- [Show abstract] [Hide abstract] ABSTRACT: Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, and anticoagulant use in this population has become common, despite the absence of FDA approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials in adults, smaller dose-finding and observational studies in children, and expert opinion. The recently FDA-approved direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, provide potential advantages over oral vitamin K antagonists and subcutaneous low molecular weight heparins. However, key questions arise regarding their potential off-label clinical application in pediatric thromboembolic disease. In this Perspectives piece, we: provide background on the use of low molecular weight heparins such as enoxaparin as the mainstay of treatment for pediatric provoked VTE; identify key questions and challenges with regard to DOAC trials and future DOAC therapy in pediatric VTE; and discuss applicable lessons learned from the recent pilot/feasibility phase of a large multicenter randomized controlled trial of anticoagulant duration in pediatric VTE. The challenges and lessons learned present opportunities to improve evidence for anticoagulant therapies in pediatric VTE through future clinical trials.
- [Show abstract] [Hide abstract] ABSTRACT: Direct thrombin inhibitors offer potential advantages over unfractionated heparin, but have been poorly studied in children. To determine appropriate dosing of bivalirudin in children and adolescents and the relationship between activated partial thromboplastin time (APTT) and plasma bivalirudin concentration. Patients/Methods The UNBLOCK (UtilizatioN of BivaLirudin On Clots in Kids) study was an open-label, single-arm, dose-finding, pharmacokinetic, safety, and efficacy study of bivalirudin for the acute treatment of deep vein thrombosis (DVT) in children 6 months to 18 years of age. Drug initiation consisted of a bolus dose (0.125 mg/kg) followed by continuous infusion (0.125 mg/kg/hour). Dose adjustments were based on the APTT, targeting a range of 1.5-2.5 times each patient's baseline APTT. Safety was assessed by specific bleeding endpoints and efficacy by repeat imaging at 48-72 hours and 25-35 days. Eighteen patients completed the study. Following the bolus dose and the initial infusion rate, most patients' APTT values were within the target range. Bivalirudin infusion rate correlated more closely with drug concentration than the APTT. At 48-72 hours, nine (50%) patients had complete or partial thrombus resolution, increasing to sixteen (89%) at 25-35 days. No major and one minor bleeding event occurred. Bivalirudin demonstrated reassuring safety and noteworthy efficacy in terms of early clot resolution in children and adolescents with DVT. Although a widely available and familiar monitoring tool, the APTT correlates poorly with plasma bivalirudin concentration, possibly limiting its utility in managing pediatric patients receiving bivalirudin for DVT. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: To characterize features of antithrombin concentrate (ATC) use in children receiving unfractionated heparin (UFH) therapy for acute thrombosis. All pediatric patients at Texas Children's Hospital who received ATC in the context of UFH therapy for acute thrombosis during February 2011 to May 2013 were analyzed. Fifty-one children received ATC during UFH therapy for acute thrombosis. Median age was 3 months (IQR 1 to 18 months). Clinical indications included venous (53%), arterial (37%), venous and arterial (6%), and intracardiac (4%) thrombosis. Median baseline antithrombin (AT) level was 61% and UFH dose was 26 U/kg/h. The median dose of ATC was 49.9 IU/kg (IQR 32.6 to 50.0 IU/kg). Although most patients (86%) did not undergo a change in UFH dose, there was a significant increase in both AT and anti-factor Xa level after the first dose of ATC (P < .001 for both). There was no correlation between ATC dose or increment in AT level above baseline and the achievement of targeted anticoagulation by anti-factor X activity level. Adverse bleeding events occurred in 10% of patients. There was a significant change in AT and anti-factor Xa activity level after a single dose of ATC despite little to no change in dose of UFH. ATC appears to facilitate anticoagulation with UFH in some children with acute thrombosis but the degree of response is variable and dependent on factors identified in this study. Bleeding and other theoretical risks must be carefully considered. Copyright © 2015 Elsevier Inc. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: To compare the efficacy of oral tranexamic acid (TA) with combined oral contraceptives (COC) in reducing menstrual blood loss (MBL) and improving quality of life in adolescent heavy menstrual bleeding (HMB). A prospective randomized crossover trial with 17 postmenarchal girls aged 21 years and younger with HMB who were seen at our institution. Patients were randomized to group A (TA arm) or group B (COC arm), each for 3 cycles, with crossover to the second arm after 1-month washout. The primary end points were difference in improvement in MBL and QOL, from baseline to end of each therapy. Seventeen patients were enrolled (mean age 14.2 years, range 11.7 to 16.8 years). Nine patients completed both arms; 8 patients withdrew from the study due to adverse events or noncompliance. Compared with baseline, significant improvement (P < .05) was demonstrated by TA and COC in MBL (mean Pictorial Blood Assessment Chart score decrease: TA, 536.4; COC, 430.6) and quality of life (mean Pediatric Quality of Life Inventory(TM) version 4.0 Generic Scales score increase: TA, 15.6; COC, 16.75), but no significant difference was noted between TA and COC (P > .05). There was statistically significant reduction in the length of menstrual cycle for COC only (mean reduction 5.3 days; P = .04) and not for TA (P = .18). Ten patients (58%) experienced adverse events that were possibly drug related (TA: n = 3, 30%; COCP: n = 7, 64%). In this pilot study, oral TA appeared as efficacious as COC in the management of adolescent HMB by reducing MBL and improving quality of life. Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Our study was developed to ascertain reference ranges of 11-dehydrothromboxane B2 (11-dhTXB2) in the urine of healthy pediatric subjects. Urine samples were analyzed using the AspirinWorks™ assay that measures levels of 11-dehydrothromboxane B2. 128 individuals (2 months to 18 years) were identified as healthy and not receiving aspirin. When adjusted as picograms/milligrams urine creatinine, there was a negative correlation between age and level of 11-dehydrothromboxane B2 (P = 0.0001). This study confirms a negative correlation between age and level of urinary 11-dehydrothromboxane B2 and provides a set of age-specific reference ranges. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
- [Show abstract] [Hide abstract] ABSTRACT: Objective To study the prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young females referred to a multidisciplinary clinic for evaluation of heavy menstrual bleeding (HMB). Methods Retrospective chart review was undertaken for 131 post-menarchal girls with HMB, 7 to 17 years of age, enrolled in the institutional ‘Menorrhagia Data Registry’ protocol. The diagnostic approach included: (1) complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, von Willebrand panel (2) platelet aggregometry, specific clotting factor assay, fibrinolytic pathway analysis, and factor XIII level as needed. The prevalence of hemostatic abnormalities and the prognostic significance of clinical variables associated with hemostatic abnormalities in young girls with HMB were evaluated. Results A hemostatic abnormality was identified in 69 (53%) young girls with HMB. Of these, 27 (21%) had an underlying bleeding disorder and 42 (32%) had a risk factor for bleeding, namely low von Willebrand factor activity. A larger number of girls with underlying bleeding disorder had personal history of other bleeding symptoms (48% vs 31%) and bleeding after surgical or dental procedure (25% vs 8%) when compared to females without hemostatic abnormality. Furthermore, girls with risk factor for bleeding (low vWF activity) were more likely to have bleeding after surgical or dental procedure (15% vs 8%) and family history of bleeding (79% vs 60%) than patients without hemostatic abnormality. Conclusions There is high prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young girls with HMB. These findings support comprehensive and systematic hemostatic evaluation in this group of patients.
- [Show abstract] [Hide abstract] ABSTRACT: Catheter directed thrombolytic therapies (CDT) for severe pulmonary embolism (PE) have been shown to be effective and safe when compared to systemic thrombolysis in adults. Pediatric studies assessing efficacy and safety of CDT for PE are lacking. Hence our aim was to review CDT as a therapy for pediatric PE. We retrospectively reviewed charts of patients less than 18 years of age, who underwent CDT for main or major branch pulmonary artery occlusion associated with hypotension or right ventricular dysfunction secondary to PE during a three-year period, in our tertiary care academic Pediatric Intensive Care Unit. Six CDT interventions were performed on five patients with PE (median age: 16.5 years). All patients presented with chest pain and dyspnea. The predisposing factors for thrombogenesis differed in all patients and all had multiple risk factors. Five out of six procedures (83%) were accompanied by ultrasound agitation with EKOS endowave infusion system (UCDT), while one had CDT without ultrasound agitation. Complete resolution of PE occurred in four instances (67%) at 24 hours, while in two cases (33%), there was partial resolution. One patient with complete resolution underwent another successful UCDT after four months for recurrence. Clinical parameters (heart rate, respiratory rate, blood pressure, oxygen saturations) and echocardiographic findings improved post treatment in all the patients. Median duration of hospital stay was 9 days with no mortality and no treatment related complications. All patients were discharged with long-term anticoagulation. Our case series is the first that describes CDT/UCDT as an effective and safe therapy for pediatric patients with severe PE. CDT is known to accelerate fibrinolysis via focused delivery of thrombolytic agent to the thrombus site. For carefully selected patients, CDT/UCDT provides a useful treatment option for severe PE irrespective of the etiology, predisposing conditions and associated co-morbidities.
- [Show abstract] [Hide abstract] ABSTRACT: Platelet function defects (PFD) are reported to occur frequently in adult women with heavy menstrual bleeding (HMB). Few studies on adolescent HMB report varying incidence rates (2-44%) for PFD. We reviewed our institutional experience in detecting and managing PFD in adolescent HMB. Postmenarchial girls and adolescents with HMB seen at our institution undergo a comprehensive bleeding disorder work-up by paediatric haematology and paediatric gynaecology providers. Whole blood platelet aggregometry (WBPA) is performed as a second tier test after excluding thrombocytopaenia, coagulation factor deficiencies and Von Willebrand disease (VWD). We retrospectively reviewed the medical records of adolescents with HMB seen between June 2009 and November 2010, as approved by the Institutional Review Board. Patient demographics, clinical features, laboratory results, therapy details and patient outcome information were analysed. Overall, 114 postmenarchial girls and adolescents with HMB were evaluated; 68 patients (59%) had WBPA study performed. Nineteen patients (28%) had at least one aggregation or secretion defect; 12 (18%) had two or more such defects. Treatment included hormonal therapy (13/19; 68%), antifibrinolytic agents (8/19; 42%) and intra-nasal DDAVP (3/19; 16%). Thirteen patients (81%) had improved outcome (median follow-up - 15.6 months; range of 1-66 months). In this study, PFD were identified in nearly one-third of girls with HMB, with the majority of these having two or more defects as identified by WBPA. Further prospective studies are needed to better define the prevalence and address appropriate management of HMB and other bleeding complications of PFD in adolescents.
- [Show abstract] [Hide abstract] ABSTRACT: Given the rising incidence of thrombotic complications in paediatric patients, understanding of the pharmacologic behaviour of anticoagulant drugs in children has gained importance. Significant developmental differences between children and adults in the haemostatic system and pharmacologic parameters for individual drugs highlight potentially unique aspects of anticoagulant pharmacology in this special and vulnerable population. This review focuses on pharmacologic information relevant to the dosing of unfractionated heparin, low molecular weight heparin, warfarin, bivalirudin, argatroban and fondaparinux in paediatric patients. The bulk of clinical experience with paediatric anticoagulation rests with the first three of these agents, each of which requires higher bodyweight-based dosing for the youngest patients, compared with adults, in order to achieve comparable pharmacodynamic effects, likely related to an inverse correlation between age and bodyweight-normalized clearance of these drugs. Whether extrapolation of therapeutic ranges targeted for adult patients prescribed these agents is valid for children, however, is unknown and a high priority for future research. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, hold promise for future use in paediatrics but require further pharmacologic study in infants, children and adolescents.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: To determine whether pediatric patients with obesity receiving weight-based dosages of unfractionated heparin (UFH) exhibit an enhanced response when dosed by actual body weight compared with nonobese patients as assessed primarily by the frequency of supratherapeutic anticoagulation. Secondary measures included UFH doses associated with therapeutic anticoagulation. Study design: This single-institution retrospective case-matched study included children with and without obesity, matched on a 1:1 basis, who received a weight-based continuous infusion of UFH. Therapeutic monitoring values were defined for activated partial thromboplastin time (aPTT) level (70-101 seconds) and anti-activated factor X (Xa) level (0.35-0.7 U/mL). Results: The study included 50 children. The percentage of patients with supratherapeutic anticoagulation at any point in the study, as measured by either aPTT or anti-Xa level, was similar in the obese and nonobese groups (76% vs 72%; P = 1.0). However, compared with patients without obesity, those with obesity received a lower mean starting dose (17.4 vs 20.2 U/kg/hour; P = .013) and a lower mean maintenance dose (19.1 vs 24.3 U/kg/hour; P = .033) to achieve stable therapeutic monitoring test values. There was no difference in mean initial post-UFH aPTT between the 2 groups, but the mean initial anti-Xa level was higher in the obese group (0.45 vs 0.29 U/mL; P = .045). Conclusion: Compared with children without obesity, those with obesity who received actual body weight-based continuous UFH infusions did not exhibit a higher frequency of supratherapeutic anticoagulation, but did require lower dosages to achieve comparable anticoagulation. Our results highlight recognized discrepancies between aPTT and anti-Xa monitoring assays.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: To determine if using actual body weight to dose enoxaparin in obese pediatric patients results in higher anti-Xa levels compared with non-obese pediatric patients. Study design: This was a retrospective case-matched study of obese and non-obese pediatric patients receiving treatment doses of enoxaparin in a tertiary care children's hospital. Patients were included if they were initiated on treatment doses of enoxaparin, had appropriate anti-Xa levels drawn, and were between 2 and 18 years of age. Patients with renal insufficiency, hyperbilirubinemia, goal anti-Xa level <0.5 or >1 unit/mL, or receiving mechanical circulatory support were excluded. Obese patients who met study criteria were matched on a 1:1 basis with non-obese patients. Results: All baseline characteristics were similar except for body mass index percentile (98.2 ± 2 vs 48.7 ± 15, P < .01). Obese patients had higher initial anti-Xa levels (0.67 ± 0.27 vs 0.53 ± 0.24 unit/mL, P = .028). Over time, obese patients required a lower mean dose to achieve therapeutic anti-Xa levels than non-obese patients (0.81 ± 0.19 vs 1.1 ± 0.4 mg/kg, P = .005). Conclusions: The mean initial anti-Xa level was higher in obese pediatric patients compared with non-obese pediatric patients, but a dosage adjustment was not required. Obese patients may need closer monitoring over time to avoid supratherapeutic levels and possible bleeding events.
- [Show abstract] [Hide abstract] ABSTRACT: Intravascular hemolysis is a major component of anemia in sickle cell disease (SCD). Plasma extracellular hemoglobin (ECHb) liberated by intravascular hemolysis has deleterious effects on the vasculature. ECHb scavenges nitric oxide (NO) and promotes the pathogenesis of several clinical events including pulmonary hypertension, priapism and non-hemorrhagic strokes. ECHb reduces the bioavailability of NO which down-regulates platelet activation, leading to platelet aggregation and vascular clot formation. Recently we have identified an additional mechanism whereby increased hemolysis can lead to a prothrombotic state in SCD by increasing the activity of von Willebrand factor (VWF), a multimeric plasma glycoprotein secreted by the endothelium. Our studies show that ECHb binds to the A2-domain on VWF at the proteolytic site of the metalloprotease, ADAMTS13, and blocks VWF cleavage in vitro. Elevated ECHb is associated with high levels of ultralarge and hyperactive VWF multimers in SCD patients' plasma. A sub-population of VWF multimers, bound to ECHb is hyperactive, and exists in greater quantity in SCD patients' plasma compared to normal controls. These results suggest a possible role for plasma ECHb in the accumulation of hyperactive VWF multimers in vivo that may mediate thrombotic and vasoocclusive complications in SCD patients.
- [Show abstract] [Hide abstract] ABSTRACT: The incidence of thromboembolic disease is increasing in children. New anticoagulants have been licensed in adults and need to be studied in children. This report describes the first prospective study of fondaparinux in children. The purpose of the study was to determine the dosing, pharmacokinetics, and safety of fondaparinux in children with deep vein thrombosis (DVT) or heparin-induced thrombocytopenia (HIT). Hospitalized children between 1 and 18 years of age with DVT or HIT received fondaparinux 0.1 mg/kg once daily. Fondaparinux-based anti-factor Xa levels were assessed at 2, 4, 12, and 24 hr following the first dose, and peak levels were measured twice weekly thereafter. Detailed pharmacokinetic analyses were performed. Twenty four subjects in 3 age cohorts were enrolled and completed the study. Pharmacokinetic modeling demonstrated that a once-daily dose of fondaparinux at 0.1 mg/kg resulted in similar concentrations known to be efficacious in adults. Safety was demonstrated with only two bleeding events: one which may have pre-dated study drug administration and one which led only to temporary discontinuation of study drug. Dosing of fondaparinux at 0.1 mg/kg once daily in children resulted in PK profiles comparable to those in adults receiving standard dosing. Fondaparinux can be considered an attractive alternative to LMWH given its once-daily dosing, acceptable safety data, and other favorable properties.
Baylor College of Medicine
Houston, TX, United States
- Department of Pediatrics