Patricia McCusker

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.

Neonatal Renal Vein Thrombosis: Review of the English-Language Literature Between 1992 and 2006

Renal vein thrombosis is a complication that occurs in neonates with various underlying risk factors. It carries a grave prognosis for affected kidneys. Anticoagulant and fibrinolytic therapies have been promoted in the past with anecdotal success in some circumstances. However, prospective controlled trials are still lacking, and to date there have been no evidence-based guidelines available for the treatment of neonates with renal vein thrombosis. We retrospectively reviewed all the available medical literature pertaining to renal vein thrombosis published in English during the past 15 years. A total of 271 patients from 13 case series were identified by using the terms “renal vein thrombosis” and “neonates” via PubMed and Cochrane Library searches. Data then were extracted from each of the studies for analysis. During the past 15 years, a male predominance (67.2%) in neonatal renal vein thrombosis has been reported. More than 70% of patients had unilateral renal vein thrombosis, which was more prevalent on the left side (63.6%). The thrombus involved the inferior vena cava and was associated with adrenal hemorrhage in 43.7% and 14.8% of neonates, respectively. Forty percent of the patients were treated conservatively with supportive care alone. Among those patients who received anticoagulation therapy, unfractionated heparin and low molecular weight heparin were used alone in 21.6% and 20.7% of the patients, respectively. Fibrinolytic treatment alone was used in 11.2% of the patients. Only a minority of patients were treated with antithrombin (1.7%), warfarin alone, (0.9%) or underwent surgical intervention (0.3%). The majority (70.6%) of the involved kidneys became atrophic. A total of 9 neonates died with non–renal vein thrombosis–related conditions during the study period. Evidence-based recommendations on treatment cannot be made at the present time. Cooperative prospective studies that involve multiple centers are needed to elucidate the optimal treatment for neonatal renal vein thrombosis.

Development of a health-related quality of life measure for boys with haemophilia: the Canadian Haemophilia Outcomes--Kids Life Assessment Tool (CHO-KLAT).

Summary.  Several measures of quality of life (QoL) are available for children with haemophilia. However, most are not disease‐specific and few focus on childrens perspectives. The purpose of this study was to develop a psychometrically sound measure of QoL that included the perspectives of boys with haemophilia. A list of potential items was developed from the literature, other measures, and input from five discussion sessions with adults with haemophilia, children with haemophilia and their parents and haemophilia nurses. The list was augmented with items generated by three focus groups with children and three focus groups with parents. These groups also prioritized items and recommended a domain structure. Supplemental information was gathered by surveying haematologists. Data from all sources were analysed to reduce the number of items using a two‐step approach, based on rules that weighted the childrens priorities most heavily. The remaining items were compiled into a questionnaire that was pilot tested with 10 children and their parents. The total item pool contained 228 potential items. Of these, 33 were removed based on three focus groups and survey responses, 72 were removed after the completion of all focus groups and 46 were removed due to redundancy. This resulted in a 77‐item version of the CHO‐KLAT. Pilot testing identified the need to subdivide two items, resulting in a 79‐item CHO‐KLAT. The CHO‐KLAT is a promising disease‐specific measure of QoL that reflects childrens unique perspectives. This child‐centric focus distinguishes the CHO‐KLAT from alternative measures of QoL. Further research will assess the measurement properties of the CHO‐KLAT.

Enoxaparin for neonatal thrombosis: A call for a higher dose for neonates

INTRODUCTION Enoxaparin is the current anticoagulant of choice for neonatal thrombosis. Present neonatal treatment guidelines of 1.5 mg/kg every 12 hours (q12 h) are extrapolated primarily from an earlier study with 9 infants less than 2 months of age. More recent studies indicate an increased dose requirement for neonates. MATERIALS AND METHODS Relevant data from articles and abstracts were identified by searching MEDLINE and pediatric and hematology conference proceedings. RESULTS Publications between 1996 and 2007 included 8 papers, 4 abstracts and 1 review article with primary research documenting enoxaparin use in 240 neonates. The mean maintenance dose of enoxaparin ranged from 1.48 to 2.27 mg/kg q12 h for all infants, but was higher for preterm neonates at 1.9-2.27 mg/kg q12 h. The efficacy of enoxaparin, causing either complete or partial resolution was between 59 and 100%. Minor side effects were common and adverse events (major bleeding) occurred in 12 patients (0-19%). CONCLUSIONS Increased experience with enoxaparin use in neonates in the past decade has indicated higher doses to achieve accepted target anti-factor Xa values. The long-term use of indwelling catheters (Insuflon catheter) for enoxaparin administration may need to be reevaluated in ELBW infants. Suggested starting doses of enoxaparin are 1.7 mg/kg q12 h for term neonates and 2.0 mg/kg q12 h for preterm neonates if there is no considerable bleeding risk. However, further prospective studies are needed to validate an increased initial dose of enoxaparin.

How well does the Canadian haemophilia Outcomes-Kids' Life Assessment Tool (CHO-KLAT) measure the quality of life of boys with haemophilia?

It is important to measure the quality of life (QoL) of boys with haemophilia, because the diagnosis has a significant impact on their lives and this impact fluctuates over time. A disease‐specific measure of QoL is required because the aspects of life that are affected by haemophilia may differ from those assessed by generic QoL measures. This paper describes the final phase of development of a disease‐specific measure of QoL for boys with haemophilia: the Canadian Haemophilia Outcomes‐Kids Life Assessment Tool (CHO‐KLAT).

Comparing two measures of quality of life for children with haemophilia: the CHO-KLAT and the Haemo-QoL

Summary.  Disease‐specific measures of quality of life (QoL) for children with haemophilia are now available for use in clinical studies [Haemophilia, 10, 2004, 9–16]. One of these measures, the Canadian Haemophilia Outcomes – Kids’ Life Assessment Tool (CHO‐KLAT), was developed in Canada with emphasis on the perspectives of children [Pediatr Blood Cancer, 47, 2006, 305–11; Haemophilia, 10, 2004, 34–43]. Another, the Haemo‐QoL, was developed in Europe, with emphasis on the perspectives of clinicians [Haemophilia, 8, 2002, 47–54; Haemophilia, 10, 2004, 17–25]. While these two measures are unique and independent, researchers from both studies were collaboratively linked throughout development and testing. This study presents the results of a joint assessment of the two measures with respect to their strengths, limitations and unique contributions.

Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with l‐asparaginase: an in vitro study

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an l‐asparaginase‐induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0·53 U/ml). LMWH 0·3 and 0·7 U/ml or melagatran 0·3 and 0·5 μmol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno‐depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66–88% decrease in ETGC in AT‐normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT‐depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.

International cross‐cultural validation study of the Canadian Haemophilia Outcomes: Kids’ Life Assessment Tool

Health‐related quality of life (HRQoL) assessment is recognized as an important outcome in the evaluation of different therapeutic regimens for persons with haemophilia. The Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO‐KLAT) is a disease‐specific measure of HRQoL for 4 to 18‐year‐old boys with haemophilia. The purpose of this study was to extend this disease‐specific, child‐centric, outcome measure for use in international clinical trials.

Updating the Canadian Hemophilia Outcomes–Kids Life Assessment Tool (CHO-KLAT Version2.0)

OBJECTIVES Hemophilia is an X-chromosome-linked disorder associated with recurrent bleeding into muscles and joints, leading to pain and limitations in physical function that may diminish quality of life. The Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT) is a disease-specific measure of quality of life that was recently revised to facilitate cross-cultural adaptation. This study assessed the validity and reliability of version 2.0 of the CHO-KLAT (CHO-KLAT2.0). METHODS Content validity was assessed via detailed cognitive debriefing to confirm that Canadian boys understood the CHO-KLAT2.0. The measurement properties of the CHO-KLAT2.0 were assessed in comparison to those of the PedsQL, the Haemo-QoL, and two global ratings. Most children completed the CHO-KLAT2.0 a second time to assess test-retest reliability. RESULTS Cognitive debriefing was completed with 12 boys (age 8.6-17.8 years) and 9 of their parents and resulted in no substantive changes. Sixty boys (mean age 11.8 years) participated in the validation phase, which showed a mean CHO-KLAT2.0 score of 75.4±12.0, strong correlations with the PedsQL (r = 0.62, P<0.001) and Haemo-QoL (r = 0.64, P<0.001), and moderate correlations with global ratings of hemophilia bother (ρ =-0.39, P = 0.002) and health (ρ =-0.47, P = 0.0002). Test-retest concordance was better among parents (0.79) than among boys (0.63). CONCLUSIONS This study establishes the measurement properties of the CHO-KLAT2.0. The summary scores are very similar to those from the original development study, and thus, these have not been affected by the revisions. These results provide reference standards for comparing data from other countries to the Canadian experience and to estimate sample sizes for future clinical trials.

Arterial Ischemic Stroke in an Adolescent With Presumed Perinatal Ischemic Stroke

The risk of recurrent ischemic stroke after presumed perinatal stroke and the risk factors for such recurrence are rarely reported. Here, we present an adolescent with a history of presumed perinatal stroke who presented with arterial ischemic stroke recurrence at the age of 15 years. Hereditary thrombophilia screening performed at the time of his stroke recurrence demonstrated protein S deficiency. No evidence-based consensus guidelines on thrombophilia screening in children with presumed perinatal stroke exist, nor has the role of secondary prophylaxis been addressed. There is a risk of stroke recurrence after presumed perinatal stroke, and routine thrombophilia screening may identify those children who are at higher risk for recurrence and who might therefore benefit from secondary prophylaxis. Clear guidelines should be developed to standardize investigations and management of children with presumed perinatal ischemic stroke.