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Perinatal stroke causes cerebral palsy and lifelong disability. Specific diseases are definable, but mechanisms are poorly understood. Evidence suggests possible associations between arterial perinatal stroke and prothrombotic disorders, but population-based, controlled, disease-specific studies are limited. Understanding thrombophilia in perinatal stroke informs pathogenesis models and clinical management. We conducted a population-based, prospective, case-control study to determine the association of specific perinatal stroke diseases with known thrombophilias. Children with idiopathic magnetic resonance imaging-classified neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or fetal periventricular venous infarction (PVI) were recruited. Standardized thrombophilia evaluations were performed after 12 months of age on stroke cases and controls, including quantified proteins C and S, antithrombin, factors VIII/IX/XI, fibrinogen, lipoprotein(a), homocysteine, lupus anticoagulant, anticardiolipin antibodies and genotyping of factor V Leiden (FVL), factor II G20210A (FII), and methylenetetrahydrofolate reductase C677T. A total of 212 children were studied: 46 with NAIS, 34 with APPIS, 55 with PVI, and 77 controls (male, 53%; median age, 4.8 years). Of 14 parameters, no differences were observed in 12, including all common thrombophilias. Mean prothrombin time was shorter in arterial strokes (P < .001). Rates of antiphospholipid antibodies were low, comparable to those in controls, and resolved on repeat testing. FVL and FII rates were comparable to population norms. Total number of possible abnormalities did not differ between cases and controls. Our prospective, population-based, controlled, disease-specific study suggests minimal association between perinatal stroke and thrombophilia. This does not exclude the possibility of disordered coagulation at the time of stroke but suggests testing in childhood is not indicated.

This study details warfarin use in a large pediatric population followed in a central anticoagulation clinic. A prospective, consecutive cohort of nonselected children were studied. Patients were divided into groups by age, target international normalized ratio (INR) range, disease, medications, and vitamin K supplemented enteral nutrition use. Groups were analyzed on multiple aspects of warfarin therapy using multivariate methods. A total of 319 patients received 352 warfarin courses representing 391 treatment years. Age independently influenced all aspects of therapy. When compared with all older children, the ≤1 year of age group required increased warfarin doses, longer overlap with heparin, longer time to achieve target INR ranges, more frequent INR testing and dose adjustments, and fewer INR values in the target range. Although significantly different than children ≤1 year, children 1 to 6 years of age showed the same findings when compared with 7- to 18-year-olds. Fontan patients required 25% decreased dosage as compared with other congenital heart disease patients. Children on corticosteroids had less INRs in the target range and children on phenobarbital/carbamazepine required increased maintenance dosages of warfarin. Also, patients receiving enteral nutrition required increased dosages of warfarin. Serious bleeding occurred in 2 children (0.5% per patient year). Recurrent thromboembolic events (TEs) occurred in 8 children. Two children had recurrences while receiving warfarin (1.3% per patient year). This study outlines the profound effect of age and relative complexity of clinical management of warfarin therapy in children.

Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.

BACKGROUND: Low-molecular-weight heparins are increasingly being used for prophylaxis of thromboembolic events (TE) in children. Fragmin offers the advantage of once-daily dosing. However appropriate dosing and pharmacokinetics (PK) of Fragmin in children are unknown. The objective of the study was to determine 1. once daily dose of Fragmin required in children to achieve anti-Xa levels of 0.10–0.40 Anti-Xa U/mL. 2. PK of Fragmin over all age groups. STUDY DESIGN: Prospective cohort study in non-selected children at increased risk for TE who were being treated at Stollery Children’s Hospital, Edmonton or Hospital for Sick Children, Toronto, Canada. All children received a starting dose of 100 mg/kg, an Anti-Xa level was drawn 4 hours post and dosages were adjusted until the target 0.1–0.4 μ/ml was reached. Children then entered the pharmacokinetic phase and blood was drawn at specified timepoints over several different days for Anti-Xa levels. A sparse sampling scheme and population-based, nonlinear mixed effect model approach were used to assess exposure targets. The primary outcomes were: 1. dose required to achieve therapeutic anti-Xa levels in each of the age groups. 2. observed maximum plasma activity (Cmax), time that Cmax was observed (Tmax), half-life (t1/2) and extravascular plasma clearance (Cl/F). Safety was assessed by collection of data on bleeding and thrombotic events. RESULTS: 43 children were enrolled, 1 developed a TE prior to receiving Fragmin 42 received drug. Two patients developed TE after one dose, 5 withdrew voluntarily and 1 had CVL removed early. 34 received the drug, 31 contributed PK data. A once compartment model with allometrically-scaled clearance and volume best explained observed concentration-time profiles. The median maintenance dose in children under 5 yrs of age was 100 IU/Kg whereas 5–10 and 10–16 yr old required 88 and 63 IU/Kg respectfully. The PK parameters are summarised in Table I. In terms of safety, there were no major bleeding events reported. Minor bleeds were reported in 4 patients: 3 bleeding at insuflon site and 1 oozing from PICC line. Two patients had asymptomatic thrombosis discovered on chance finding: 1 patient with a portal vein thrombosis discovered on routine renal ultrasound which did not resolve on treatment. One patient had a small clot at tip of CVL discovered on routine echocardiogram which did resolve on treatment. CONCLUSIONS: Dosing of Fragmin is age-dependent. The PK studies showed an increase in clearance of Fragmin in younger children. The volume of distribution is approximately equal to plasma volume and remains constant across the studied age ranges. The shift in time to maximum Anti-Xa level maybe due to absorption-related differences which means the 4-hour sampling paradigm is not adequate to judge therapeutic exposure across age groups. | | 0−2 months (n=6) | 2–12 Months (n=8) | 1−5 Years (n=6) | 5−10 years (n=4) | 10–16 years (n=7) | |:---------------- | ---------------- | ----------------- | --------------- | ---------------- | ----------------- | | Cmax [IU/mL] | 0.13 | 0.26 | 0.26 | 0.29 | 0.34 | | Tmax [hours] | 1.6 | 1.8 | 2.1 | 2.3 | 2.6 | | T1.2 [hours] | 0.50 | 0.61 | 0.77 | 0.90 | 1.08 | | CL/F [L/hour/kg] | 0.046 | 0.032 | 0.031 | 0.024 | 0.019 | Table I: Pharmacokinetic parameters

BACKGROUND: Asymptomatic deep venous thrombosis (DVT) are well-known complications of treatment of acute lymphoblastic leukemia (ALL) in children. However, the clinical significance of radiographically detected, asymptomatic DVT is unclear and controversial, as there are no studies on long-term outcome of asymptomatic DVT in children available. There are two likely reasons for the studies not being done in this area. First, there is a lack of defined cohorts of pediatric patients screened for DVT and secondly, there is a great deal of difficulty in following patients over many years. The study, Prophylaxis with Antithrombin Replacement in Kids with ALL treated with L-Asparaginase (PARKAA) was a multicentre randomized controlled trial in which children with ALL were screened for DVT. As survivors of childhood cancer, the PARKAA cohort continues to be followed in their respective centers. Therefore, establishment of the PARKAA cohort (1997–99) and the ability to locate these patients provided a unique opportunity to study the long-term outcome of asymptomatic DVT. OBJECTIVE: To assess the incidence of PTS in children with ALL who previously had an asymptomatic DVT. The objective were approached in two ways. Firstly, to assess the outcome of asymptomatic DVT by determining the prevalence of PTS in children with a history of ALL with radiographically diagnosed DVT (PARKAA cohort); secondly, to corroborate the findings by determining the prevalence of PTS in an unselected group of survivors of childhood ALL. METHODS: Cross-sectional study in two separate populations: Group I comprised of children enrolled in the PARKAA multicentre study who had been screened for, and diagnosed with, DVT in the upper venous system. Group II consisted of non-selected patients < 21 years with a history of ALL followed at Stollery Children’s Hospital, Edmonton. Patients were invited for a follow-up at their treatment centre (Group I) or were assessed for PTS childhood cancer survivor clinic (Group II). PTS was assessed by two of the investigators (Group I) or by the attending oncologist (Group II), respectively, using a standardized scoring sheet. RESULTS: Group I: 13 PARKAA patients with a history of ALL and objectively diagnosed DVT were assessed for PTS (4 males; median age 11.9 years; median age at diagnosis of ALL 4.4 years). 7/13 patients had PTS (54%, 95%CI 25;81). All patients with PTS had collaterals on examination, 3 also had increased arm circumference. Group II: 41 patients with a history of ALL were enrolled (61% males; median age at diagnosis 3.0 years; 28% high-risk, 67% standard risk). Mean length of follow-up since diagnosis was 9.5 years. PTS was diagnosed in 10/41 (24%; 95%CI 11–38) patients. All patients with PTS had collaterals on examination, 5 (50%) also had increased arm circumference. CONCLUSIONS: There is a clinically significant prevalence of PTS in children with a history of ALL and radiographically diagnosed DVT. A significant proportion of survivors of ALL develop PTS, indicating previously undiagnosed DVT in this population.

BACKGROUND: Only recently, thromboembolic events have emerged as one of the most serious and frequent secondary complications to occur in children who, with modern therapy, are surviving previously life-threatening diseases. One of the most common primary disorders is congenital heart disease (CHD), accounting for approximately 1/3 of children presenting with thrombosis. However, rigorous determination of the actual prevalence in order to establish how pervasive this newly appreciated thromboembolic disease is in children with CHD is lacking. The current standard of practice in children with CHD is not to use anticoagulants for primary prophylaxis, predominantly because of the lack of firm data on prevalence of thrombosis. The primary objective of the current study was to determine the incidence of thrombosis in children with CHD in the post operative period. The secondary objective was to determine clinical risk factors for thrombosis. STUDY DESIGN. A prospective cohort of non-selected children undergoing surgical intervention for CHD at Stollery Children’s Hospital, Edmonton, Canada. To be eligible for inclusion in the study, children had to be planned to undergo cardiopulmonary bypass and too have a central venous line placed. All patients were screened for thrombosis by ultrasound in either the upper or lower venous system depending on the location of the central venous line and echocardiogram of the heart. Testing was performed on children in the post operative period when the patients were stable and after the central venous line was removed. Clinically significant thrombosis was defined as thrombi greater than 3mm. Demographic data on the cohort where collected prospectively. The study was reviewed by the ethics board and informed consent was obtained from all guardians and/or children. RESULTS: A total of 128 children were recruited, median age 10 months (range 0.23–192) 44% were females and 70% were Caucasian. A total of 63 children (49%) had evidence of a thrombosis, but some of the thrombi were small, non occlusive and considered clinically nonsignificant. However, 34 patients 27% (95% Confidence Interval 19%-35%) had evidence of a thrombotic event with significant occlusion that required therapeutic anticoagulant therapy. Fifty percent of thrombosis was in the right internal jugular reflecting the primary location of the central venous line. Children with clinically significant thrombosis were younger and had more complex underlying cardiac disorders (see table below). CONCLUSION: There is a significant incidence of thrombosis in children with CHD in the post operative period. Younger children and children with complex cardiac disorders are at increased risk. Carefully designed clinical trials of prevention are urgently needed. Risk factors for thrombosis Thrombosis Positive (n=34) Thrombosis negative (n=94) Age (months) 6 (1–168) 28 (0.23–192) UNDERLYING DIAGNOSIS Single Ventrical 35% (n=12) 16%(n=15) Transposition of the great arteries 9% (n=3) 3% (n=3) Tetraology of Fallot 23% (n=8) 11% (n=10) Venticular Septal defect 3% (n=1) 18% (n=17) Arterial Septal defect 6% (n=2) 20% (n=19) Other 23% (n=8) 32% (n=30)

Background: Renal vein thrombosis (RVT) is the most frequent site of primary venous thrombosis in neonates. At present, there is no conventional therapeutic regimen for this condition. Objective: To establish current clinical guidelines based on data from the Canadian Pediatric Hemostasis and Thrombosis Network (CPHTN). Materials and Methods: A standardized questionnaire was sent to CPHTN members involved with pediatric thrombosis care. Clinical variables included thrombus location (unilateral vs. bilateral), severity (non-occlusive vs. occlusive), extension to the inferior vena cava (IVC+), and concomitant bleeding at diagnosis [i.e. hematuria with thrombocytopenia (H/T+), with/without ≥ grade 2 intraventricular hemorrhage (IVH+/−)]. Results: A total of 16 pediatric hematologists participated, with a response rate of approximately 80%. Regarding diagnostic imaging, the most utilized methods were the following: a) Doppler ultrasound (U/S) in 14/16 (87.5%); b) U/S without Doppler in 1/16 (6.25%); and c) contrast venography in 1/16 (6.25%). 12/16 (75%) of the physicians would have ordered a thrombophilia work up. For unilateral, non-occlusive, H/T− or H/T+ cases, management included, respectively: 1) no therapy in 11/16 (68.75%) and 9/16 (56.25%); 2) low-molecular-weight heparin (LMWH) in 2/16 (12.5%) (3-month-course) and 3/16 (18.75%) (14-day or 3-month course); and 3) therapy based on radiologic follow up (f/u) in 3/16 (18.75%) and 4/16 (25%). For unilateral, occlusive, H/T+, IVH− or IVH+ cases, management included: 1) no therapy in 5/16 (31.25%) and 10/16 (62.5%); 2) LMWH in 6/16 (37.5%) and 4/16 (25%); and 3) treatment based on f/u findings in 5/16 (31.25%) and 2/16 (12.5%). For bilateral, occlusive, IVC−, IVH− cases, management included: 1) LMWH (2 weeks to 3 months) in 12/16 (75%); 2) tissue-plasminogen activator (t-PA) in 1/16 (6.25%); 3) LMWH and t-PA in 2/16 (12.5%); and 4) therapy based on f/u in 1/16 (6.25%). Finally, for bilateral, occlusive, IVC+, IVH− or +, the responses were, in that order: 1) LMWH (6 weeks to 3 months) in 10/16 (62.5%) and 11/16 (68.75%); 2) t-PA in 3/16 (18.75%) and 0/16; 3) LMWH and t-PA in 2/16 (12.5%) and 0/16; 4) treatment based on f/u in 1/16 (6.25%) in both groups; 5) no therapy in 2/16 (12.5%) of the latter group only; and 6) unknown in 2/16 (12.5%) of the latter group only. The anti-Xa level (0.5 to 1.0 range) was the only assay suggested for monitoring LMWH. Standard heparin was monitored by anti-Xa levels in only 3/16 (18.75%) of cases. Consultation sources included 1) combined sources (i.e. books, protocols, journals) in 10/16 (62.5%) cases; 2) journals in 4/16 (25%) cases; and 3) 1-800-NO-CLOTS in 2/16 (12.5%) cases. 15/16 (93.75%) of the participating physicians supported the idea of developing therapeutic protocols. Conclusions: Currently, there are no standard therapeutic practices with respect to neonatal RVT. It would be difficult to successfully complete a randomized clinical trial due to small numbers. However, multicenter, prospective studies utilizing consistent therapeutic approaches would be extremely helpful in this clinical setting.

BACKGROUND: Over the last 10 years, children with congenital heart disease (CHD) have been experiencing increased survival due to diagnostic and surgical techniques. However, associated with this is a requirement for prolonged central venous access which has serious associated sequelae, of which thrombosis is one of the most important. In a busy comprehensive cardiovascular program, the diagnosis, treatment and management of children with or at risk for thrombosis is extremely demanding and constantly changing based on current evidence based recommendations. The Stollery Children’s Hospital, a member of the Western Canadian Children’s Heart Network (WCCHN), is the cardiovascular surgical centre for children with CHD from British Columbia, Manitoba, Alberta, and Saskatchewan An expert Pediatric Thrombosis Team has been incorporated into the multi disciplinary management of children with CHD. This team is dedicated entirely to the diagnosis, management and long term followup of children requiring anticoagulation. MATERIALS/METHODS: A standard approach to the diagnosis, management and long term followup of children with CHD with or at risk for thrombosis was initiated. The Pendragon data base was custom designed to prospectively collect the following data on all children: demographics, treatment and long term outcome. RESULTS: Since the inception of the Thrombosis service (Oct 2003) there have been 325 children who required cardiac surgery with 40% (n=129) of these children requiring Thrombosis consultation. The 4 most common causes for Thrombosis referral have been primary prophylaxis post CHD surgery including mechanical valves, Blalock Taussig shunts, and Fontan procedures, 51% (n=66), suspected CVL related thrombosis 26% (n=33), arterial catheter related thrombosis (catheterization or monitoring) 16% (n=19), and extracorporeal membranous oxygenation 9% (n=11). By Oct 2004, it is anticipated that 300 children will have been consulted on. CONCLUSIONS: The 1st year results of the data collected on this prospective cohort will be presented including demographics, reason for anticoagulation, diagnosis, and long term outcome.

BACKGROUND: Unfractionated heparin (UFH) is one of the most frequently prescribed drugs in paediatric tertiary care centres and is used in a diverse group of disorders including cardiopulmonary bypass, extra corporeal membrane oxygenation, dialyses and maintenance of both venous and arterial catheter patency. Dosing of UFH in children is extrapolated from adults and is assessed by either a chromogenic Anti-Xa assay or a clot-based activated partial thromboplastin time (aPTT). The overall objective of the study was to assess safety of current standard of practice in the use of therapeutic UFH in children. Objective #1: The primary objective was to determine the incidence of bleeding and the incidence of recurrent thrombosis in children receiving UFH. Objective #2: To assess the monitoring UFH by assessing the relationship of the aPTT and Anti-Xa heparin levels to heparin dose. STUDY DESIGN: A prospective cohort study in nonselected children in a intensive care setting. The primary outcomes were major bleeding events and recurrent thrombosis. The secondary outcomes were assessing the APTT and Anti-Xa levels. Inclusion Criteria: Patients 〉 36 weeks gestation and 〈18 years of age requiring therapeutic doses of UFH. Exclusion Criteria: patients who received UFH for less than 1 day. Major bleeding was defined aprior as any of the following: CNS bleeding, retroperitoneal bleeding, and/or bleeding that results in stopping UFH infusion. RESULTS: Patient Population 39 patients were enrolled, 22 (56%) male, 32 (82%) < 1 year of age and 90% of which where cardiac patients. Major Bleeding events: 11/39 patients had a major bleeding event 28.2% (95% CI 15.0–44.9%). No patient had recurrent thrombosis. Relationship of aPPT and Anti-Xa to heparin dose; A total of 188 paired aPTTs and anti-Xa levels were performed. There was little correlation between aPTT and anti-Xa levels (r2=0.205) and APTT and UFH dose (r2=0.054). There was no relationship between anti-Xa levels and UFH dose (r2=0.0089). (Figure 1 and 2) Figure Figure CONCLUSIONS:. There is an unacceptably high rate of bleeding in children receiving UFH for clinical care. There is little or no relationship of aPPT and Anti-Xa to heparin dose. Clinical trials are needed to assess the appropriate use of UFH therapy in children.