Fiona Newall

Developmental haemostasis : Impact for clinical haemostasis laboratories

Developmental haemostasis is a concept, now universally accepted, introduced by Andrew et al. in the late 1980s. However, coagulation analysers and reagents have changed significantly over the past 15 years. Coagulation testing is known to be sensitive to changes in individual reagents and analysers. We hypothesised that the reference ranges developed by Andrew et al. may not be appropriate for use in a modern coagulation laboratory. Our study was designed to determine whether a current day coagulation testing system (STA Compact analyser and Diagnostica Stago reagent system) was sensitive to age-related changes in coagulation assays. This is the first large scale study since Andrew et al. to determine the age associated numerical changes in coagulation proteins. Our results confirm the concepts of developmental haemostasis elucidated by Andrew et al. However, our results clearly demonstrate that the absolute values of reference ranges for coagulation assays in neonates and children vary with analyser and reagent systems. The results confirm the need for coagulation laboratories to develop age-related reference ranges specific to their own testing systems. Without this, accurate diagnosis and management of neonates and children with suspected bleeding or clotting disorders is not possible. Finally we present age related reference ranges for D-dimers, TFPI, and endogenous thrombin potential, previously not described.

Reduced bone density in children on long-term warfarin.

Vitamin K is essential for development of normal bone density and achieving adequate peak bone mass in childhood and is thought to be important in preventing the development of osteoporosis in later life. Warfarin, a vitamin K antagonist, is being used with greater frequency in children. The long-term effect of warfarin on bone density of children is not known. We performed a case control study survey of bone density in children on long-term warfarin (n = 17, average duration of warfarin treatment 8.2 y) compared with randomly selected controls (n = 321). There was a marked reduction in bone mineral apparent density of lumbar spine between patients and controls [patients 0.10 g/cm3; 95% confidence interval (CI), 0.93–0.11 g/cm3, controls 0.12 g/cm3; 95% CI, 0.11–0.12 g/cm3, p < 0.001). The lumbar spine areal bone mineral density Z-score of patients was reduced compared with controls [patients, −1.96 (95% CI, −2.52 to −1.40). This difference persisted after adjustment for age and body size. The etiology for the reduced bone density is likely to be multifactorial, however, screening of children on long-term warfarin for reduced bone density should be considered.

Arterial ischaemic stroke in children.

Objective:  Arterial ischaemic stroke (AIS) in childhood is a serious disorder about which little is published. The aim of this study is to determine the epidemiology and outcome of AIS in Australian children.

Heparin-induced thrombocytopenia in children.

Objective:  To audit the frequency of heparinoid (standard heparin and low molecular weight heparin) use in a tertiary paediatric hospital, and to determine the occurrence of heparin‐induced thrombocytopenia (HIT).

Unfractionated Heparin Therapy in Infants and Children

Unfractionated heparin is frequently used in tertiary pediatric centers for the prophylaxis and treatment of thromboembolic disease. Recent evidence suggests that the clinical outcomes of unfractionated heparin therapy in children are poor, as determined by target-range achievement and adverse-event rates. These reports of poor outcomes may be related to an age-dependent mechanism of action of unfractionated heparin. Furthermore, several published studies have indicated that unfractionated heparin–monitoring assays currently in clinical use have significant limitations that likely affect the safety and efficacy of anticoagulant management. This review summarizes the growing body of evidence suggesting that pediatric-specific recommendations for unfractionated heparin therapy management are required to improve clinical outcomes related to this commonly prescribed medication.

In vivo age dependency of unfractionated heparin in infants and children

INTRODUCTION Unfractionated Heparin (UFH) is used widely in paediatrics. Paediatric specific recommendations for UFH therapy are few, with the majority of recommendations being extrapolated from adult practice. In vitro studies have shown that this practice may be suboptimal. This study aimed to improve the understanding of the impact of age upon UFH response in vivo. MATERIALS AND METHODS This prospective, observational study, conducted in the Paediatric Intensive Care Unit (PICU), included: patients 16 years or younger; treated with UFH of at least 10 U/Kg/hr. Laboratory analysis included: Antithrombin, APTT, Anti-Xa, Anti-IIa and thrombin generation expressed as the Endogenous Thrombin Potential. Results were grouped according to patient age (i.e. <1, 1-5, 6-10 and 11-16 years). RESULTS 85 patients received an equivalent mean UFH dose with a median duration of 3 days. Antithrombin levels were decreased compared to age-related norms in children up to 11 years of age. APTT results were comparable across the age-groups. The Anti-Xa results using two different assays showed a trend for lower values in younger children. All children less than one year old recorded Anti-Xa values outside the therapeutic range for heparin therapy, for both assays. There was a trend for decreased Anti-IIa activity in younger children. Endogenous Thrombin Potential showed a significant trend for increased inhibition in older children. In vitro Antithrombin supplementation did not change the Anti-Xa or thrombin generation. CONCLUSIONS This study confirms that, in vivo, for the same dose of UFH, the anti Xa and anti IIa effect, as well as the inhibition of endogenous thrombin potential is age dependent and that these differences are not purely AT dependent. The implication is that the anticoagulant and antithrombotic effect of a given dose of UFH differs with age. Clinical outcome studies to determine the optimal dosing for each age group are warranted.

Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.

Low molecular weight heparins (LMWHs) are commonly used in paediatric tertiary institutions for primary prophylaxis and treatment of thromboembolic events. Despite this widespread use, the therapeutic and prophylactic guidelines for LMWH therapy in children are extrapolated from adult guidelines. In fact, there is very little information regarding the pharmacokinetics, clinical effectiveness, adverse event profile and optimal dose schedule for LMWH therapy in children. This study was designed to determine whether paediatric‐specific dosage requirements for LMWH are justified, by investigating the doses required to achieve target therapeutic ranges. Patients who were treated with enoxaparin between October 2003 and July 2007 were identified for inclusion in this study. One hundred forty patients had an anti‐activated factor X assay result with a total of 55 (39%) patients achieving therapeutic levels 4–6 h post dose. Children younger than 1 year required the highest dose of enoxaparin/kg and highest number of dose changes to achieve the target therapeutic range. Major bleeding occurred in one patient, equating to 0·7%, with complete clot resolution recorded in 16 (11%) patients. This study demonstrated a 2–3‐fold variation in individual dose requirements for LMWH in children ≤5 years of age, and further mandates the need for age‐specific dosage requirements in children receiving enoxaparin.

Cerebral sinus venous thrombosis in children

Objective:  Cerebral sinus venous thrombosis (cerebral SVT) is rare in children. Information on clinical characteristics, radiological findings and outcome is emerging.

Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin

Previous studies investigating continuous unfractionated heparin (UFH) therapy report age-related differences in UFH response in children, as measured by APTT and anti-Xa assay. This study determined the age-related response following administration of a single UFH bolus of 75-100 IU/kg in children. Venous blood samples were collected from children (n=56) at 15, 30, 45 and 120 minutes post-UFH. Anti-Xa, anti-IIa, APTT, TCT and protamine titration were performed on all samples. Age-dependent differences in the effect and concentration of UFH were identified for the anti-Xa, anti-IIa and protamine titration assays, respectively. In addition, a trend suggesting a proportional increase in anti-Xa and anti-IIa-mediated UFH effect with age was evident. Logistic regression demonstrated an increase in protamine titration of 0.6 IU/ml for every year of age in samples collected 15 minutes post-UFH. UFH-mediated anti-IIa activity was reduced compared to anti-Xa activity across childhood, with a two-fold increase in anti-Xa to anti-IIa ratio in infants less than one year of age compared to teenagers in the setting of high UFH concentrations. This study demonstrates that the previously reported age-dependent response to UFH occurs in the context of an age-dependent serum concentration of UFH. The trend toward increased UFH serum concentration and anticoagulant activity with age may be related to short-term differences in UFH binding to coagulant and competitive plasma proteins in vivo.

Venous thromboembolic disease: a single-centre case series study.

Aim:  The epidemiology of venous thromboembolism in children has likely changed since first being described a decade ago because of evolving management strategies and a greater awareness of predisposing factors for thrombosis in children. The Royal Childrens Hospital commenced a 4‐year prospective registry of venous thrombosis in 1999 to determine the current Australian epidemiology of venous thrombosis in infants and children.