M.P. Massicotte

Outcome of pediatric thromboembolic disease : A report from the Canadian Childhood thrombophilia Registry

The outcome for children with deep vein thrombosis (DVT) and pulmonary embolism (PE) is unknown. An understanding of morbidity and mortality of DVT/PE is crucial to the development of rational treatment protocols. The Canadian Childhood Thrombophilia Registry has followed 405 children aged 1 mo to 18 y with DVT/PE for a mean of 2.86 y (range, 2 wk to 6 y) to assess outcome. The all-cause mortality was 65 of 405 children (16%). Mortality directly attributable to DVT/PE occurred in nine children (2.2%), all of whom had central venous line–associated thrombosis. Morbidity was substantial, with 33 children (8.1%) having recurrent thrombosis, and 50 children (12.4%) having postphlebitic syndrome. Recurrent thrombosis and postphlebitic syndrome were more common in older children, although deaths occurred equally in all age groups. The incidence of recurrent thrombosis and postphlebitic syndrome are likely underestimated because of difficulties in diagnosis, especially in younger children. The significant mortality and morbidity found in our study supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with DVT/PE.

Accuracy of the CoaguChek XS for point-of-care international normalized ratio (INR) measurement in children requiring warfarin

Point-of-care INR (POC INR) meters can provide a safe and effective method for monitoring oral vitamin K antagonists (VKAs) in children. Stollery Childrens Hospital has a large POC INR meter loan program for children requiring oral VKAs. Our protocol requires that POC INR results be compared to the standard laboratory INR for each child on several consecutive tests to ensure accuracy of CoaguChek XS (Roche Diagnostics, Basel Switzerland) meter. It was the objective of the study to determine the accuracy of the CoaguChek XS by comparing whole blood INR results from the CoaguChek XS to plasma INR results from the standard laboratory in children. POC INR meter validations were performed on plasma samples from two time points from 62 children receiving warfarin by drawing a venous blood sample for laboratory prothrombin (PT)-INR measurements and simultaneous INR determinations using the POC-INR meter. Agreement between CoaguChek XS INR and laboratory INR was assessed using Bland-Altman plots. Bland-Altmans 95% limits of agreement were 0.11 (-0.20; 0.42) and 0.13 (-0.22; 0.48) at the two time points, respectively. In conclusion, the CoaguChek XS meter appraisal generates an accurate and precise INR measure in children when compared to laboratory INR test results.

Thrombosis in children with malignancy.

Purpose of review The association between thrombosis and malignancy in adults is well known. Children are now surviving malignancies that previously resulted in mortality. Complications, however, occur including thrombosis that result in mortality and morbidity. This review will explore the association in children and discuss the epidemiology and evidence-based diagnosis and treatment of thrombosis in this cohort. Recent findings Thrombin is an important link between malignancy, metastases, and inflammation. The accurate diagnosis of thrombosis in the upper venous system is directly related to the diagnostic technique used. Antithrombotic treatment is challenging owing to higher risks of bleeding, for example, decreased platelet counts, tiffelitis, large vascular tumor, etc. Summary Thrombosis and malignancy are associated in children. Properly designed studies are urgently required to further define the epidemiology of thrombosis in different malignancies and to find the best way to diagnose and treat thrombosis in children.

EMPoWarMENT: Edmonton pediatric warfarin self-management pilot study in children with primarily cardiac disease.

UNLABELLED Increasing numbers of children require warfarin thromboprophylaxis. Home INR testing by the patient (PST) has revolutionized warfarin management. However, the family/patient must contact the health team for guidance for warfarin dosing. Patient self management(PSM) prepares a patient performing PST to take an active role in warfarin dosing. Adult studies demonstrate that PSM is safe and effective with improved adherence and treatment satisfaction quality of life (QOL). OBJECTIVE To estimate the safety and efficacy in children performing PSM or PST, to evaluate warfarin dose decision making in PSM, and warfarin related QOL. METHODS Warfarinized children performing PST for >3m were randomized to PST or PSM. The PSM group underwent warfarin management education and assumed independent warfarin management. INRs were collected for a year prior to and for 1 year of study to determine TTR and warfarin decision making. QOL was assessed through inventory completion and interviews. RESULTS 28 children were randomized and followed for 12 months. TTR was (83.9% pre/ post), and 77.7% pre to 83.0% post for PST and PSM (p=0.312). Appropriate warfarin decision making was 90% with no major bleeding episodes and no thromboembolic events. PSM was preferred by families. CONCLUSIONS PSM for children may be a safe and effective management strategy for warfarinized children. Clinical studies with larger sample size are required.

Central venous catheter sampling of low molecular heparin levels: An approach to increasing result reliability

Background: The low molecular weight heparin effect in children is monitored using the anti-factor Xa level. Venipuncture is recommended; however, central venous catheter blood sampling is often necessary. Heparin infused through central venous catheters may contaminate central venous catheter blood samples, preventing reliable anti-factor Xa level measurement. Simultaneous anti-factor Xa/partial thromboplastin time measurement with central venous catheter blood sampling may predict anti-factor Xa reliability. Objectives: To determine the prevalence of heparin contamination as measured by the partial thromboplastin time/anti-factor Xa in central venous catheter blood samples and whether careful sampling could minimize heparin contamination of anti-factor Xa levels from central venous catheter blood sampling. Methods: Simultaneous partial thromboplastin time/anti-factor Xa measurements from central venous catheter blood sampling determined the prevalence of heparin contamination of central venous catheter blood samples. In phase II, children receiving low molecular weight heparin had routine central venous catheter blood sampling to measure the peak anti-factor Xa and the simultaneous partial thromboplastin time. Anti-factor Xa levels with a partial thromboplastin time of >40 secs (pair 1) were identified; there was no low molecular weight heparin dose change, and the paired sample was repeated using a careful sampling technique (pair 2). Pairs 1 and 2 were compared to determine the efficiency of the sampling technique in removing heparin from the central venous catheter blood samples. Results: In phase I, 100 children had 485 paired anti-factor Xa/partial thromboplastin time central venous catheter blood samples with 29% ± 4.1% (95% confidence interval 25% to 33%) anti-factor Xa with partial thromboplastin times of >40 secs. In phase II, 43 children had 129 paired anti-factor Xa/partial thromboplastin time samples with partial thromboplastin times of >40 secs. The pair 1 mean partial thromboplastin times/anti-factor Xa levels were 109.8 secs (SD 53.1, range 34.0 to >200 secs) and 1.03 units/mL (SD 0.56, range 0.26–4.2 units/mL). Repeated partial thromboplastin times/anti-factor Xa levels (pair 2) were significantly decreased from those of pair 1 (p < .001) with means of 58.5 secs (SD 21.2, range 22–152 secs) vs. 109.8 secs (SD 53.1, range 34.0 to > 200 secs, p < .001) and 0.63 unit/mL (SD 0.30, range 0.02–1.77 units/mL) vs. 1.03 units/mL (SD 0.56, range 0.26–4.2 units/mL), respectively. Conclusions: Measurement of the partial thromboplastin time performed in combination with that of the anti-factor Xa level can be used to assist health practitioners to identify unfractionated heparin contamination of anti-factor Xa levels drawn from central venous catheters. A careful sampling technique may minimize heparin contamination in central venous catheter blood samples.

Antithrombotic therapy for ventricular assist devices in children: do we really know what to do?

The use of ventricular assist devices (VADs) in children is increasing. Stroke and device‐related thromboembolism remain the most feared complications associated with VAD therapy in children. The presence of a VAD causes dysregulation of hemostasis due to the presence of foreign materials and sheer forces intrinsic to the device resulting in hypercoagulability and potentially life‐threatening thrombosis. The use of antithrombotic therapy in adults with VADs modulates this disruption in hemostasis, decreasing the risk of thrombosis. Yet, differences in hemostasis in children (developmental hemostasis) may result in variances in dysregulation by these devices and preclude the use of adult guidelines. Consequently, pediatric device studies must include safety and efficacy estimates of device‐specific antithrombotic therapy guidelines. This review will discuss mechanisms of hemostatic dysregulation as it pertains to VADs, goals of VAD antithrombotic therapy for children and adults, and emerging antithrombotic strategies for VAD use in children.

EMPoWARed: Edmonton pediatric warfarin self-management study

BACKGROUND Patient self-management (PSM) in adults is safer and more cost effective than conventional management. Warfarin is a narrow therapeutic index drug with individual patient response to changes and frequently a long-term therapy. Children and their families are proposed to be able to effectively manage their childs warfarin therapy. Increased health related quality of life is highly associated with effective therapy in patients with chronic conditions. OBJECTIVES The aim of this study is to evaluate the safety and efficacy of PSM over time including HRQOL and variables that may influence PFU success at PSM. PATIENTS/METHODS Children and their family units (PFUs) current performing patient self-testing/monitoring for ≥ 3 months were enrolled in this cohort study. PFUs participated in comprehensive education on warfarin testing and management followed by an apprenticeship. Socio-demographic, clinical, and laboratory data were collected to evaluate safety and efficacy and health related quality of life. Outcomes were compared between the first 6 months on PSM (phase 1) and the last 6 months data collected on PSM (phase 2). RESULTS Forty-two patients performed PSM for a median of 2.7 years (range: 1.1-6.2 years). Time in therapeutic range was 90% and 92.9% (p=0.30) in phases 1 and 2 respectively. All measures were strongly associated with improved heath related quality of life. PFUs socio-demographic status did not influence success at PSM. All PFUs maintained warfarin knowledge and INR testing competency. Warfarin dosing decision errors median 0 (range: 0-5, p=0.73) and a median 0 (range 0-4, p=0.55) per patient in phases 1 and 2 respectively. There were no adverse hemorrhagic or thrombotic events. CONCLUSIONS Empowering PFUs to self-manage warfarin results in increased knowledge and understanding of their health condition, improved commitment to their health care and adherence to medication regimens and is demonstrated to be sustainable over time.

Improving evidence on anticoagulant therapies for venous thromboembolism in children: key challenges and opportunities

Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, and anticoagulant use in this population has become common, despite the absence of US Food and Drug Administration (FDA) approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials (RCTs) 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 (LMWHs). However, key questions arise regarding their potential off-label clinical application in pediatric thromboembolic disease. In this Perspective, we provide background on the use of LMWHs such as enoxaparin as the mainstay of treatment of 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 RCT 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.

Antithrombin concentrate in pediatric patients requiring unfractionated heparin anticoagulation: a retrospective cohort study.

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.

Recommendations for point-of-care home International Normalized Ratio testing in children on vitamin K antagonist therapy

*Pediatrics, Stollery Childrens Hospital, University of Alberta, Edmonton, AB, Canada; and †Clinical Hematology, Royal Children’s Hospital,Department of Pediatrics, University of Melbourne, Melbourne, Victoria, AustraliaTo cite this article: Bauman ME, Bruce A, Jones S, Newall F, Massicotte MP, Monagle P. Recommendations for point-of-care home interna-tional normalized ratio testing in children on vitamin K antagonist therapy. J Thromb Haemost 2013; 11: 366–8.