Showing papers by "Anthony K.C. Chan published in 2015"

Thrombolysis in Pediatric Stroke Study

Abstract: Stroke is an important acute neurological condition in children with an annual incidence ranging from 2.3 to 13 per 100 000 children.1–3 Although most children who experience stroke do not die of the acute disorder, the consequences of the brain injury are amortized during the lengthy life span that follows.4–8 The reduction potential in lifelong morbidity by timely and effective intervention with a thrombolytic agent, such as tissue-type plasminogen activator (tPA), in children with acute arterial ischemic stroke (AIS) constituted the core rationale for the study of tPA treatment of acute AIS in children. The perceived high potential for benefit after treatment justified assumption of risk for intracranial hemorrhage (ICH) after its use.9 Because in adults, the risk of hemorrhage after tPA use was thought to be related to infarct volume; this principle was assumed for children. The known developmental trajectory of the fibrinolytic system includes lower levels of endogenous tPA and higher levels of plasminogen activator inhibitor-1 in young children than are found in adults and warranted a dose-finding study beginning at doses lower than that used in adults with incremental increase through the currently used adult dose of 0.9 mg/kg and careful assessment of tPA pharmacokinetics.10 Currently, information on children treated with tPA consists of case reports, small case series, and hospital database documentation. Best practice for the treatment of children with acute stroke has received little rigorous study. Clinical approach varies widely among centers and reflects a dearth of research on which to base treatment protocols. Although tPA is not approved for use in childhood stroke, ≤2% of children with acute stroke are reported to have been treated with tPA in the United States, despite lack of safety and efficacy data.11–14 In 2010, the National Institute …

Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study

Abstract: Objectives We evaluated clinical features, treatment practices and early outcome in a multicentre cohort of children with cerebral sinovenous thrombosis (CSVT). Methods Children with CSVT from 10 countries were enrolled from January 2003 to July 2007 in the International Paediatric Stroke Study. We analysed clinical symptoms, underlying conditions, antithrombotic treatment and neurological outcome at hospital discharge in 170 children. Results Of 170 children enrolled, 60% were male; median age 7.2 years (IQR 2.9-12.4). Headache, altered consciousness, focal deficits and seizures were common presenting clinical features. Infarction affected 37% and intracranial haemorrhage 31%. Risk factors included chronic disease in 50%; acute systemic illness or head/neck disorders 41%; prothrombotic state 20% and other haematological abnormality 19%. Discharge neurological status was normal in 48%, abnormal in 43% and unknown in 5%. Antithrombotic therapy was common, most often low molecular weight heparin was common, with significant regional variation in treatment practices. Mortality was low (4%) and was associated with no anticoagulation but not underlying chronic disease, anatomic extent of thrombosis or intracranial haemorrhage. Abnormal neurological status at discharge or death was associated with decreased level of consciousness at presentation and the presence of an identified prothrombotic state. Conclusions Our study extends the observations of previously published smaller studies in children with CSVT that this is a morbid disease with diverse underlying causes and risk factors. Divergent treatment practices among highly specialised centres as well as limited data on treatment efficacy and safety suggest that further study of this condition is warranted.

Sedentary Time and Screen-Based Sedentary Behaviors of Children With a Chronic Disease

Abstract: The objectives of this study were to (i) assess sedentary time and prevalence of screen-based sedentary behaviors of children with a chronic disease and (ii) compare sedentary time and prevalence of screen-based sedentary behaviors to age- and sex-matched healthy controls. Sixty-five children (aged 6-18 years) with a chronic disease participated: survivors of a brain tumor, hemophilia, type 1 diabetes mellitus, juvenile idiopathic arthritis, cystic fibrosis, and Crohn’s disease. Twenty-nine of these participants were compared with age- and sex-matched healthy controls. Sedentary time was measured objectively by an ActiGraph GT1M or GT3x accelerometer worn for 7 consecutive days and defined as less than 100 counts per min. A questionnaire was used to assess screen-based sedentary behaviors. Children with a chronic disease engaged in an average of 10.2 ± 1.4 hr of sedentary time per day, which comprised 76.5 ± 7.1% of average daily monitoring time. There were no differences between children with a chronic d...

Surface modification of poly(dimethylsiloxane) with a covalent antithrombin-heparin complex for the prevention of thrombosis: use of polydopamine as bonding agent.

Abstract: A modified poly(dimethyl siloxane) (PDMS) material is under development for use in an extracorporeal microfluidic blood oxygenator designed as an artificial placenta to treat newborn infants suffering from severe respiratory insufficiency. To prevent thrombosis triggered by blood-material contact, an antithrombin–heparin (ATH) covalent complex was coated on PDMS surface using polydopamine (PDA) as a “bioglue”. Experiments using radiolabelled ATH showed that the ATH coating on PDA-modified PDMS remained substantially intact after incubation in plasma, 2% SDS solution, or whole blood over a three day period. The anticoagulant activity of the ATH-modified surfaces was also demonstrated: in contact with plasma the ATH-coated PDMS was shown to bind antithrombin (AT) selectively from plasma and to inhibit clotting factor Xa. It is concluded that modification of PDMS with polydopamine and ATH shows promise as a means of improving the blood compatibility of PDMS and hence of the oxygenator device.

Point of care ultrasonography in haemophilia care: recommendations for training and competency evaluation

Abstract: K. L. STRIKE,* A. IORIO,*† S. JACKSON,‡ W. LAWSON,§ L. SCOTT,* S. SQUIRE‡ and A. K. CHAN*¶ *Hamilton Niagara Regional Hemophilia Program, Hamilton Health Sciences, Hamilton, ON; †Clinical Epidemiology and Biostatistics McMaster University, Hamilton, ON, Canada; ‡Hemophilia Program – Adult Division, St. Paul’s Hospital, Vancouver, BC; §McMaster University Mohawk College Institute of Applied Health Sciences, Hamilton, ON, Canada; and ¶Department of Pediatrics McMaster University, Hamilton, ON, Canada

Experience with central venous access devices (CVADs) in the Canadian hemophilia primary prophylaxis study (CHPS).

Abstract: Introduction Haemophilia A treatment with factor VIII concentrates requires frequent venipunctures; a central venous access device (CVAD) may be required to facilitate reliable venous access, especially in young children. While CVADs provide reliable venous access, complications such as infection and thrombosis may occur. Aim The aim of this study was to assess CVAD use in the Canadian Hemophilia Primary Prophylaxis Study (CHPS), a single-arm, multi-centre prospective study whereby factor use is tailored to individual prophylactic need. Methods Participants received a tailored, escalating dose, prophylaxis regimen of increasing frequency of FVIII infusions: step-1: 50 IU kg−1 once weekly; step-2: 30 IU kg−1 twice weekly; and step-3: 25 IU kg−1 on alternate days, according to their level of bleeding. CVAD insertion was at the discretion of the local health care team. Details regarding CVAD use during this protocol were analysed. Results Fifty six boys were enrolled, 21 required 25 CVADs due to difficult venous access. CVADs were inserted at a median age of 1.3 years (range: 0.6–2.1) and were removed at a median age of 8.7 years (range 6.3–11.8). Six participants experienced non-life threatening CVAD-complications, the most frequent being device malfunction requiring CVAD replacement (n = 4). Two boys were shown to have CVAD-associated thrombosis detected on routine imaging; one required removal due to infusion difficulties and the other was asymptomatic and did not require device removal. No CVAD-related infections were documented. Conclusion Our study shows that the CHPS tailored prophylaxis regimen is associated with a decreased requirement for CVADs and with few device-related complications.

Treatment decision-making among Canadian youth with severe haemophilia: a qualitative approach.

Abstract: Summary The first generation of young men using primary prophylaxis is coming of age. Important questions regarding the management of severe haemophilia with prophylaxis persist: Can prophylaxis be stopped? At what age? To what effect? Can the regimen be individualized? The reasons why some individuals discontinue or poorly comply with prophylaxis are not well understood. These issues have been explored using predominantly quantitative rese-arch approaches, yielding little insight into treatment decision-making from the perspectives of persons with haemophilia (PWH). Positioning the PWH as a source of expertise about their condition and its management, we undertook a qualitative study: (i) to explore and understand the lived experience of young men with severe haemophilia A or B and (ii) to identify the factors and inter-relationships between factors that affect young men's treatment decision-making. This manuscript reports primarily on the second objective. A modified Straussian, grounded theory methodology was used for data collection (interviews) and preliminary analysis. The study sample, youth aged 15–29, with severe haemophilia A or B, was chosen selectively and recruited through three Canadian Haemophilia Treatment Centres. We found treatment decision-making to be multi-factorial and used the Framework method to analyze the inter-relationships between factors. A typology of four distinct approaches to treatment was identified: lifestyle routine prophylaxis, situational prophylaxis, strict routine prophylaxis and no prophylaxis. Standardized treatment definitions (i.e.: ‘primary’ and ‘secondary’, ‘prophylaxis’) do not adequately describe the ways participants treat. Naming the variation of approaches documented in this study can improve PWH/provider communication, treatment planning and education.

Feasibility and safety of enoxaparin whole milligram dosing in premature and term neonates.

Abstract: The objective of our study was to determine the feasibility and safety of enoxaparin whole milligram dosing in premature and term neonates, and to assess response to treatment Retrospective study of neonates with thrombosis treated between January 2008 and December 2014 Nineteen premature and 21 term neonates were treated with whole milligram doses of enoxaparin The mean starting and therapeutic enoxaparin doses were 172±017 and 186±017 mg kg−1, respectively Twenty-five (64%) reached therapeutic antifactor Xa (anti-Xa) levels with the starting dose, whereas 14 (36%) required dose adjustments One neonate reached a supratherapeutic anti-Xa level (>10 IU ml−1) in the loading phase No bleeding episodes occurred The mean treatment duration was 12 weeks Among 34 (85%) evaluable patients, 23 (68%) had a complete response, 9 (26%) partial and 2 (6%) had a stable thrombotic state Whole milligram dosing of enoxaparin for thrombosis is feasible, safe and effective in premature and term neonates

c.1058C>T variant in the SERPINC1 gene is pathogenic for antithrombin deficiency

Abstract: Antithrombin (AT) deficiency, a rare autosomal-dominant thrombophilia, has an estimated prevalence of 1 in 2000 to 1 in 5000 individuals and is associated with a 1 to 1 7% annual incidence of venous thromboembolism (VTE) (Tait et al, 1994; Martinelli et al, 1998; Vossen et al, 2005). AT, a 58 kDa glycoprotein, belongs to the serine protease (serpin) superfamily, and is a potent inhibitor of multiple coagulation proteins including thrombin and factor Xa. More than 300 mutations in the SERPINC1 gene (encoding AT) have been reported, which result in either a quantitative deficiency (type I) or a qualitative defect (type II) in the protein synthesized (Patnaik & Moll, 2008). Recent studies in both adult and paediatric cohorts have documented an association between the mutation subtype in SERPINC1 and risk of venous and arterial clots, with null mutations being associated with a significantly greater risk of VTE as compared to missense mutations (Luxembourg et al, 2013; Kumar et al, 2014). Internationally, there is an attempt to better classify AT deficiency based on the underlying mutation type. The c.1058C>T p.Pro353Leu variant on exon 5 of the SERPINC1 gene was first described by Luxembourg et al (2011) in a 27-yearold female with a family history of VTE, who suffered a deep vein thrombosis (DVT) and pulmonary embolism (PE) in the setting of oral contraception use (Dr B Luxembourg, Institute of Transfusion Medicine and Immunohaematology, DRK Blood Donor Service, BadenW€ urttemberg, Germany, personal communication;Luxembourg et al, 2011). Given limited data of its molecular basis, this variant was later re-classified as being of uncertain pathogenicity in the Human Genetic Mutation Database (www.hgmd.org, accessed 14 August 2014).

Abstract 18061: Supplementation to Treat Antithrombin Deficiency Improves Sensitivity to Heparin, Anticoagulation and Decreased Thrombogenecity in Neonates and Infants Undergoing Cardiac Surgery With Cardiopulmonary Bypass

Abstract: Introduction: Preoperative antithrombin (AT) deficiency is common in infants undergoing cardiac surgery with cardiopulmonary bypass (CPB), and is associated with heparin resistance, difficulties achieving optimal intraoperative anticoagulation and post-operative thrombosis. Methods: We performed a pilot randomized trial of pooled human AT supplementation for children <1 year with preoperative AT <0.85U/ml. Subjects received a split (patient and CPB prime) dose of AT before heparinization. AT was dosed to reach a predicted AT activity of 1.2U/ml during CPB calculated from preoperative AT level and patient weight. Results: We randomized 18 subjects; 17 completed the study (9 controls, 8 AT). Mean preoperative AT level was similar between groups (Control: 0.65±0.10 vs. AT: 0.68±0.15 U/mL, p=0.66). AT group subjects had higher AT than controls immediately after start of CPB (Control: 0.44±0.10 vs. AT: 1.15±0.20 U/mL, p<0.001) and at the end of CPB (Control: 0.67±0.14 vs. AT: 1.19±0.16 U/mL, p<0.001). AT supplementation was associated with increased activated clotting time (ACT) post-heparinization (Control: 500±72 vs. AT: 639±172 seconds, p=0.02), increased heparin sensitivity (Control: 89±23 vs. AT: 114±22 ACT seconds per 100U/kg heparin, p=0.02), and decreased heparin dose given during CPB (Control: 1126±344 vs. AT: 845±165 U/kg, p=0.03). After primary heparinization, 56% of control subjects did not achieve ACT target vs. 25% of AT subjects. At the end of CPB, AT group subjects had lower prothrombin levels (Control: 746±372 vs. AT: 460±102 ng/mL, p=0.02) and lower levels of inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-8 and TNFα). Supplementation with AT was not associated with increased chest tube volume loss or blood product requirements. One subject in each group had severe bleeding, and one in each group had post-operative infection. Thrombosis was noted for 3 controls and 1 AT subjects. Conclusions: AT supplementation to treat preoperative AT deficiency in young children is associated with decreased heparin resistance, improved anticoagulation and decreased thrombogenecity. Safety profile regarding bleeding and infections appears favorable. Equipoise exists for a larger definitive outcome trial.