Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events.

In children, there is an increasing off-label use of low molecular weight heparin (LMWH). However, there is an absence of information on dosing and pharmacokinetics of LMWH over all age groups. The objectives of the current study were to determine i) the once daily dose required to achieve anti-Xa levels of 0.5-1.0 IU/mL, ii) the pharmacokinetics and iii) preliminary safety data using tinzaparin. The study took the form of a single centre open-label Phase II study performed in 35 children requiring anticoagulation for treatment of thromboembolism. Age groups studied were: 0- < 2 months; 2 months- < 1 year; 1- < 5 years; 5- < 10 years; 10-16 years. Both population pharmacokinetic analysis using nonlinear mixed-effect modeling techniques and model-independent pharmacokinetic methods were employed. Results showed a relationship of age and dose requirements, clearance, time to peak anti-Xa level and volume of distribution. Younger children required an increased dose, cleared tinzaparin more rapidly, had anti-Xa levels peak earlier and had an increased volume of distribution. Younger children were more likely to be below target range than older children,with up to 75% of children < 1 year being below the target anti-Xa level. Four recurrences and one major bleed occurred. In conclusion, there is an inverse relationship of age on dose requirements related to volume of distribution, clearance and time to peak anti-Xa. Children < 5 years likely require dose adjustment samples to be drawn 2-3 hours post injection. Infants require anti-Xa levels to be monitored at least twice monthly.

Dissemination to research subjects: operationalizing investigator accountability.

Recent articles have argued from principles of bioethics for the right of research subjects to receive the results of the studies in which they have participated. We argue that accountability is a powerful tool of meso-level analysis appropriate to reasoning about answerability in research ethics, and that it captures the responsibility of researchers to disseminate study results to research subjects. We offer the following features of the research situation as relevant to the manner of dissemination to study subject, in addition to factors already proposed in the literature (risk and impact on health outcome): (a) features of the research subject in relation to identity, personal investment, disease, and community; (b) characteristics of the research study and field of inquiry in relation to certainty and significance; and (c) relationships among the research subjects and the healthcare workers involved in their care and in the research.

An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial.

OBJECTIVE(S): Venous thromboembolic events (VTE) are serious complications in children and for which the standard of care, unfractionated heparin followed by oral anticoagulation (UFH/OA), is problematic. The objective of REVIVE was to compare the efficacy and safety of a low molecular weight heparin (reviparin-sodium) to UFH/OA for the treatment of VTE in children. STUDY DESIGN: This multicenter, open-label study, with blinded central outcome adjudication, randomized patients with objectively confirmed VTE to receive either reviparin-sodium or UFH/OA. Dose adjustments were made using nomograms. The efficacy outcome was based on recurrent VTE and death due to VTE during the 3-month treatment period. The safety outcomes were major bleeding, minor bleeding and death. Due to slow patient accrual, REVIVE was closed prematurely. RESULTS: At 3 months, with reviparin-sodium, 2/36 patients (5.6%) had recurrent VTE or death compared to 4/40 patients (10.0%) receiving UFH/OA (odds ratio=0.53; 95% CI=(0.05, 4.00); Fisher's exact test: 2P=0.677). There were 7 major bleeds, 2/36 (5.6%) in the reviparin-sodium group and 5/40 (12.5%) in UFH/OA group (odds ratio=0.41; 95% confidence interval 0.04, 2.76); Fisher's exact test: P=0.435). There were 5 deaths during the study period, 1 (2.8%) in the reviparin-sodium group and 4 (10.0%) in the UFH/OA group. All five deaths were unrelated to VTE but one was due to an intracranial hemorrhage in the UFH/OA group. CONCLUSIONS: Although limited by small sample size, REVIVE provides valuable information on the incidence of recurrent VTE, major bleeding and problematic issues associated with therapy of VTE in children.

A cross-sectional study evaluating post-thrombotic syndrome in children.

BACKGROUND: Post-thrombotic syndrome (PTS) in adults, characterized by swelling, skin pigmentation, pain, and ulceration of the limb, is secondary to deep vein thrombosis (DVT). In contrast to the extensive documentation on PTS in adults, little is known about the risk of PTS in children. OBJECTIVE: To determine the incidence, clinical characteristics, and predictors of PTS in children. METHODS: A cross-sectional study in 153 nonselected children with objectively confirmed DVT. All children were assessed for PTS using a standardized score. As per the PTS score, severity was classified as: absent, mild, moderate, or severe. RESULTS: Post-thrombotic syndrome was present in 96/153 children (63%), in which 80 (83%) were mild and 16 (17%) were moderate. Swelling was the most frequently recorded subjective symptom (43%) while increased limb circumference (71%) and presence of collateral circulation (53%) were the most frequently recorded objective symptoms. Risk factors for development of PTS were: lack of resolution of the DVT by radiographic assessment (OR 3.96, 95% CI 1.68-9.30), number of vessels involved in the initial DVT (OR 2.05, 95% CI 1.52-2.77), and length of follow-up (OR 1.22, 95% CI 1.08-1.39). CONCLUSIONS: These findings demonstrate that PTS is a clinically significant disease in children with previous DVT.

Dose-finding and pharmacokinetic profiles of prophylactic doses of a low molecular weight heparin (reviparin-sodium) in pediatric patients.

INTRODUCTION: The low molecular weight heparin (LMWH), reviparin-sodium was studied in dose-finding and pharmacokinetic studies in children with central venous lines (CVLs). MATERIALS AND METHODS: The dose-finding study was performed in 24 patients aged 3 days to 16 years. Dose adjustments were made using a nomogram based on anti-factor Xa levels (units (U)/ml) (target of 0.1-0.3 U/ml). The pharmacokinetic study was performed in 19 patients, 9 less than or equal to 5 kg (7 of whom were less than 3 months) and 10 greater than 5 kg (all more than 3 months). RESULTS: The dose-finding study demonstrated that children over 5 kg required 30 International Units (IU)/kilogram (kg), subcutaneous (SC) twice daily (BID), and children less than or equal to 5 kg required 50 IU/kg, SC BID, to achieve target levels. The pharmacokinetic study demonstrated that 80% of anti-factor Xa levels were within the target range with both patient groups having similar peak (average=0.26 U/ml) and trough (average=0.13 U/ml) levels. CONCLUSIONS: Peak anti-factor Xa levels (0.1-0.3 U/ml) using reviparin-sodium are achieved by administering 50 IU/kg in children greater than 3 months of age and 30 U/kg in children less than 3 months of age.

An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial.

OBJECTIVE(S): Central venous lines (CVLs) are major risk factors for venous thromboembolism (VTE) in children. The objective of PROTEKT was to determine if a low molecular weight heparin (reviparin-sodium) safely prevents CVL-related VTE. STUDY DESIGN: This multi-center, open-label study, with blinded central outcome adjudication, randomized patients with new CVLs to twice-daily reviparin-sodium or standard care. The efficacy outcome was based on an exit venogram at Day 30 (+14 days), or earlier in case of CVL removal, or confirmed symptomatic VTE. The safety outcomes were major bleeding and death. Due to slow and restricted patient accrual, PROTEKT was closed prematurely. RESULTS: With reviparin-sodium, 14.1% (11:78) of patients had VTE compared to 12.5% (10:80) of control patients (odds ratio=1.15; 95% confidence interval 0.42, 3.23); 2P=0.82). One patient had a major bleed and there were two deaths, all three events occurring in the standard care group. CONCLUSIONS: The use of reviparin-sodium for short-term prophylaxis of CVL-related VTE in children was safe but its efficacy remains unclear. Although underpowered, PROTEKT provided valuable information on event rates and predictors of CVL-related VTE.

Effective treatment of ligneous conjunctivitis with topical plasminogen.

PURPOSE: The etiology of ligneous conjunctivitis is now known to be due to an underlying type 1 plasminogen deficiency. We hereby report the clinical features of three cases and their response to topically administered plasminogen. DESIGN: Observational case series. METHODS: Two Caucasian females aged 5 years and an 18-month male of north African descent presented with a membranous conjunctivitis, which recurred after surgical excision. Case 1 presented before the association with plasminogen deficiency was known with a bilateral chronic membranous mucopurulent conjunctivitis from the age of 14 months associated with bronchiolitis and gingival hyperplasia. A diagnosis of ligneous conjunctivitis was entertained and a number of drops were instituted. At the age of 4 years plasminogen levels were ordered. Case 2 presented at the age of 4 years with a unilateral chronic membranous conjunctivitis. Plasminogen levels were requested as soon as a diagnosis of ligneous conjunctivitis was suspected. Case 3 was born with congenital hydrocephalus. Conjunctivitis was treated with antibiotics from the age of 1 month. He presented to the eye clinic at the age of 5 months when a clinical diagnosis of ligneous conjunctivitis was entertained and treated with a number of medications. Plasminogen levels were available at 9 months of age. RESULTS: The two female patients returned plasminogen levels of 0.25 U/ml and 0.3 U/ml, well below the normal level of 0.7-1.0 U/ml. Functional plasminogen levels in the male infant were not recordable with plasminogen antigen levels of 0.125 U/ml (normal range, 0.52-1.82). All cases have responded well to excision of the membranes and institution of topical plasminogen drops. There has been no recurrence with more than 12 months' follow-up. CONCLUSIONS: With the knowledge of the etiology of ligneous conjunctivitis, efforts are underway to identify the best method of delivery of plasminogen. Topical plasminogen concentrate from fresh frozen plasma holds promise as the definitive treatment for this chronic membranous conjunctivitis

Heparin-bonded central venous catheters do not reduce thrombosis in infants with congenital heart disease: a blinded randomized, controlled trial.

BACKGROUND: Infants with congenital heart disease who require central venous lines are at increased risk of thrombosis. Heparin-bonded catheters provide protection from thrombotic events in some children. However, heparin-bonded catheters may not be as effective in infants