Efficacy and safety of Wilate in paediatric VWD patients under 6 years of age - results of a prospective multicentre clinical study including recovery information.

Treatment with exogenous von Willebrand factor (VWF) is indicated in patients with von Willebrand disease (VWD) in whom treatment with 1-deamino-8-d-arginine vasopressin/desmopressin is contraindicated. Wilate is a new generation plasma-derived concentrate of native VWF and coagulation factor VIII (FVIII) (in a physiological 1:1 ratio) developed for the treatment of VWD. This is the first study to report safety, efficacy and in vivo recovery (IVR) data from 15 paediatric patients less than 6 years of age who received Wilate for either prophylaxis, on-demand treatment or for treatment in surgical procedures during a prospective open-label trial (VWD type 1: 5, type 2A: 1, type 2B: 2, type 3: 6, unknown type: 1 patients). Analysis of IVR for VWF and FVIII suggested an appropriate and consistent rise in coagulation activity after Wilate administration. Overall efficacy was rated as excellent or good for 99.7% [prophylactic infusions] and 100% [bleeding episodes/surgical procedures]. More than 82% of bleeding episodes resolved after 1 day of treatment, and a Wilate dosage of 20-50 IU kg(-1) was sufficient to achieve haemostasis in 97% of bleeding episodes. All surgical procedures were successfully managed with Wilate. No thromboembolic events were observed during the study, and no patient developed anti-VWF antibodies or FVIII inhibitors. In conclusion, this study confirms both the expected IVR profile in paediatric patients and the excellent efficacy, tolerability and safety profile of Wilate observed previously in adults. Wilate showed excellent efficacy in the treatment of bleeding when used prophylactically or on-demand, and in the treatment of surgical procedures.

Diagnosis and management of neonatal purpura fulminans.

Neonatal purpura fulminans is a rare, life-threatening condition, caused by congenital or acquired deficiencies of protein C or S. The condition is often fatal unless there is early recognition of the clinical symptoms, prompt diagnosis, and judicious replacement therapy is initiated. The clinical presentation is that of acute disseminated intravascular coagulation and hemorrhagic skin necrosis. The management includes an acute phase of replacement therapy with fresh frozen plasma or protein C concentrate and a maintenance therapy that includes anticoagulation with warfarin or low molecular weight heparin. This review focuses on the management of severe protein C deficiency.

Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study.

BACKGROUND: Enoxaparin has been extensively studied in adults on its safety and efficacy during prevention of symptomatic thromboembolism when acute anticoagulation or secondary prevention is required as a result of venous thrombosis or stroke. In children, it is still used off-label and little is known about the pharmacokinetics in children. OBJECTIVES: The aim of the present study was to evaluate whether a once- or twice-daily dosing regimen would be feasible in children to achieve appropriate plasma levels of enoxaparin. PATIENTS/METHODS: A population pharmacokinetic model was developed using anti-factor (F)Xa activity data from 126 children (median age: 5.9 years) receiving enoxaparin either as a once- or twice-daily dosing regimen. RESULTS: A two-compartment model was adequate for describing the enoxaparin kinetics. Body weight proved to be the most predictive covariate for clearance and central volume of distribution: clearance 15 mL h⁻¹ kg⁻¹, central volume of distribution 169 mL kg⁻¹, intercompartmental clearance 58 mL h⁻¹, peripheral volume of distribution 10 L and absorption rate 0.414 h⁻¹. Interindividual variability was found to be 54% for clearance and 42% for volume of distribution. CONCLUSION: The model is capable of describing all age groups and dosing levels of our population and predicts 12 h and 24 h enoxaparin activities sufficiently. According to our results, a once-daily enoxaparin dosing regimen with frequent monitoring is feasible. In 53.2% of the patients the median 24 h trough level was above the desired range of 0.1 IU mL⁻¹ anti-FXa activity for prophylaxis therapy.

Thrombophilia in the young.

Venous thromboembolism (VTE) is a rare disease that is being increasingly diagnosed and recognized in paediatrics in the past decade, usually as a secondary complication of primary severe underlying diseases. Apart from acquired thrombophilic risk factors, such as lupus anticoagulants, inherited thrombophilias (IT) have been established as risk factors for venous thromboembolic events in adults. In children with idiopathic VTE and in paediatric populations in which thromboses were associated with underlying medical diseases, IT have been described as additional prothrombotic risk factors. Follow-up data for VTE recurrence in children are available and suggest a recurrence rate of approximately 3% in neonates and 8% in other children. Here we present a review of the impact of IT on early onset of VTE and recurrence in children. Statistically significant associations between the IT traits investigated, e.g. factor V G1691A, factor II G20210A, protein C-, protein S-, antithrombin deficiency, elevated lipoprotein (a), combined IT and VTE onset were reported. In addition, statistically significant associations with recurrent VTE were calculated for protein S-, antithrombin-deficiency, and the factor II variant and combined IT. The absolute risk increase for VTE recurrence associated with IT ranged from 9.8 % for children carrying the factorII variant to 26% and 29% in children with combined IT and protein S-deficiency, respectively. Data obtained gave evidence that the detection of IT is clinically meaningful in children with VTE and underlines the importance of a paediatric thrombophilia screening program. Based on these data treatment algorithms have to be discussed.

Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children.

Since the early nineties it has been shown that low molecular weight heparin (LMWH) has significant advantages over unfractionated heparin and oral anticoagulants for both the treatment and the prevention of thrombosis, not only in adults, but also in children. The present review was based on an 'EMBASE', 'Medline' and 'PubMed' search including literature published in any language since 1980 on LMWH in neonates, infants and children. It included paediatric pharmacokinetic studies, the use of LMWH in children with venous thrombosis, LMWH administration in paediatric patients with ischaemic stroke, and its use in order to prevent symptomatic thromboembolism in children at risk. An increasing rate of off-label use of LMWH in children has been reported, showing that LMWHs offer important benefits to children with symptomatic thromboembolic events and poor venous access. Two well-conducted pharmacokinetic studies in this age group showed that neonates and younger infants require higher LMWH doses than older children to achieve the targeted anti-Xa levels, due to an increased extra vascular clearance. Recurrent symptomatic thromboses under LMWH occur in approximately 4% of children treated for venous thrombosis, and in 7% of children treated for stroke; major bleed was documented in 3% of children with therapeutic target LMWH anti-Xa levels, whereas minor bleeding was reported in approximately 23% of children receiving either therapeutic or prophylactic doses, respectively. Further randomized controlled trials are recommended to evaluate the optimum duration and application for different LMWH indications in children.

Role of elevated alpha2-macroglobulin revisited: results of a case-control study in children with symptomatic thromboembolism.

OBJECTIVE: alpha(2)-Macroglobulin (alpha2MG) is a broad-spectrum protease inhibitor that is known to neutralize alpha-thrombin, plasmin, and activated protein C, which suggests that it has anticoagulant as well as procoagulant properties. The present study was conducted to evaluate the role of alpha2MG in children with venous thromboembolism [VTE: paradoxical embolism causing ischemic stroke (IS) or deep-vein thrombosis (DVT)]. METHODS: alpha2MG levels measured after acute VTE onset in white patients were compared with data obtained from age- and gender-matched healthy controls. In addition, to compare the rate of elevated alpha2MG and prothrombotic risk factors [factor V G1691A, prothrombin G20210A, raised lipoprotein (a)] between patients and controls and to evaluate the interaction between elevated alpha2MG levels and other thrombophilias, odds ratios (ORs) together with 95% confidence intervals (CIs) were estimated using a logistic regression model. The model was adjusted for age and fibrinogen. RESULTS: alpha2MG levels were significantly higher in patients than in controls (320/139-524 vs. 302/109-406; P = 0.005). In the group of patients (IS n = 103; DVT n = 92), the risk of symptomatic thromboembolism was significantly increased with elevated alpha2MG levels, with a gradual increase per mg dL(-1). In addition, when elevated alpha2MG levels > 90th percentile were compared with values below the cut-off, including established prothrombotic risk factors in the multivariate analysis, patients had a significantly increased OR/95% CI for fibrinogen-adjusted alpha2MG levels (IS, 5.9/1.9-18.3; DVT, 7.2/2.1-24.4). CONCLUSIONS: The procoagulant properties of elevated alpha2MG levels independently increase the odds of stroke and DVT in white children.