Unfractionated heparin therapy in paediatrics

Abstract

Unfractionated heparin (UFH) therapy is frequently used in tertiary paediatric healthcare facilities despite a lack of paediatric-specific research informing the optimal therapeutic intensity, monitoring recommendations or side-effect-profile in infants and children. As a result, the majority of clinical recommendations regarding UFH management in children have been extrapolated from adult evidence. The process of developmental haemostasis, in association with the variable pathogenesis of thromboembolic disease (TED) in children compared to adults, suggests that extrapolation of adult guidelines for UFH management to children is not ideal.

This study hypothesised that the process of developmental haemostasis would influence both the action and effect of UFH in children of different ages. This hypothesis was tested by addressing the following aims: 1. To determine the pharmacokinetics (PK) of UFH in children of different ages; 2. To compare the different methods of monitoring UFH in children of different ages; 3. To identify the impact of competitive plasma binding of UFH in children of different ages; 4. To determine the impact of UFH upon tissue factor pathway inhibitor (TFPI) release in children.

A prospective cohort study of children receiving a single bolus dose of UFH for primary thromboprophylaxis in the setting of cardiac angiography was conducted. Venous blood samples were collected prior to the UFH, then at 15, 30, 45 and 120 minutes post-UFH bolus. Laboratory assays performed included activated partial thromboplastin time (APTT), anti-Xa assay, anti-IIa assay, thrombin clotting time (TCT), protamine titration and TFPI. Levels of two plasma proteins known to competitively bind UFH (vitronectin and platelet factor 4) were determined and the impact of competitive plasma binding upon UFH activity, as measured by the anti-Xa assay, was quantified. A population approach to pharmacokinetic analysis, based on protamine titration results, was performed using WinNonMix™ Professional 2.0.1 (®1998-2000 Pharsight Corporation, Mountain View, CA, USA). Results were analysed according to the following age-groups: less than one year; one to five years; six to ten years; 11-16 years.

Sixty-four children were recruited, ranging in age from six months to fifteen-and-ahalf years. The mean dose/Kg of UFH across the entire cohort was 90.9± 15.5 IU/Kg.

Pharmacokinetic model specifications were systematically assessed, investigating the impact of parameter covariates and different error models upon objective function value and/or curve fitting. A first-order kinetic model best fitted the data. This model used weight 0.75 as the covariate of clearance and total weight as the covariate for volume of distribution. Parameter estimates for clearance and volume of distribution both demonstrated variance from adult and small neonatal PK studies of UFH, however methodological differences in PK analysis techniques limited comparisons. The half-life of UFH reported in this study was consistently and significantly shorter than that previously reported for adults, but longer than that reported for neonates.

All measures of UFH-effect demonstrated a significant and prolonged increase post- UFH bolus. The mean APTT was 261 seconds 102 ± 25 minutes post-UFH, representing a seven-fold increase from the mean baseline APTT (38 seconds). Anti- Xa assay levels were within the therapeutic range for TED management (0.35 to 0.7 IU/mL), or greater, at every post-UFH bolus timepoint. This prolonged UFH-effect was evident to nearly two hours post-UFH bolus, without concurrent UFH infusion. Age-related differences in UFH-response were evident for anti-Xa, anti-IIa and protamine titration results. Furthermore, during periods of high UFH concentration, the ratio of anti-Xa to anti-IIa activity in children less than one year of age significantly favoured UFH-mediated anti-Xa effect over anti-IIa effect (1.9), compared to teenagers (1.3).

This study demonstrated poor correlation between protamine titration and both the anti-Xa assay (r2 = 0.47) and APTT (r2 = 0.56). Use of the anti-Xa assay (0.35 to 0.7 IU/mL) or protamine titration assay (0.2 to 0.4 IU/mL) to establish APTT-based reference ranges for therapeutic management of TED resulted in APTT ranges with upper limits greater than 250 seconds.

No age-related quantitative differences in plasma levels of vitronectin or platelet factor 4 were identified across the childhood years. The addition of dextran sulphate (DS) to ex vivo study samples demonstrated no change in anti-Xa activity in samples collected within 20 minutes of UFH bolus, however a significant increase in anti-Xa activity following the addition of DS was evident at all later timepoints post-UFH bolus.

The measurement of TFPI before and after a single bolus dose of UFH demonstrated children have a similar immediate increase in TFPI activity following intravenous UFH compared to adults. However, the children in this series demonstrated a significantly prolonged level of increased TFPI activity, out to 102 ± 25 minutes post-UFH, compared to that reported in adult patients.

This study has developed the first paediatric-specific PK profile of UFH and has elucidated a number of age-dependent UFH-mechanisms of action that contribute to the previously reported age-dependent response to UFH in children. The results of this study support the hypothesis that developmental haemostasis influences both the action and effect of UFH in children of different ages.