis Abel,Varela Nelson Miguel Biomedica : revista del Instituto Nacional de Salud We present the clinical case of a 10-year-old patient diagnosed with dilated cardiomyopathy who registered INR values above 10 upon receiving standard doses of acenocoumarol, as well as other values reported as uncoagulable, forcing the discontinuation and restart of treatment more than once. Expected and stable INR levels were achieved after more than 30 days of treatment, surprisingly with half the recommended dose for a patient of her age and weight.We decided to conduct a retrospective pharmacogenomic analysis including nucleotide genetic polymorphisms (SNPs) with different degrees of association with the dose/response to antivitamin K (AVK) drugs: rs2108622 (gene CYP4F2), rs9923231, rs7294 (gene VKORC1), rs1799853, and rs1057910 (CYP2C9 gene) using TaqMan® RT-PCR. The patient was homozygous for rs9923231 (VKORC1) and heterozygous for rs2108622 (CYP4F2),a genetic profile strongly associated with a requirement of lower AVK doses as shown by national and international evidence.In conclusion, the pharmacogenetic analysis confirmed that this patient’s genetic conditions, involving low expression of the VKA therapeutic target, required a lower dose than that established in clinical protocols as recommended by the Food and Drug Administration (FDA) and the PharmGKB® for coumarin drugs. A previous genotypic analysis of the patient would have allowed reaching the therapeutic range sooner, thus avoiding potential bleeding risks. This shows the importance of pharmacogenetic analyses for highly variable treatments with a narrow therapeutic range. 10.7705/biomedica.5840
    Anticoagulants in children and adolescents. Young Guy Hematology. American Society of Hematology. Education Program Thrombotic complications are increasing at a steady and significant rate in children, resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the older multitargeted agents (heparin, low-molecular-weight heparin, and warfarin) and the newer targeted agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the multitargeted and targeted anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. The various agents differ in their pharmacokinetics, requirements for therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The targeted anticoagulants have properties that may make them more attractive for use in specific clinical situations. Prospective clinical trial data are presented supporting the current and future use of these agents in children. 10.1182/asheducation-2015.1.111
    Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature. Branstetter Joshua W,Kiskaddon Amy L,King Madeleine A,Coalter Carli,Grubbs Kimberly M,Fly Hunter,Male Christoph,Brandão Leonardo,Goldenberg Neil A Seminars in thrombosis and hemostasis 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 , 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. 10.1055/s-0041-1725944
    Characterizing the use of anticoagulants in children using the American Thrombosis and Hemostasis Network Dataset (ATHNdataset). Davila Jennifer,Cheng Dunlei,Raffini Leslie,Thornburg Courtney D,Corrales-Medina Fernando F Thrombosis research 10.1016/j.thromres.2020.10.029
    ENNOBLE-ATE trial: an open-label, randomised, multi-centre, observational study of edoxaban for children with cardiac diseases at risk of thromboembolism. Bhatt Mihir D,Portman Michael A,Berger Felix,Jacobs Jeffrey P,Newburger Jane,Duggal Anil,Grosso Michael,Pandya Grishma,Dave Jay,Goldenberg Neil A Cardiology in the young 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. 10.1017/S1047951121002523
    Direct Oral Anticoagulants: Overcoming the Challenges of Managing Venous Thromboembolism in Children. Male Christoph,Monagle Paul,Albisetti Manuela,Brandão Leonardo R,Young Guy The Journal of pediatrics 10.1016/j.jpeds.2021.09.025
    Anticoagulants for the prevention and treatment of catheter-related thrombosis in adults and children on parenteral nutrition: a systematic review and critical appraisal. Barco Stefano,Atema Jasper J,Coppens Michiel,Serlie Mireille J,Middeldorp Saskia Blood transfusion = Trasfusione del sangue BACKGROUND:Patients on parenteral nutrition require a central venous access and are at risk of catheter-related thrombosis, pulmonary embolism, and vena cava syndrome. Parenteral nutrition guidelines suggest anticoagulation for the primary prevention of catheter-related thrombosis during long-term parenteral nutrition. We conducted a systematic review of the efficacy, safety and feasibility of anticoagulant use for preventing and treating catheter-related thrombosis during parenteral nutrition. MATERIALS AND METHODS:We searched for interventional and observational studies on adults and children receiving systemic anticoagulants during either short- or long-term parenteral nutrition delivered via central venous access. Primary outcomes were: objectively-confirmed catheter-related thrombosis, pulmonary embolism and bleeding. Secondary outcomes were: heparin-induced thrombocytopenia, prevalence of anticoagulation, and quality of International Normalised Ratio management in vitamin K antagonist-treated patients. RESULTS:We identified 1,199 studies, of which 23 were included. Seven interventional studies of short-term parenteral nutrition (adult population, n=5) were classified as low-quality: in those, intravenous unfractionated heparin did not prevent catheter-related thrombosis if compared to saline. No interventional studies were conducted in patients on long-term parenteral nutrition. Observational data were sparse, rarely focusing on anticoagulation, and overall of low quality. The reported use of anticoagulants was between 22 and 66% in recent multicentre cohorts. DISCUSSION:The amount and quality of data in this area are very suboptimal: most studies are outdated and involved heterogeneous populations. Currently, there is insufficient evidence to allow conclusions to be reached regarding the efficacy and safety of anticoagulants in this setting. 10.2450/2016.0031-16
    Management of thrombosis in children and neonates: practical use of anticoagulants in children. Monagle Paul,Newall Fiona Hematology. American Society of Hematology. Education Program Venous thrombosis (VTE) in children and neonates presents numerous management challenges. Although increasing in frequency, VTE in children and neonates is still uncommon compared with adults. The epidemiology of VTE is vastly different in neonates vs children vs adolescents vs adults. In reality, pediatric thrombosis should be viewed as a multitude of rare diseases (eg, renal vein thrombosis, spontaneous thrombosis, catheter-related thrombosis, cerebral sinovenous thrombosis), all requiring different approaches to diagnosis and with different short- and long-term consequences, but linked by the use of common therapeutic agents. Further, children have fundamentally different physiology in terms of blood flow, developmental hemostasis, and, likely, endothelial function. provides up-to-date evidence-based guidelines related to treatment. Therefore, this article will focus on the practical use of therapeutic agents in the management of pediatric VTE, especially unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists, as the most common anticoagulants used in children. Direct oral anticoagulants (DOACs) remain in clinical trials in children and should not be used outside of formal trials for the foreseeable future. 10.1182/asheducation-2018.1.399
    Progression over time of changes in anticoagulant treatment in a tertiary hospital. Hernández Paula,Polanco Lucia,Santiago Ignacio,Fayos Marina,Valero Carmen Medicina clinica INTRODUCTION:The use of direct oral anticoagulants (DOACs) has modified anticoagulant therapy guidelines. OBJECTIVES:To determine changes and trends in the anticoagulant therapy of inpatients at an Internal medicine department. MATERIAL AND METHODS:1584 inpatients of the internal medicine department (Hospital Marqués de Valdecilla. Santander) were studied in 2008 and 2018. The use of anticoagulant treatment, type of treatment, atrial fibrillation, comorbidity index, thrombotic and haemorrhagic complications were collected from the discharge reports. RESULTS:The prevalence of anticoagulants increased by 5.7% (13.1% to 18.8%; P=0.002). The mean age increased by 7 years (76.2±11.1 yrs. vs. 83.6±8.9 yrs; P<0.001). The percentage of anticoagulated patients older than 75 yrs doubled. In 2018, 52% of anticoagulated took a DOAC. The prevalence of atrial fibrillation increased by 4% (30% vs. 34%; p=0.04) and by 24% that of anticoagulated atrial fibrillation by 24% (32.3% vs. 56%; P<0.001). The mean age is 6 years older (78.4±8.2 vs. 84.2±8.0; P<0.001). CONCLUSIONS:The percentage of anticoagulated patients in internal medicine has increased, especially in those with atrial fibrillation. 10.1016/j.medcli.2020.07.029
    Anticoagulant Effects of Dabigatran on Coagulation Laboratory Parameters in Pediatric Patients: Combined Data from Five Pediatric Clinical Trials. Thrombosis and haemostasis BACKGROUND: Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children. OBJECTIVES: This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]). METHODS: Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [ = 358]; dTT 2,348 [ = 324]; ECT 2,929 [ = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements;  = 1,978). Population models were fitted using nonlinear mixed-effects modeling. Covariates (e.g., sex, age) were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure. RESULTS: Overall, relationships between dabigatran, aPTT, dTT, and ECT were similar in children and adults. For children aged <6 months, a higher proportion of baseline samples were outside or close to the upper aPTT and ECT adult ranges. No age-related differences were detected for dTT. With increasing dabigatran concentration, aPTT rose nonlinearly (half the maximum effect at 368 ng/mL dabigatran) while dTT and ECT increased linearly (0.37 and 0.73% change per ng/mL dabigatran, respectively). Mean baseline aPTT (45 vs. 36 seconds) and ECT (40 vs. 36 seconds) were slightly increased for those aged <6 months versus older children. CONCLUSION: The similar relationships of laboratory parameters observed across pediatric age groups suggests that developmental changes in the hemostatic system may have little effect on response to dabigatran. 10.1055/s-0042-1744542
    Anticoagulant Effects of Dabigatran in Paediatric Patients Compared with Adults: Combined Data from Three Paediatric Clinical Trials. Maas Hugo,Gropper Savion,Huang Fenglei,Stangier Joachim,Tartakovsky Igor,Brueckmann Martina,Halton Jacqueline M L,Mitchell Lesley G Thrombosis and haemostasis BACKGROUND: Physiological age-related changes in the haemostatic and coagulation systems result in differing anticoagulant assay responses to standard anticoagulants. Therefore, we investigated the response of anticoagulant assays to dabigatran etexilate (DE) in children compared with adults. OBJECTIVE: This article assesses the relationship between plasma dabigatran concentration and coagulation assay results across age groups in children and adults. PATIENTS AND METHODS: Data from three clinical trials in which children received DE following standard of care for venous thromboembolism were compared with data from adult clinical trials. The effects of dabigatran concentration on diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) were analysed graphically and with modelling. RESULTS: The concentration-dTT relationships were consistent in children across all ages and adults in the graphical analysis. For ECT and aPTT, relationships based on ratios over baseline were similar across all ages; absolute clotting times showed that the same exposure resulted in longer clotting times in some of the children aged < 1 year versus adults. Modelling showed concentration-clotting time relationships for all three assays were largely comparable between adults and children, except in those aged < 2 months, in whom there was a slight upward shift in ECT and aPTT relative to adults. CONCLUSION: Results suggest that developmental haemostatic changes will have little impact on response to DE. However, further paediatric clinical trials assessing the relationship between coagulation assay responses and clinical outcomes will be needed to confirm this finding. 10.1055/s-0038-1668132
    Use of Direct Oral Anticoagulants in Children and Adolescents. Albisetti Manuela Hamostaseologie While the need for anticoagulation in children has increased over the last decades, dose regimens of currently used anticoagulants, including low-molecular-weight heparin (LMWH) and vitamin K antagonist (VKA), are still extrapolated from adult guidelines because well-designed clinical trials were never performed in children. This approach is not optimal due to specific pediatric features of the hemostatic system and pathophysiology of thrombosis. These anticoagulants also present several disadvantages that further hamper optimal anticoagulation of pediatric patients, especially newborns and infants. The new direct oral anticoagulants (DOACs), which have the potential to overcome these disadvantages, were extensively investigated in adults and have become a valid alternative to LMWH and VKA for anticoagulation in the adult population. Several pediatric trials on all approved DOACs are currently ongoing, providing specific pediatric formulations and age- and weight-adjusted dose guidelines. First results of phase III trials indicate that DOACs are at least as efficient and safe as LMWH and VKA for the treatment and prevention of thrombotic events in children with different clinical conditions. This review article summarizes available data from terminated and ongoing controlled trials on DOACs in children and adolescents. 10.1055/s-0039-3400491
    New Anticoagulants in Neonates, Children, and Adolescents. Hamostaseologie Thrombotic events are an increasing challenge in pediatrics. Standard-of-care anticoagulants for pediatric thrombosis have several disadvantages which could be overcome by using direct oral anticoagulants (DOACs). Until recently, there was not enough evidence from clinical trials to recommend for or against the use of any of the four DOACs in children with thrombosis. In this literature review, we looked at the latest clinical trials in this field. On clinicaltrials.gov, we found 13 current studies with published results. For two of the four DOACs, namely dabigatran and rivaroxaban, we found successful phase III studies which led to the approval for the use in children. The results of these pivotal phase III studies allow to finally recommend rivaroxaban and dabigatran for the prophylaxis and treatment of thrombotic events in children. 10.1055/a-1740-7080
    In vitro assessment of edoxaban anticoagulant effect in pediatric plasma. Sinegre Thomas,Zlobecki Mélissa,Doré Eric,Pereira Bruno,Grèze Victoria,Lebreton Aurélien Thrombosis research INTRODUCTION:Anticoagulant therapy in pediatric patients remains an issue and safer therapies, such as direct oral anticoagulants could overcome the limitations of conventional anticoagulant treatments in this population. Edoxaban, a factor Xa inhibitor, is used for the prevention and treatment of venous thromboembolism. Due to its pharmacokinetic characteristics, edoxaban is a promising candidate molecule for children. This study compared edoxaban in vitro effect in children and adults. MATERIALS AND METHODS:Blood samples were prospectively collected from 87 adults and 97 children (n = 12: <2 year-old; n = 8: 2-4 year-old; n = 9: 5-7 year-old; n = 14: 8-9 year-old; n = 10: 10-13 year-old; n = 15: 14-15 year-old; and n = 29: 16-18 year-old). Plasma samples were supplemented in vitro with edoxaban to a final concentration of 50, 150 or 300 ng/mL, and then edoxaban effect on prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen (Clauss assay), specific anti-factor Xa activity and thrombin generation assay (TGA) (with 5pM tissue factor and 4 nM phospholipids) was evaluated. RESULTS:PT, aPTT, and specific anti-Xa activity exhibited similar dose-dependent responses to edoxaban in the different age groups. The reduction of thrombin peak, the most edoxaban-sensitive TGA parameter, was similar in adults and children, but for the youngest group (<2 year-old) where the peak value reduction (median [Q1-Q3]) was higher than in adults (51% [44-59] versus 40% [32-46], p < 0.01; 74% [63-80] versus 65% [58-70], p < 0.05; and 84% [73-88] versus 76% [70-80], p < 0.05 for 50, 150 and 300 ng/mL edoxaban, respectively). CONCLUSIONS:Edoxaban in vitro effect are comparable in children and adults except in the <2-year-old group. 10.1016/j.thromres.2019.04.014
    Direct oral anticoagulants: What will be their role in children? Male Christoph,Thom Katharina,O'Brien Sarah H Thrombosis research Thrombotic events in children differ from those in adults in epidemiology, pathophysiology, and anatomical location. However, anticoagulation in children is mostly based on evidence from adults while scarce evidence exists from children. The classical anticoagulants currently used in children have several limitations, resulting in the need for regular monitoring. Several direct oral anticoagulants (DOACs) are now authorized for adults in whom they have established efficacy and safety without the need for monitoring. Given their pharmacological properties and the special characteristics of children requiring anticoagulation, the DOACs have the potential to be particularly suitable for children. All currently approved DOACs have paediatric development plans, targeting various indications for prevention and treatment of thrombosis. Paediatric formulations are being developed and systematic age-specific dosing information will be generated. Whether therapeutic drug monitoring will be necessary in certain situations in children remains to be elucidated. The results of ongoing clinical studies still need to demonstrate whether there is a positive benefit-risk balance in all targeted paediatric indications and age-groups, particularly in indications that have not been explored in adults, such as catheter-related thrombosis or congenital heart disease. If the advantages of DOACs bear out in the results of the current paediatric studies, they will likely be used widely in children. As of now, the DOACs should not be used routinely in children as there is still insufficient information on appropriate dosing, safety and efficacy. The paediatric community is encouraged to promote participation of children and adolescents into the multiple ongoing studies of DOACs. 10.1016/j.thromres.2018.06.021
    Health-related quality of life correlates with time in therapeutic range in children on anticoagulants with International Normalised Ratio self-monitoring. Abassi Hamouda,Bajolle Fanny,Werner Oscar,Auer Annie,Marquina Amandine,Mura Thibault,Lavastre Kathleen,Guillaumont Sophie,Manna Federico,Auquier Pascal,Bonnet Damien,Amedro Pascal Archives of cardiovascular diseases BACKGROUND:Managing oral anticoagulant therapy with vitamin K antagonists remains challenging in paediatric medicine. AIMS:This study aimed to assess the correlation between time in therapeutic range and quality of life in children participating in a non-selective International Normalised Ratio self-monitoring and vitamin K antagonist education programme. METHODS:Children aged from 2 to 18 years and receiving vitamin K antagonist therapy were eligible for this prospective multicentre study. Clinical and demographic data were collected. Health-related quality of life was assessed using the PedsQL™ 4.0 questionnaire. Correlations between quality of life scores and time in therapeutic range were measured. RESULTS:A total of 121 children were included in the study (mean age 9.6±4.9 years). Cardiac conditions were the predominant indication for vitamin K antagonists. The mean time in therapeutic range was 0.78±0.15 overall, and 0.76±0.24 over the 3-month period before quality of life assessment. The mean total quality of life score was 76.2±18 in self reports, 71.4±22 in mother reports and 73.5±19 in father reports. The time in therapeutic range correlated with the total quality of life scores in self reports (r=0.22; P=0.04), mother reports (r=0.23; P=0.02) and father reports (r=0.28; P=0.02). The time in therapeutic range predominantly correlated with school functioning in self reports (r=0.38; P=0.002) and mother reports (r=0.40; P<0.001), and with physical functioning in father reports (r=0.28; P=0.03). CONCLUSIONS:Time in therapeutic range correlated with quality of life in children participating in a non-selective International Normalised Ratio self-monitoring and vitamin K antagonist education programme. Regular assessment of quality of life in patient education programmes contributes towards understanding the concerns and needs of patients. 10.1016/j.acvd.2020.05.022
    Oral anticoagulant therapy interruption in children: A single centre experience. Campbell Sally,Monagle Paul,Newall Fiona Thrombosis research BACKGROUND:The use of anticoagulant therapy in paediatrics is common, with vitamin K antagonists remaining the most commonly prescribed therapy. There is a weak evidence base behind many of the recommendations for anticoagulant therapy in paediatric patients. One of the areas requiring further research is the management of anticoagulant therapy interruption. Interruption to anticoagulation is the period surrounding a planned invasive procedure whereby long term anticoagulation is ceased, and recommenced post procedure. The word bridging refers to the use of low molecular weight heparin or unfractionated heparin to anticoagulate during the period of sub therapeutic INR. To date institutional protocols for bridging anticoagulation are based on adult guidelines. However, there are currently no studies validating the extrapolation of these guidelines to paediatrics. This study seeks to review the clinical outcomes associated with current bridging practices employed at a tertiary metropolitan children's hospital. METHODS:The patient population was selected from the warfarin management registry of a Clinical Haematology service of a major metropolitan children's hospital. The admission history of these patients was queried to identify admissions where anticoagulation interruption would typically be required. Namely, these were dental extraction, cerebral or cardiac angiography, or cardiac catheterization. Data relating to demographics, anticoagulant therapy interruption plan, and clinical outcomes were recorded. RESULTS:A total of 61 admissions for children aged between 1 year and 17 years and 11 months were analysed for this study. Congenital heart disease (CHD) was the primary underlying disease for which long-term oral anticoagulation with warfarin was indicated. Children with Moyamoya in this cohort were treated more consistently compared to the other disease groups. There were no instances of major bleeding (n=0) or thrombotic events (n=0). CONCLUSION:This study describes the current practices and outcomes associated with anticoagulant therapy interruption at one institution thereby filling an evidence gap in the paediatric anticoagulant management. It achieved this by analysing the largest and most representative cohort to date. This project is a stepping stone from which future studies of safety and efficacy of paediatric anticoagulation interruption management can be developed. 10.1016/j.thromres.2016.01.010
    A guide to the use of anticoagulant drugs in children. Law Connie,Raffini Leslie Paediatric drugs Increasing thrombotic complications in children with complex medication conditions have led to more widespread use of anticoagulants [Raffini et al. in Pediatrics 124(4):1001-8, 2009]. While current guidelines for the management of antithrombotic therapy in neonates and children exist, they are based on low- and very low-quality evidence [Monagle et al. in Chest 141(2 Suppl):e737-801S, 2012]. Despite numerous differences, current anticoagulation practice is largely extrapolated from adult studies. This is sub-optimal, particularly in neonates who have a rapidly evolving hemostatic system. The majority of pediatric patients have underlying medical conditions that may significantly influence drug choice and bleeding risk. This article reviews the use of anticoagulants in children with thrombosis, focusing on practical aspects such as dosing, monitoring, and complications. Low molecular weight heparin has become the preferred anticoagulant in children, although unfractionated heparin and warfarin remain frequently used. Other anticoagulants, including fondaparinux, direct thrombin inhibitors, and the newer target-specific oral anticoagulants are also discussed. Given the many unique challenges surrounding the use of anticoagulants in children, pediatric hospitals should have written practice guidelines as well as experienced providers to care for children with thrombosis. This is an evolving field, and further studies of the use of anticoagulants in neonates and children are greatly needed to help optimize care. 10.1007/s40272-015-0120-x
    Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Male Christoph,Lensing Anthonie W A,Palumbo Joseph S,Kumar Riten,Nurmeev Ildar,Hege Kerry,Bonnet Damien,Connor Philip,Hooimeijer Hélène L,Torres Marcela,Chan Anthony K C,Kenet Gili,Holzhauer Susanne,Santamaría Amparo,Amedro Pascal,Chalmers Elizabeth,Simioni Paolo,Bhat Rukhmi V,Yee Donald L,Lvova Olga,Beyer-Westendorf Jan,Biss Tina T,Martinelli Ida,Saracco Paola,Peters Marjolein,Kállay Krisztián,Gauger Cynthia A,Massicotte M Patricia,Young Guy,Pap Akos F,Majumder Madhurima,Smith William T,Heubach Jürgen F,Berkowitz Scott D,Thelen Kirstin,Kubitza Dagmar,Crowther Mark,Prins Martin H,Monagle Paul, The Lancet. Haematology BACKGROUND:Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS:In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS:From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION:In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING:Bayer AG and Janssen Research & Development. 10.1016/S2352-3026(19)30219-4
    A multi-national trial of a direct oral anticoagulant in children with cardiac disease: Design and rationale of the Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE) study. Payne R Mark,Burns Kristin M,Glatz Andrew C,Li Danshi,Li Xiaodong,Monagle Paul,Newburger Jane W,Swan Elizabeth A,Wheaton Olivia,Male Christoph, American heart journal Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials. 10.1016/j.ahj.2019.08.002
    Anticoagulant Treatment for Pediatric Infection-Related Cerebral Venous Thrombosis. Sánchez van Kammen Mayte,Male Christoph,Connor Philip,Monagle Paul,Coutinho Jonathan M,Lensing Anthonie W A, Pediatric neurology BACKGROUND:We aimed to describe the clinical presentation, risk of bleeding and recurrent thrombosis, and perioperative anticoagulant management of children with cerebral venous thrombosis (CVT) and an associated head or neck infection. METHODS:In this subgroup analysis of the EINSTEIN-Jr study, we included children with CVT and an associated head or neck infection who received therapeutic anticoagulants with either low-molecular-weight heparin (with or without subsequent vitamin K antagonists) or rivaroxaban for a period of 3 months. Analyses are descriptive. RESULTS:Of 74 included children, 59 (80%) had otomastoiditis, 21 (28%) a central nervous system infection, 18 (24%) sinusitis, and 9 (12%) another upper respiratory tract infection; 29 (39%) had infection of multiple regions of the head or neck. All 74 children received antibiotics and therapeutic anticoagulants; 41 (55%) underwent surgery, of whom 34 were diagnosed with CVT preoperatively. Anticoagulation was started before surgery in 12 children and interrupted 0-1 days prior to surgery. Anticoagulation was (re)started in all 34 children at a median of 1 day (interquartile range: 0-1) postoperatively, in therapeutic doses in 94%. Overall, one child (1%, 95% confidence interval: 0-7) had recurrent thrombosis, and one (1%, 95% confidence interval: 0-7) had major bleeding; neither was associated with surgery. At 3 months, no children had died, 3 (4%) had persistent focal neurologic deficits, and 2 (3%) had impaired vision. CONCLUSIONS:Children with CVT and an associated head or neck infection administered therapeutic anticoagulants generally had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation. 10.1016/j.pediatrneurol.2021.12.011
    Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE). Thom Katharina,Lensing Anthonie W A,Nurmeev Ildar,Bajolle Fanny,Bonnet Damien,Kenet Gili,Massicotte M Patricia,Karakas Zeynep,Palumbo Joseph S,Saracco Paola,Amedro Pascal,Chain Juan,Chan Anthony K,Ikeyama Takanari,Lam Joyce C M,Gauger Cynthia,Pap Ákos Ferenc,Majumder Madhurima,Kubitza Dagmar,Smith William T,Berkowitz Scott D,Prins Martin H,Monagle Paul,Young Guy,Male Christoph Blood advances Anticoagulant treatment of pediatric central venous catheter-related venous thromboembolism (CVC-VTE) has not been specifically evaluated. In EINSTEIN-Jr, 500 children with any VTE received rivaroxaban or standard anticoagulants. A predefined analysis of the CVC-VTE cohort was performed. Children with CVC-VTE (age, birth to 17 years) were administered rivaroxaban or standard anticoagulants during the 1-month (children <2 years) or 3-month (all other children) study period. Predefined outcomes were recurrent VTE, change in thrombotic burden on repeat imaging, and bleeding. Predictors for continuation of anticoagulant therapy beyond the study period were evaluated. One hundred twenty-six children with symptomatic (n = 76, 60%) or asymptomatic (n = 50, 40%) CVC-VTE received either rivaroxaban (n = 90) or standard anticoagulants (n = 36). There was no recurrent VTE (0%; 95% confidence interval [CI], 0.0%-2.8%). Three children had the principal safety outcome: none had major bleeding and 3 children had clinically relevant nonmajor bleeding (2.4%; 95% CI, 0.7%-6.5%), all in the rivaroxaban arm. Complete or partial vein recanalization occurred in 57 (55%) and 38 (37%) of 103 evaluable children, respectively. Results were similar for symptomatic and asymptomatic CVC-VTE. Continuation of anticoagulant therapy beyond the study period occurred in 61 (48%) of children and was associated with residual VTE but only in children <2 years (odds ratio [OR], 20.9; P = .003) and continued CVC use (OR, 6.7; P = .002). Anticoagulant therapy appeared safe and efficacious and was associated with reduced clot burden in most children with symptomatic or asymptomatic CVC-VTE. Residual VTE and continued CVC use were associated with extended anticoagulation. This trial was registered at www.clinicaltrials.gov as #NCT02234843. 10.1182/bloodadvances.2020002637
    The Effects of Indirect- and Direct-Acting Anticoagulants on Lupus Anticoagulant Assays: A Large, Retrospective Study at a Coagulation Reference Laboratory. Seheult Jansen N,Meyer Michael P,Bontempo Franklin A,Chibisov Irina American journal of clinical pathology OBJECTIVES:To investigate the effects of indirect- and direct-acting anticoagulants on the interpretation of lupus anticoagulant (LAC) assays. METHODS:A retrospective database review was performed to identify all LAC panels from November 2012 to November 2015. The positivity rates for three LAC tests were compared among various anticoagulant medications. RESULTS:This analysis included 7,721 LAC panels. Direct oral anticoagulants, warfarin, and unfractionated heparin (UFH) were associated with higher LAC positivity rates compared with patients not receiving documented anticoagulation (83% for argatroban, 58% for dabigatran, 72% for rivaroxaban, 53% for apixaban, 56% for warfarin, and 36% for UFH vs 29% for no anticoagulation, P < .025). Direct thrombin inhibitors mainly affected the activated partial thromboplastin time-based assays and the tissue thromboplastin inhibition index (TTI), while direct factor Xa inhibitors mainly affected the TTI and the dilute Russell viper venom ratio. CONCLUSIONS:Results of LAC testing performed while patients are receiving anticoagulant therapies should be interpreted with caution to avoid misdiagnosing patients with the antiphospholipid syndrome and potentially committing them to long-term anticoagulation therapy. 10.1093/ajcp/aqx035
    Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues. Newall F,Branchford B,Male C Journal of thrombosis and haemostasis : JTH This review is aimed at describing the unique challenges of anticoagulant prophylaxis and treatment in children, and highlighting areas for research for improving clinical outcomes of children with thromboembolic disease. The evidence presented demonstrates the challenges of advancing the evidence base informing optimal management of thromboembolic disease in children. Recent observational studies have identified risk factors for venous thromboembolism in children, but there are few interventional studies assessing the benefit-risk balance of using thromboprophylaxis in risk-stratified clinical subgroups. A risk level-based framework is proposed for administering mechanical and pharmacological thromboprophylaxis. More research is required to refine the assignment of risk levels. The anticoagulants currently used predominantly in children are unfractionated heparin, low molecular weight heparin, and vitamin K antagonists. There is a paucity of robust evidence on the age-specific pharmacology of these agents, and their efficacy and safety for prevention and treatment of thrombosis in children. The available literature is heterogeneous, reflecting age-specific differences, and the various clinical settings for anticoagulation in children. Monitoring assays and target ranges are not well established. Nevertheless, weight-based dosing appears to achieve acceptable outcomes in most indications. Given the limitations of the classical anticoagulants for children, there is great interest in the direct oral anticoagulants (DOACs), whose properties appear to be particularly suitable for children. All DOACs currently approved for adults have Pediatric Investigation Plans ongoing or planned. These are generating age-specific formulations and systematic dosing information. The ongoing pediatric studies still have to establish whether DOACs have a positive benefit-risk balance in the various pediatric indications and age groups. 10.1111/jth.13913
    Real-World Anticoagulant Use and Incidence of Venous Thromboembolism and Major Bleeding in Children. Hardin Jill,Michelson Alan D,McCrindle Brian W,Pina L Miriam,Peluso Colleen,Simpkins Pamela,Truong Huy,Knoll Christopher,Yuan Zhong Clinical therapeutics PURPOSE:Children generally have a lower risk of venous thromboembolism (VTE) than adults, but those with acute and chronic conditions requiring hospitalization and surgical procedures are at increased risk. Anticoagulant use in children has not been systematically studied, and limited data exist. This study aimed to provide data on the conditions associated with use of anticoagulants, the type of anticoagulant used in children, and the incidence of thromboembolism and major bleeding events reported in this population. METHODS:To increase understanding of the use of anticoagulant therapies in children with at-risk conditions, 3 health claims databases in the United States were analyzed to describe the characteristics of use of heparins, warfarin, and direct oral anticoagulants (DOACs). Cumulative drug exposure was determined for continuous exposure, defined as >30 days. Unadjusted event rates of VTE and major bleeding after exposure to these therapies were reported. The data were presented descriptively and are not intended for comparison or to imply any causation. FINDINGS:Anticoagulants were infrequently used in the pediatric population, including at any time point after Fontan surgery for congenital heart disease. Heparins were used most frequently in the population overall and especially for patients aged <12 years. DOACs were used least often and primarily for patients ages 12 to <18 years. Among pediatric patients exposed to anticoagulants, unadjusted incidence rates of VTE per 1000 person-years of exposure ranged from 30.8 to 34.0 for all DOACs, 21.6 to 46.2 for warfarin, and 6.0 to 7.3 for heparins. Rates per 1000 person-years for major bleeding ranged from 0 to 4.9 for all DOACs, 4.3 to 6.7 for warfarin, and 3.7 to 4.6 for heparins. IMPLICATIONS:With results from clinical trials evaluating DOACs in the pediatric population expected in the next 2 years, these descriptive real-world data may provide a baseline understanding of current prescribing patterns and outcomes associated with the use of DOACs and other anticoagulants in routine pediatric clinical practice. This information represents the use of real-world evidence and may function as the benchmark for evaluating changes in prescription practices and potential outcomes in the future. 10.1016/j.clinthera.2021.09.021
    Factors affecting the duration of coronary artery lesions in patients with the Kawasaki disease: a retrospective cohort study. Zhang Xuting,He Yuee,Shao Yiping,Hang Biyao,Xu Zhipeng,Chu Maoping Pediatric rheumatology online journal BACKGROUND:Coronary artery lesions (CALs) are the most severe complication of Kawasaki disease (KD). Approximately 9-20% of the patients with KD develop CAL despite receiving regular treatment (intravenous immunoglobulin [IVIG] and aspirin). Some patients develop coronary aneurysms, leading to coronary artery stenosis or thrombosis, resulting in ischaemic heart disease and significantly affect the patients' lives. The purpose of this study was to investigate the factors associated with the duration of CAL in patients with KD. METHODS:The data of 464 patients with KD and CAL admitted to the Children's Heart Centre, The Second Affiliated Hospital and Yuying Children's Hospital from 2010 to 2018 were retrospectively analysed. Demographic and clinical information and echocardiographic follow-up data were collected. Kaplan-Meier curves were used to estimate the overall CAL duration, and the log-rank test was used to compare statistical differences. Univariate and multivariate Cox regression models were used to identify variables related to the CAL duration. RESULTS:The median CAL duration was 46 days (95% confidence interval: 41-54 days). CALs were observed in 61.5, 41.5, 33.3, 22.3, 10.3, and 7.7% of the patients at 1 month, 2 months, 3 months, 6 months, 1 year, and 2 years after the onset of KD, respectively. Univariate Cox regression model showed that sex (p = 0.016), rash symptoms (p = 0.035), delayed IVIG treatment (p = 0.022), CAL type (p < 0.001), degree of CAL (p < 0.001), white blood cell count before IVIG treatment (p = 0.019), and platelet count after IVIG treatment (p = 0.003) were statistically significant factors associated with the overall CAL duration. Multivariable Cox regression showed that delayed IVIG treatment (p = 0.020), multiple dilatations (p < 0.001), a greater degree of dilatation (p < 0.001), and higher platelet count after IVIG treatment (p = 0.007) were positively related to CAL duration. CONCLUSIONS:CAL duration was affected by delayed IVIG treatment, type of CAL, degree of CAL, and platelet count after IVIG treatment. These factors should be monitored carefully during the follow-up and management of patients with KD and CAL. 10.1186/s12969-021-00589-z
    Extensive coronary and systemic arterial aneurysm development in severe refractory Kawasaki disease. Johnston Niall,Coleman David,McMahon Colin J Cardiology in the young We describe the case of an 8-week-old infant with late presentation of severe refractory atypical Kawasaki disease. In addition to developing giant coronary arterial aneurysms and coronary thrombosis, she formed extensive bilateral arterial aneurysms throughout her systemic circulation. 10.1017/S1047951116001967
    Low-Molecular-Weight Heparin vs Warfarin for Thromboprophylaxis in Children With Coronary Artery Aneurysms After Kawasaki Disease: A Pragmatic Registry Trial. Manlhiot Cedric,Newburger Jane W,Low Tisiana,Dahdah Nagib,Mackie Andrew S,Raghuveer Geetha,Giglia Therese M,Dallaire Frederic,Mathew Mathew,Runeckles Kyle,Pahl Elfriede,Harahsheh Ashraf S,Norozi Kambiz,de Ferranti Sarah D,Friedman Kevin,Yetman Anji T,Kutty Shelby,Mondal Tapas,McCrindle Brian W, The Canadian journal of cardiology BACKGROUND:The substantial risk of thrombosis in large coronary artery aneurysms (CAAs) (maximum z-score ≥ 10) after Kawasaki disease (KD) mandates effective thromboprophylaxis. We sought to determine the effectiveness of anticoagulation (low-molecular-weight heparin [LMWH] or warfarin) for thromboprophylaxis in large CAAs. METHODS:Data from 383 patients enrolled in the International KD Registry (IKDR) were used. Time-to-event analysis was used to account for differences in treatment duration and follow-up. RESULTS:From diagnosis onward (96% received acetylsalicylic acid concomitantly), 114 patients received LMWH (median duration 6.2 months, interquartile range [IQR] 2.5-12.7), 80 warfarin (median duration 2.2 years, IQR 0.9-7.1), and 189 no anticoagulation. Cumulative incidence of coronary artery thrombosis with LMWH was 5.7 ± 3.0%, with warfarin 6.7 ± 3.7%, and with no anticoagulation 20.6 ± 3.0% (P < 0.001) at 2.5 years after the start of thromboprophylaxis (LMWH vs warfarin HR 1.5, 95% confidence interval [CI] 0.4-5.1; P = 0.56). A total of 51/63 patients with coronary artery thrombosis received secondary thromboprophylaxis (ie, thromboprophylaxis after a previous thrombus): 27 LMWH, 24 warfarin. There were no differences in incidence of further coronary artery thrombosis between strategies (HR 2.9, 95% CI 0.6-13.5; P = 0.19). Severe bleeding complications were generally rare (1.6 events per 100 patient-years) and were noted equally for patients on LMWH and warfarin (HR 2.3, 95% CI 0.6-8.9; P = 0.25). CONCLUSIONS:LMWH and warfarin appear to have equivalent effectiveness for preventing thrombosis in large CAAs after KD, although event rates for secondary thromboprophylaxis and safety outcomes were low. Based on our findings, all patients with CAA z-score ≥ 10 should receive anticoagulation, but the choice of agent might be informed by secondary risk factors and patient preferences. 10.1016/j.cjca.2020.01.016
    ST-elevation myocardial infarction in a young adult secondary to giant coronary aneurysm thrombosis: an important sequela of Kawasaki disease and a management challenge. Potter Elizabeth L,Meredith Ian T,Psaltis Peter James BMJ case reports Thrombosis of a coronary artery aneurysm (CAA) is a rare trigger for ST-elevation myocardial infarction (STEMI) and an important cause of STEMI in young adults previously affected by Kawasaki disease. Initial management should proceed in line with standard STEMI-management guidelines advocating antiplatelet medication and emergency coronary angiography. Acute CAA thrombosis presents the interventional cardiologist with unique challenges during attempted percutaneous revascularisation. In the absence of consensus guidelines, experiential reporting can therefore be of great value. We report on a 36-year-old Vietnamese woman presenting with an inferior STEMI secondary to two giant thrombosed aneurysms of the right coronary artery. Coronary wiring and thrombus aspiration temporarily improved coronary flow but recurrent thrombus with distal embolisation resulted in ventricular fibrillation and cardiogenic shock. Emergency surgical revascularisation subsequently provided a definitive and successful outcome. We discuss the challenges of percutaneous coronary intervention in this scenario and review previous reports to give an overview of principles of decision-making and management. 10.1136/bcr-2015-213622
    Anti-thrombosis management of patients with Kawasaki disease: Results from an international survey. Dionne Audrey,Dahdah Nagib,Singh-Grewal Davinder,Burgner David P,Newburger Jane W,de Ferranti Sarah D International journal of cardiology BACKGROUND:Patients with coronary artery aneurysms (CAA) after Kawasaki disease (KD) are at risk of thrombosis, which can lead to myocardial infarction or sudden death. Clinical practice guidelines recommend anticoagulation for high-risk patients. METHODS:Web-based worldwide survey of physicians completed between 2016 and 2017 investigating anti-thrombotic management after KD. We compared management of patients by geographic location, Human Development Index (HDI) tier, and medical specialty. RESULTS:The survey was completed by 603 physicians from 63 countries. In patients with normal coronaries, 95 (25%) of physicians recommended low-dose aspirin during long-term follow-up (>3 months after diagnosis). In patients with non-giant CAA, dual antiplatelet (e.g. aspirin and clopidogrel) was used by 121 (32%) of physicians, and anticoagulation by 72 (19%) of physicians. In patients with giant CAA, dual antiplatelet was used by 39 (10%) of physicians and anticoagulation by 285 (74%). In multivariable analysis, cardiology (OR 6.4 [95% CI 2.7, 16.1]) and rheumatology (OR 4.3 [95% CI 1.6, 12.6]) specialty (versus general pediatrics) were the only independent predictors of anticoagulant use in patients with giant CAA. CONCLUSION:There is significant variation in anti-thrombosis management of patients with CAA after KD, with 26% of physicians not recommending anticoagulation of patients with giant CAA. Further studies are needed to evaluate the drivers of this practice variation to inform educational initiatives and to ascertain impact on long-term outcomes. 10.1016/j.ijcard.2019.10.045
    Lymph-node-first Kawasaki disease and giant coronary artery aneurysm. Ramly Bazlin BMJ case reports A 8-year-old Irish ethnicity girl presented with 3 days of fever with right-sided neck swelling which was first thought as acute tonsillitis with right-sided lymphadenitis. She was started on intravenous antibiotics. At day 7 of illness, she was diagnosed to have Kawasaki disease with clinical and biochemical evidence. Echocardiogram at day 9 of illness and subsequently CT cardiac angiogram performed revealed giant aneurysm at the right coronary artery with non-obstructing thrombus seen. The patient then commenced on clopidogrel and continued with a regular dose of aspirin. Due to the evidence of thrombus with a giant coronary aneurysm, she was also put on long-term warfarin therapy with regular monitoring of her international normalised ratio to be kept at the range of 2.0-3.0. 10.1136/bcr-2018-226897
    [Aftermaths of lesions of coronary arteries in Kawasaki disease]. Vostokova A A,Grunina E A,Klemenov A V Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery Kawasaki disease, also known as cutaneous-mucous-glandular mucocutaneous glandular syndrome, is acute systemic vasculitis of small-to-medium calibre arteries, frequently involving coronary arteries, affect almost exceptionally children, with reports concerning cases of Kawasaki syndrome in 20-to-30-year-old adults being extremely rare. The most serious manifestation of Kawasaki disease is coronaritis and formation of coronary artery aneurysms. The dynamics of the formed coronary aneurysms and, consequently, the fate of patients may be different. Thrombosis of an aneurysm in the early period of the disease and stenosing of the affected coronary artery later on present possible complications of Kawasaki disease and potential causes of myocardial infection in young adults. Increased risk of coronary artery thromboses in Kawasaki disease is conditioned by a decrease in velocity of blood flow and its turbulent pattern in the aneurysms, endothelial dysfunction due to currently existing or endured coronaritis and thrombocytosis typical of this pathology. Predisposing factors of coronary artery stenosing are unfavourable haemodynamic conditions appearing at the sites of the "entry" and "exit" of the aneurysm. Described herein are two case reports of myocardial infarction, one of which being a complication of an acute case of Kawasaki disease in a 29-year-old patient, with the second one being a consequence of coronary artery stenosing in a 25-year-old patient who had endured Kawasaki disease in his childhood.
    Chronic occluded coronary aneurysm as a complication of Kawasaki disease: a long-term follow-up. Peters Alan A,Abbuehl Heidi,Spano Giancarlo,Graeni Christoph,Huber Adrian T Journal of cardiovascular medicine (Hagerstown, Md.) 10.2459/JCM.0000000000001244
    Incomplete Kawasaki disease with development of fatal coronary artery thrombosis in a 13-year-old male. Pacheco David A,Miller Catherine R,Boor Paul J,Mambo Nobby C Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology Kawasaki disease (KD) is among one of the most common causes of vasculitis in children. Since KD was first described in 1967, there have been several reports of patients who did not meet the full diagnostic criteria for KD but who ultimately developed significant coronary artery lesions. Children with incomplete KD are at similar risk of developing coronary artery abnormalities to those with complete Kawasaki. A previously healthy 13-year-old Asian male was seen at a clinic for fever, pharyngitis, and conjunctivitis. He was given antibiotics for a presumed streptococcal pharyngitis. Two weeks later, the decedent complained of chest pain, collapsed, and was transported by Emergency Medical Services to a nearby hospital where he was pronounced deceased on arrival. A complete autopsy was done by the local medical examiner. Histologically, all three coronary arteries showed varying degrees of severe transmural lymphoplasmacytic inflammation, marked vascular smooth muscle intimal proliferation, focal destruction of muscular and elastic layers, and luminal stenosis. Some vessels had recent thrombi. We present an example of incomplete KD in an older child and reiterate the importance of obtaining relevant medical history in sudden death cases that come to the Medical Examiner Office, especially in the pediatric age group. 10.1016/j.carpath.2019.04.002
    Visualizing high-intensity thrombosis with plaque imaging of coronary aneurysm in Kawasaki disease. Pediatrics international : official journal of the Japan Pediatric Society 10.1111/ped.14847