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Research evaluating hemostatic agents for the treatment of clinically significant bleeding has been hampered by inconsistency and lack of standardized primary clinical trial outcomes. Clinical trials of hemostatic agents in both cardiac surgery and mechanical circulatory support, such as extracorporeal membrane oxygenation and ventricular assist devices, are examples of studies that lack implementation of universally accepted outcomes.A subgroup of experts convened by the National Heart, Lung, and Blood Institute and the US Department of Defense developed consensus recommendations for primary outcomes in cardiac surgery and mechanical circulatory support.For cardiac surgery the primary efficacy endpoint of total allogeneic blood products (units vs mL/kg for pediatric patients) administered intraoperatively and postoperatively through day 5 or hospital discharge is recommended. For mechanical circulatory support outside the perioperative period the recommended primary outcome for extracorporeal membrane oxygenation is a 5-point ordinal score of thrombosis and bleeding severity adapted from the Common Terminology Criteria for Adverse Events version 5.0. The recommended primary endpoint for ventricular assist device is freedom from disabling stroke (Common Terminology Criteria for Adverse Events AE ≥ grade 3) through day 180.The proposed composite risk scores could impact the design of upcoming clinical trials and enable comparability of future investigations. Harmonizing and disseminating global consensus definitions and management guidelines can also reduce patient heterogeneity that would confound standardized primary outcomes in future research.

OBJECTIVES Objective of this study was to determine if bivalirudin resulted in less circuit interventions than unfractionated heparin. A secondary objective was to examine associations between bivalirudin dose and partial thromboplastin time, international normalized ratio, and activated clotting time. DESIGN Prospective observational. SETTING Medical-surgical and cardiac PICUs. PATIENTS Neonatal and pediatric extracorporeal membrane oxygenation patients who received bivalirudin anticoagulation. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Twenty extracorporeal membrane oxygenation runs in 18 patients used bivalirudin; 90% were venoarterial. Median (interquartile range) age was 4.5 months (1.6-35 mo). Thirteen patients (72%) had an underlying cardiac diagnosis. Of the 20 runs using bivalirudin, 16 (80%) were initially started on unfractionated heparin and transitioned to bivalirudin due to ongoing circuit thrombosis despite therapeutic anti-Xa levels (n = 13), ongoing circuit thrombosis with unfractionated heparin greater than or equal to 40 U/kg/hr (n = 2), or absence of increase in ACT after bolus of 100 U/kg of unfractionated heparin and escalation of unfractionated heparin infusion (n = 1). Initial bivalirudin dose ranged from 0.2 to 0.5 mg/kg/hr; no bolus doses were used. Median (range) bivalirudin dose was 0.9 mg/kg/hr (0.15-1.6 mg/kg/hr). Median (interquartile range) time on extracorporeal membrane oxygenation was 226.5 hours (150.5-393.0 hr) including 84 hours (47-335 hr) on bivalirudin. Nonparametric results are as follows: the rate of circuit intervention was significantly lower in patients on bivalirudin than on unfractionated heparin (median [interquartile range]: 0 [0-1] and 1 [1-2], respectively; Wilcoxon p = 0.0126). Bivalirudin dose was correlated to PTT (rs = 0.4760; p < 0.0001), INR (rs = 0.6833; p < 0.0001), and ACT (rs = 0.6161; p < 0.0001). Four patients had a significant bleeding complication on bivalirudin. Survival to hospital discharge was 56%. CONCLUSIONS Bivalirudin appears to be a viable option for systemic anticoagulation in pediatric extracorporeal membrane oxygenation patients who have failed unfractionated heparin, but questions remain namely its optimal monitoring strategy. This pilot study supports the need for larger prospective studies of bivalirudin in pediatric extracorporeal membrane oxygenation, particularly focusing on meaningful monitoring variables.

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

Background: Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Methods: Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to (0-24)ss] and trough [C trough,ss] and maximum [C max,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients. Results: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Discussion: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.

Background: Recently, the randomised EINSTEIN-Jr. study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for acute and continued treatment of paediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, ≥12

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) 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 /=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. 01 januari 2020

Mechanical circulatory support (MCS) is the overarching term that encompasses the temporary and durable devices used in patients with severe heart failure. MCS disturbs the hematologic and coagulation system, leading to platelet activation, activation of the contact pathway of coagulation, and acquired von Willebrand syndrome. Ischemic stroke and major hemorrhage occur in up to 30% of patients. Hematologists are an essential part of the MCS team because they understand the delicate balance between bleeding and clotting and alteration of hemostasis with antithrombotic therapy. However, prior to this important collaborative role, learning the terminology used in the field and types of MCS devices allows improved communication with the MCS team and best patient care. Understanding which antithromobotic therapies are used at baseline is also required to provide recommendations if hemorrhage or thrombosis occurs. Additional challenging consultations in MCS patients include the influence of thrombophilia on the risk for thrombosis and management of heparin-induced thrombocytopenia. This narrative review will provide a foundation to understand MCS devices how to prevent, diagnose, and manage MCS thrombosis for the practicing hematologist.

Children maintain balanced hemostasis despite many hemostatic differences in comparison to adults with the incidence of thrombosis and hemorrhage in normal children being diminutive. However, there are cohorts of children demonstrated to be a high-risk for thrombosis, which specifically include children with a ventricular assist device (VAD). Adult studies demonstrate that the addition of a VAD to the circulatory system results in hemostatic activation, which unless modulated by antithrombotic therapy (AT), may result in stroke, pump thrombosis, and possibly death. Similar morbidities occur in children with a VAD and with higher incidences [1–5]; yet few studies exist to guide safe and effective AT [2,6,7]. The effect of developmental hemostasis [8,9] and drug metabolism in the presence of a VAD in infants and children are largely unknown. Developmental differences preclude the use of adult guidelines and may predispose children to morbidity and/or mortality. Studies are urgently required to understand the interface between VADs and developmental differences, especially hemostasis.

Background: Treatment of venous thromboembolism (VTE) in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. Methods: In a parallel-group open-label randomised study, 500 children aged birth to 17 years with documented acute VTE who had started heparinisation were assigned, in a 2:1 ratio, to receive bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants. The main treatment period was 3 months (1 month in children under 2 years with catheter-related VTE). Symptomatic recurrent VTE and bleeding were centrally assessed unaware of treatment assignment. Repeat imaging was obtained at the end of the treatment period. Findings: Recurrent VTE was the primary efficacy outcome and occurred in 4 of the 335 (1.2%) children allocated to rivaroxaban and in 5 of the 165 (3.0%) children allocated to standard anticoagulants (64.2% of whom received subcutaneous heparins only), for a hazard ratio of 0.40 (95% confidence interval, 0.11 to 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 was the principal safety outcome and occurred in 10 children (3.0%; all non-major) with rivaroxaban and in 3 children (1.9%; two major and 1 non-major) with standard anticoagulants. Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were comparable those obtained in rivaroxaban studies in adults. Interpretation: In children with acute VTE, treatment with rivaroxaban resulted in a low recurrence risk and a reduced thrombotic burden without increased bleeding, as compared to standard anticoagulants. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT02234843. Funding Statement: Bayer AG and Janssen Research & Development, LLC. Declaration of Interests: CM reports receiving personal fees and fees, paid to his institution, from Bayer, Bristol-Myers-Squibb, Pfizer and fees, paid to his institution, from BoehringerIngelheim; AWAL being employed by Bayer; RK receiving personal fees from Bayer, CSL Behring, and Kedrion; DB receiving personal fees and grant support from Actelion Pharmaceuticals, Bayer, Eli Lilly, BMS, and Novartis and grant support from AbbVie; PC receiving personal fees from Onyx Health Limited; AKC receiving personal fees from Bayer and fees, paid to his institution, from Bayer, Pfizer, Daiichi Sankyo, and Bristol-Myers-Squibb; GK receiving personal fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo and fees, paid to her institution from Pfizer; SH receiving personal fees from P and fees, paid to her institution, from Bayer, Pfizer, and Daiichi Sankyo; AS receiving personal fees from Bayer, Pfizer, Daiichi Sankyo and Boehringer Ingelheim; PA receiving personal fees and fees, paid to his institution, from Abbvie and Bayer, and fees paid to his institution from Actelion, Novartis, and Daiichi Sankyo; EC receiving personal fees from Boehringer Ingelheim and Bristol-Myers-Squibb, and fees, paid to her institution from Bayer, Pfizer, and Daiichi Sankyo; DLY receiving fees, paid to his institution, from Bayer, Pfizer, and Bristol-Myers Squibb; OL receiving personal fees from Bayer, Pfizer, Boehringer Ingelheim, and Novartis, and fees, paid to her institution, from Bayer; JB-W receiving personal fees and fees, paid to his institution, from Bayer, Daiichi Sankyo, DOASENSE and Portola and fees, paid to his institution, from Pfizer; TTB receiving fees from Boehringer Ingelheim and Bayer, and grant support from Leo Pharma; IM receiving fees from Sanofi and Bayer; MP receiving grant support from Pfizer and Sobi; MPM receiving personal fees from Bayer; GY receiving receiving personal fees from GlaxoSmithKline and Portola and personal fees and fees paid to his institution from Bayer and Daiichi Sankyo; AFP, MM, WTS, SDB, KT, DK being employed by Bayer; JH was employed by Bayer; MC receiving grant support from and serving on a data and safety monitoring board for Bayer, receiving advisory board fees from Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Asahi Kasei, receiving educational funding from Alexion Pharmaceuticals, Pfizer, CSL Behring, and Diagnostica Stago, receiving grant support, paid to his institution, from Leo Pharma, serving on a data and safety monitoring board for Daiichi Sankyo, owning stock in Alnylam Pharmaceuticals, and receiving educational funding and advisory board fees from Servier Canada; MHP receiving personal fees from Bayer; no other potential conflict of interest relevant to this article was reported. Ethics Approval Statement: The protocol was approved by the institutional review board at each participating center. Written permission from a parent or guardian and, when appropriate, child assent, were obtained.

Background Venous thromboembolism (VTE) is a relatively rare condition in childhood with treatment mainly based on extrapolation from studies in adults. Therefore, clinical trials of anticoagulation in children require novel approaches to deal with numerous challenges. The EINSTEIN-Jr program identified pediatric rivaroxaban regimens commencing with in vitro dose finding studies followed by evaluation of children of different ages through phase I and II studies using extensive modeling to determine bodyweight-related doses. Use of this approach resulted in drug exposure similar to that observed in young adults treated with rivaroxaban 20 mg once-daily. Methods EINSTEIN-Jr phase III is a randomized, open-label, study comparing the efficacy and safety of rivaroxaban 20 mg-equivalent dose regimens with those of standard anticoagulation for the treatment of any types of acute VTE in children aged 0–18 years. A total of approximately 500 children are expected to be included during the 4-year study window. Flexibility of treatment duration is allowed with study treatment to be given for 3 months with the option to continue treatment in 3-month increments, up to a total of 12 months. However, based on most common current practice, children younger than 2 years with catheter-related thrombosis will have a main treatment period of 1 month with the option to prolong treatment in 1-month increments, up to a total of 3 months. Conclusions EINSTEIN-Jr will compare previously established 20 mg-equivalent rivaroxaban dosing regimens with standard anticoagulation for the treatment of VTE in children. Demonstration of similarity of disease, as well as equivalent rivaroxaban exposure and exposure-response will enable extrapolation of efficacy from adult trials, which is critical given the challenges of enrollment in pediatric anticoagulation trials. Trial registration Clinicaltrials.gov NCT02234843, registered on 9 September 2014.

Management of antithrombotic therapy (ATT) for pediatric ventricular assist devices is challenging, and the Berlin EXCOR remains the only Food and Drug Administration (FDA)-approved option. Among those on the EXCOR, 28% have neurologic complications and major bleeding occurs in 50%. The Edmonton Protocol was developed to guide ATT, but the adverse event rate remains high, leading most centers to make modifications. The objective of this study is to characterize antithrombotic practice variation among North American pediatric ventricular assist device programs, in order to guide future research. In this descriptive cross-sectional study, a survey assessing antithrombotic (AT) practices was distributed by Berlin Heart Inc. to centers that implanted ≥1 EXCOR between January 2012 and January 2016. Practices were compared at high- versus low-volume centers. High volume was defined as ≥14 implants in this period. Seventeen of 38 centers (44.7%) participated; 4 were high volume. At half of all centers (9/17), ≤2 clinicians managed all AT decisions. Although 47.1% (8/17) followed the protocol "extremely/very closely," only 5.9% (1/17) felt it to be "very effective." Most centers (10/15; 66.7%) deviated in ≥2 protocol aspects. Over half modified either recommended antiplatelet agents (5/15) or anticoagulants (4/15). Adjunct medication use was highly variable. Most (11/17; 64.7%) deviated from protocol in either timing or type of AT lab monitoring. Despite widespread use of Thromboelastography (TEG)/Platelet Mapping (PM), concerns of inaccuracy were common. Most high-volume centers (3/4; 75%) abandoned TEG/PM as a primary tool. These practice variation analyses have identified areas in ATT that are amenable to care standardization and further research. Systematic study of optimal AT medication dosing and monitoring is needed.

Introduction Ventricular Assist Devices (VADs) are increasingly utilised in children with end-stage heart failure, and experience high bleeding and clotting rates. In particular, pediatric VAD patients are more challenging than adults to anticoagulate due to developmental hemostasis, lack of suitable drug preparations, and difficult anticoagulation monitoring often due to poor vascular access; in addition to difficulties of VAD design in smaller children. This review aims to summarize the current evidence related to antithrombotic therapy in pediatric VAD patients. Materials and methods A search of 2 databases across a 17-year period of time was undertaken using key words selected a priori. Identified publications were then categorized according to VAD types utilised and the anticoagulation protocols described. Results 27 articles were identified consistent with the inclusion criteria developed for this review. Devices included in the cohort were Berlin Heart EXCOR, Thoratec, Medos, Novacor, HeartMate II and HeartWare HVAD. Most studies reported the use of unfractionated heparin post-operatively with a transition to low molecular weight heparin and warfarin. Antiplatelet regimens most commonly included aspirin and dipyridamole. Definition of bleeding and clotting events differed between cohorts. The incidence of bleeding overall was 37% (209/558; range of 0 to 89%) and 26% (143/554; range of 8.3 to 100%) for thromboembolism events. All studies reported had significant methodological limitations. Conclusions The clinical use of antithrombotic therapies – including dosages, timing and monitoring – varies considerably. This review highlights the further research required to improve understanding of hemostasis in the pediatric VAD field.

A continuous infusion of unfractionated heparin is the most common anticoagulant used for pediatric patients on extracorporeal life support. The objective of this study was to compare extracorporeal life support complications and outcomes between two large-volume pediatric extracorporeal life support centers that use different anticoagulation strategies.Prospective, observational cohort study.The University of Michigan used simple anticoagulation monitoring, whereas the University of Alberta used an intensive anticoagulation monitoring strategy.Pediatric patients on extracorporeal life support.None.The primary outcome measure was major bleeding per extracorporeal life support run defined as bleeding that was retroperitoneal, pulmonary, or involved the CNS; bleeding greater than 20 mL/kg over 24 hours; or bleeding that required surgical intervention. Secondary outcomes measured were patient thrombosis per run, circuit thrombosis per run, and survival to hospital discharge per patient. Eighty-eight patients (95 runs) less than 18 years old were enrolled at the two centers over 2 years. The two centers enrolled different extracorporeal life support populations; University of Alberta enrolled more postcardiac surgical patients (74% vs 47%; p = 0.005). The indication for extracorporeal life support support also varied by center (p = 0.04). The two centers used similar proportions of VA extracorporeal life support (p = 0.3). Median (interquartile range) unfractionated heparin doses were similar between University of Michigan and University of Alberta, 30 (21-34) U/kg/hr and 26 (22-31) U/kg/hr, p value equals to 0.3, respectively. Median (interquartile range) antifactor Xa was lower in the University of Michigan cohort (0.23 [0.19-0.28] vs 0.41 [0.36-0.46] U/mL; p0.001). There was no significant difference in major bleeding (15% University of Michigan vs 21% University of Alberta; p = 0.6) or in patient thromboses (18% University of Michigan vs 13% University of Alberta; p = 0.5). There was no significant difference in survival to hospital discharge (University of Michigan 63% vs University of Alberta 73%; p = 0.1).Although this prospective cohort study compared different pediatric extracorporeal life support populations, the results did not identify a significant difference in outcomes between simple and intensive anticoagulation monitoring strategies.

BACKGROUND: Pediatric arterial ischemic stroke remains incompletely understood. Population-based epidemiological data inform clinical trial design but are scant in this condition. We aimed to determine age-specific epidemiological characteristics of arterial ischemic stroke in neonates (birth to 28 days) and older children (29 days to 18 years). METHODS: We conducted a 16-year, prospective, national population-based study, the Canadian Pediatric Ischemic Stroke Registry, across all 16 Canadian acute care children's hospitals. We prospectively enrolled children with arterial ischemic stroke from January 1992 to December 2001 and documented disease incidence, presentations, risk factors, and treatments. Study outcomes were assessed throughout 2008, including abnormal clinical outcomes (stroke-related death or neurological deficit) and recurrent arterial ischemic stroke or transient ischemic attack. RESULTS: Among 1129 children enrolled with arterial ischemic stroke, stroke incidence was 1.72/100,000/year, (neonates 10.2/100,000 live births). Detailed clinical and radiological information were available for 933 children (232 neonates and 701 older children, 55% male). The predominant clinical presentations were seizures in neonates (88%), focal deficits in older children (77%), and diffuse neurological signs (54%) in both. Among neonates, 44% had no discernible risk factors. In older children, arteriopathy (49% of patients with vascular imaging), cardiac disorders (28%), and prothrombotic disorders (35% of patients tested) predominated. Antithrombotic treatment increased during the study period (P < 0.001). Stroke-specific mortality was 5%. Outcomes included neurological deficits in 60% of neonates and 70% of older children. Among neonates, deficits emerged during follow-up in 39%. Overall, an initially decreased level of consciousness, a nonspecific systemic presentation, and the presence of stroke risk factors predicted abnormal outcomes. For neonates, predictors were decreased level of consciousness, nonspecific systemic presentation, and basal ganglia infarcts. For older children, predictors were initial seizures, nonspecific systemic presentation, risk factors, and lack of antithrombotic treatment. Recurrent arterial ischemic stroke or transient ischemic attack developed in 12% of older children and was predicted by arteriopathy, presentation without seizures, and lack of antithrombotic treatment. Emerging deficit was predicted by neonatal age at stroke and by cardiac disease. CONCLUSIONS: This national data set provides a population-based disease incidence rate and demonstrates the protective effect of antithrombotic treatment in older children, and frequent long-term emerging deficits in neonates and in children with cardiac disorders. Further clinical trials are required to develop effective age-appropriate treatments for children with acute arterial ischemic stroke.

The Infant Jarvik ventricular assist device (VAD; Jarvik Heart, Inc., New York, NY) has been developed to support the circulation of infants and children with advanced heart failure. The first version of the device was determined to have elevated hemolysis under certain conditions. The objective of this work was to determine appropriate modifications to the Infant Jarvik VAD that would result in acceptably low hemolysis levels. In vitro hemolysis testing revealed that hemolysis was related to the shape of the pump blade tips and a critical speed over which hemolysis would occur. Various design modifications were tested and a final design was selected that met the hemolysis performance goal. The new version was named the Jarvik 2015 VAD. Chronic in vivo tests, virtual fit studies, and a series of other performance tests were carried out to assess the device's performance characteristics. In vivo test results revealed acceptable hemolysis levels in a series of animals and virtual fit studies showed that the device would fit into children 8 kg and above, but could fit in smaller children as well. Additional FDA-required testing has been completed and all of the data are being submitted to the FDA so that a clinical trial of the Jarvik 2015 VAD can begin. Development of a Jarvik VAD for use in young children has been challenging for various reasons. However, with the hemolysis issue addressed in the Jarvik 2015 VAD, the device is well-poised for the start of the PumpKIN clinical trial in the near future.

In preparation to the 15th International Congress on Antiphospholipid Antibodies (aPL), a multidisciplinary pediatric antiphospholipid syndrome (APS) task force was created in order to review the accumulated knowledge of the pediatric APS (pathogenesis, clinical and laboratory features, diagnosis, classification, and treatment), assess modifications to the APS classification criteria (applicability to children and neonates), and make recommendations for future research. This report covers a brief review of hemostasis including vessel damage and platelet response (adhesion, activation, and aggregation); thrombin generation in the cell-based model of coagulation, fibrinolysis (clot dissolution), and modulation; and hemostasis measurement. There follows a discussion of developmental hemostasis (highlighting the differences between children and adults), thrombosis risk assessment (genetic and extrinsic), clinical and laboratory features of APS in children, prevention and treatment of APS in children, and long-term follow-up of children born to mothers with aPL. The report concludes with acknowledgment of the progress made to date in literature reviews, surveys of practice patterns, refinement of registry data entry, and the need for published proposals for revised classification criteria. Studies including validation of proposed criteria, evaluation of therapies (especially the newer agents), and development and testing of risk stratification models by patient age still need to be performed.

Thrombosis has long been recognized as a potentially life-threatening complication in children with congenital heart disease (CHD), children with acquired heart disease, and in adults with CHD. High-risk groups include patients with shunt- dependent single ventricles (shunt thrombosis, 8%–12%; 4%

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Background The Infant Jarvik 2015 is an implantable axial-flow ventricular assist device (VAD) that has undergone the major evolutionary design modifications to improve hemocompatibility. This study was conducted in anticipation of data submission to the US Food and Drug Administration to obtain Investigational Device Exemption approval. Methods The VAD was implanted via a left thoracotomy in Barbado sheep (n = 10, 26 (19-34] kg). Anticoagulation was maintained with coumadin, with a target international normalized ratio of greater than the individual sheep's baseline values. The VAD was managed at the highest possible speed as clinically tolerable. Complete necropsy was performed at the end of the study. Results There were 2 early mortalities: tension pneumothorax (n = 1) and shower emboli of the fragmented myocardium (n = 1). The remaining 8 sheep (2 with 30-day and 6 with 60-day protocols) completed the anticipated study duration in excellent condition, with the 6 completing 60-day sheep showing appropriate weight gain during support. There were no signs of clinically significant hemolysis, with the final plasma-free hemoglobin of 2 (1-17) mg/dL. Necropsy showed old renal infarction in 7 sheep. Although thromboembolism can be the potential etiology, given the mild anticoagulation regimen, other sources of emboli were identified in 2 sheep (graft coating material and fragmented myocardium). Flow study demonstrated favorable increase in flow (up to 3.0 L/min) in proportion to change in pump speed. Conclusions This study has demonstrated that the Infant Jarvik 2015 VAD is capable of maintaining its functionality for an extended period of time with minimal hemolysis.

Background:The need for long-term thromboprophylaxis in children using warfarin therapy is increasing. Natural health products (NHPs) are administered to children by parents who perceive them to be useful and acceptable adjuncts or alternatives to conventional therapies. Interactions of NHPs with prescribed therapies may result in serious adverse events. NHP usage is underevaluated in children and there are no studies evaluating NHP usage in warfarinized children.Objectives:To explore NHP use in warfarinized children and their siblings to determine the prevalence, varieties, and reasons for NHP usage, as well as the potential effect on warfarinization (eg, time in therapeutic range [TTR]).Methods:This is a 3-phase cross-sectional cohort study that includes the (1) prevalence (2) NHP education and knowledge assessment, and (3) the follow-up NHP utilization phase.Results:Forty-six percent of warfarinized children consumed NHPs, with time in therapeutic range of 74%. The mean score for baseline knowledge of NHPs and warfarin following the education phase was 67%. Follow-up NHP use was 30%, and increased consistency of utilization with TTR was 83% (p < 0.05), consistent with education provided.Conclusions:The consistent prevalence rates over time of NHP usage in warfarinized children indicate the need for future studies. Education remains vital to combat the potential risks of NHP-warfarin interaction, encouraging patient disclosure and consistency.

Arterial ischemic stroke occurs as a result of abnormal clinical circumstances that alter hemostasis and cause thrombosis, either within a vessel or as an embolic event. Understanding normal hemostasis, including differences between children (developmental hemostasis) and adults, will provide background for determining the pathophysiology of stroke and potential treatments.

Hemostasis is the balance between bleeding and clotting and includes coagulation and fibrinolysis with platelet interactions. Despite developmental hemostasis that describes the major differences between neonates and older children and adults, neonates do not have increased bleeding or clotting unless clinical situations disturb the "balance." Perinatal asphyxia alters the balance of hemostasis, resulting in abnormalities that may result in bleeding and thrombosis. The following discussion will describe normal hemostasis, laboratory measures of hemostasis, developmental hemostasis, and the effects of asphyxia on hemostasis.

Background Beginning in 2000 and accelerating in 2004, the Berlin Heart EXCOR (Berlin Heart Inc Woodlands, TX) became the first pediatric-specific ventricular assist device (VAD) applied throughout North America for children of all sizes. This retrospective study analyzed the initial Berlin Heart EXCOR pediatric experience as a bridge to transplantation. Methods Between June 2000 and May 2007, 97 EXCOR VADs were implanted in North America at 29 different institutions. The analysis is limited to 73 patients (75%) from 17 institutions, for which retrospective data were available. Results Median age and weight at VAD implant were 2.1years (range, 12 days–17.8 years) and 11 kg (range, 3–87.6 kg), respectively. The primary diagnoses were dilated cardiomyopathy in 42 (58%), congenital heart disease in 19 (26%), myocarditis in 7 (10%), and other cardiomyopathies in 5 (7%). Pre-implant clinical condition was critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), or other in 2 (3%). Extracorporeal membrane oxygenation was used as a bridge to EXCOR in 22 patients (30%). Device selection was left VAD (LVAD) in 42 (57%) and biventricular assist devices (BiVAD) in 31 (43%). The EXCOR bridged 51 patients (70%) to transplant and 5 (7%) to recovery. Mortality on the EXCOR was 23% ( n = 17) overall, including 35% (11 of 31) in BiVAD vs 14% (6 of 42) in LVAD patients ( p = 0.003). Multivariate analysis showed younger age and BiVAD support were significant risk factors for death while on the EXCOR. Conclusions This limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The prospective investigational device evaluation trial presently underway will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation.

Background Recent guidelines discourage routine use of thrombolytic agents for treatment of venous thromboembolism (VTE) in pediatric patients, but actual practice patterns are unknown. Procedure An electronic survey was emailed to all active and trainee members of the American Society of Pediatric Hematology/Oncology in April 2008. Respondents were asked a series of multiple-choice questions based on hypothetical case scenarios describing pediatric VTE, pertinent to the implementation of thrombolytic therapy and other professional demographic information. Results Two hundred eighty-five evaluable responses were obtained (22% response rate) which varied greatly with respect to all spheres of questioning. Tissue plasminogen activator (tPA) was the thrombolytic agent chosen by most respondents, but no clear consensus emerged as to appropriate indications (although preference for thrombolytic therapy increased with severity of the posed clinical scenario), mode of tPA delivery (systemic vs. catheter-directed), dose (high-dose vs. low-dose regimen) or a suitable maximum duration of therapy (range: 1–168 hr; varied according to specific dosing regimen chosen). Expertise in pediatric thrombosis, years out from fellowship training and volume of experience with cases of pediatric thrombosis were not largely associated with respondent choices; however, institutional experience with pharmacologic thrombolysis exhibited the most notable association of the professional demographic factors analyzed. Conclusions The survey results support that clinical practice pertaining to use of thrombolytic agents in pediatric VTE varies widely but also provide useful benchmarks to aid clinical decision-making and future clinical trial design. Such varied practices stem from the lack of strong evidence supporting one therapeutic approach versus another. Pediatr Blood Cancer 2009;53:960–966. © 2009 Wiley-Liss, Inc.

SummaryIncreasing the starting dose of enoxaparin results in the early achievement of therapeutic anti-factor Xa levels in children receiving enoxaparin which is critical for effective therapy and the reduction of venipunctures. The aim of this study was: i) to determine the enoxaparin dose required to achieve therapeutic anti-factor Xa levels in infants and children, and ii) to establish whether increasing the starting dose of enoxaparin influenced the time required to reach the therapeutic range and the number of venipunctures required for dose-adjustment, and iii) the radiographic outcome of the thrombosis, where applicable. A retrospective chart review of children who received enoxaparin was carried out at the Stollery Children’s Hospital, Edmonton, Alberta, Canada. Patients treated with standard-dose enoxaparin (1.5 mg/kg for children ≤3 months of age, 1.0 mg/kg for children ≥3 months of age), were compared with children who received a higher initial starting dose of enoxaparin (1.7 mg/kg for children ≥3 months of age, 1.2 mg/kg for children ≥3 months of age). Infants

Many children are surviving primary illnesses and now require thromboprophylaxis as a result of advances in management. Vitamin K antagonists are commonly prescribed to prevent or treat thrombosis. These agents are far more challenging to effectively manage in children. As a result of these challenges, frequent blood monitoring to measure international normalized ratio (INR) values is required. Point-of-care (POC) INR monitors use a capillary blood sample that has been expressed as a solution to improve effective management of vitamin K antagonist therapy. POC INR meters have been demonstrated to be accurate and precise in measuring INRs. Implementation of a standardized education program prior to patient use of POC meters results in differences between measured laboratory INRs and POC INR comparisons that meet criteria for clinical relevance. This indicates that POC INR meters are safe and effective for use in children.

Mechanical circulatory support (MCS) provides a bridge to heart transplant in children and adults with life-threatening heart failure and sustains patients ineligible for transplant. Extracorporeal membrane oxygenation (ECMO) provides temporary support for patients in cardiac or pulmonary failure through external gas exchange and continuous flow of blood. Because the median time to heart transplant exceeds event-free time on ECMO, pulsatile left ventricular assist devices (LVADs) are used to support infants and children. Continuous flow LVADs are preferred in adolescents and adults due to increased pump durability and improved overall survival. The shear stress created by the mechanical pumps cause changes in the hematologic system; acquired von Willebrand syndrome occurs in almost all patients treated with MCS. Despite the improvements in survival, major bleeding occurs in one-third of patients with a LVAD and ischemic stroke and LVAD thrombosis can affect 12% of adults and 29% of children. An antithrombotic strategy to mitigate LVAD bleeding and thrombotic complications has been tested in a randomized trial in children, but intensity of antithrombotic therapy in adults varies widely. Consensus guidelines for antithrombotic therapy during ECMO were created due to significant differences in management across centers. Because of the high risk for both bleeding and thrombotic complications, experts in hemostasis can significantly impact care of patients requiring mechanical circulatory support and are a necessary part of the management team.

Evidence based recommendations for antithrombotic therapy in infants and children have been summarized and published by the American Academy of Chest Physicians (AACP). The guidelines are updated and republished every 4 years by an expert panel in pediatric anticoagulation. The guidelines are graded based on the level of evidence supporting each recommendation thus clarifying for the treating physician how strong the recommendations are. The grading is based on an estimate of risk and benefit and the methodologic strength of the studies supporting the recommendation. Grade 1 and grade 2 recommendations differ in that the estimate of risk and benefit associated with each approach was either clear or unclear, respectively. The methodologic strength of the study(ies) providing support for the recommendation is then graded as wither A, B, or C. Grade A and B represent randomized trials without or with important limitations, respectively. Grade C represents observational studies. The latest summary further clarifies the recommendation by including any underlying values and preferences associated with the recommendation. Summary of pediatric recommendations for antithrombotic therapy

Children with congenital and acquired heart disease are at risk for thrombotic events which, along with complications from thromboprophylaxis and antithrombotic therapy, are increasingly recognized as important contributors to morbidity and mortality in this heterogeneous group of patients.1 The prevalence and clinical relevance of thrombosis in these populations are influenced by developmental,2 acquired, and hemodynamic factors.3 Nevertheless, the pathophysiology, incidence, associated risk factors, and optimal strategies for prevention, detection/surveillance, and management of thrombosis in these populations have not been clearly defined by rigorous clinical investigations. The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group meeting on June 14 to 15, 2012 in Bethesda, Maryland, to explore the issues relevant to thrombosis in children with heart disease. The goals of the Working Group were to (1) review the current state of knowledge about thrombosis and incorporate additional knowledge derived from studies and guidelines relevant to adult populations, (2) identify gaps in the evidence base and prioritize opportunities for using basic and clinical research, and (3) identify common methodological issues and potential solutions to those issues for future studies in children. Given the broad topic, we purposely excluded discussion of cardiopulmonary bypass and extracorporeal membrane oxygenation, because these 2 topics are associated with unique issues and were thought to be beyond the focus of the Working Group. The Working Group consisted of experts in pediatric cardiology, hematology and neurology, adult cardiology and hematology, basic science of coagulation, imaging, clinical trial methodologies, quantitative analyses, and the dissemination and implementation of guidelines, along with representatives from the pharmaceutical industry and the Food and Drug Administration. This article represents the Working Group’s discussions on evidence gaps, challenges for this population, and recommendations for strategic research. There is insufficient evidence to guide the surveillance, prevention, and treatment of thrombosis in …

Objective To describe antithrombin levels, altered unfractionated heparin effect (anti-factor Xa activity and activated partial thromboplastin time), and adverse effects post administration of a single high dose of antithrombin concentrate. Design Retrospective review. Patients Infants and children with antithrombin levels less than 50% and a subtherapeutic unfractionated heparin effect. Setting Quaternary care children's hospital with a dedicated anticoagulation program. Interventions None. Measurements and main results A single high dose of antithrombin concentrate was administered. Antithrombin level, anti-factor Xa, and activated partial thromboplastin times were measured post antithrombin concentrate infusion and daily until stable. One hundred twenty-one patients received 246 doses of antithrombin. Patients were described using two cohorts based on the ability to obtain exact heparin doses. Cohort 1 included all patients between January 2004 and May 2008 when complete heparin dosing was unavailable. Cohort 2 included patients from May 2008 to May 2011 when heparin dose was available. Median age and weight were 3.7 months and 4.1 kg. Mean antithrombin concentrate dose was 222 IU/kg. Mean antithrombin level increased from 0.39 to 1.20 U/mL following antithrombin concentrate administration. In cohort 2, unfractionated heparin doses to achieve a target anti-factor Xa activity pre-post antithrombin concentrate were 28 and 19 U/kg/hr, respectively, for children 12 months old or younger and 25 and 19 U/kg/hr, respectively, for children older than 12 months. There were no hemorrhagic, thrombotic, or allergic events within 1 week of antithrombin concentrate administration. Conclusions This is the largest study of antithrombin concentrate evaluation in children. Administration of antithrombin concentrate increases anti-factor Xa activity with lower administered unfractionated heparin doses.

Objective: Low molecular weight heparins (LMWHs) offer several advantages over standard anticoagulant therapy (unfractionated heparin/warfarin) including predictable pharmacokinetics, minimal monitoring, and subcutaneous administration. Our objective was to determine the safety and efficacy of LMWHs in children. Methods: A prospective cohort of children treated with the LMWH enoxaparin (Rhone Poulenc Rorer) was monitored at the Hospital for Sick Children, Toronto, Canada, from March 1994 until July 1997. Results: There were 146 courses of LMWH administered for treatment and 31 courses for prophylaxis of thromboembolic events (TEs). Clinical resolution of TEs occurred in 94% of children receiving therapeutic doses of LMWH, and 96% of children receiving prophylactic doses of LMWH had no symptoms of recurrent or new TEs. Major bleeding occurred in 5% of children receiving therapeutic doses. Recurrent or new TEs occurred in 1% and 3% of children receiving therapeutic and prophylactic doses of LMWH, respectively. Conclusion: LMWH appears to be efficacious and safe for both management and prophylaxis of TEs. The results of this cohort study justify a randomized controlled trial comparing LMWH with standard therapy for the management of TEs in children.(J Pediatr 2000;136:439-45)

This is a commentary on a Cochrane review, published in this issue of EBCH, first published as: Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD002772. DOI: 10.1002/14 651 858.CD002772.pub3. Further information for this Cochrane review is available in this issue of EBCH in the accompanying EBCH Summary and Characteristics and Key Findings Tables. Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The Cochrane Collaboration

Children in the cardiac intensive care unit (CICU) with congenital or acquired heart disease are at risk for hematologic complications, both hemorrhage and thrombosis. The overall incidence of hematologic complications in the CICU is unknown, but risk factors and target groups have been identified where the essential physiologic balance between bleeding and clotting has been disrupted. Although the best management of life-threatening bleeding and clotting is prevention, the cardiac intensivist is often faced with managing life-threatening hematologic events involving patients from within the unit or those who present from outside. Part I of this review deals with the propensity of children with congenital and acquired heart disease to complications of both bleeding and clotting, and includes discussions of perioperative bleeding, thromboses in single-ventricle patients, clotting of Blalock-Taussig shunts and thrombotic complications of mechanical valves. Part II deals with the subject of stroke in children with heart disease. Part III reviews monitoring the effectiveness of anticoagulation and thrombolysis in the CICU. Currently available diagnostics modalities, medications and management strategies are reviewed and future directions discussed.

Background— Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. Methods and Results— This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early ( Conclusions— Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.