Thrombosis and Haemostasis 103.5/2010 1 © Schattauer 2010 New Technologies, Diagnostic Tools and Drugs Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin Fiona Newall 1,2,3,4 ; Vera Ignjatovic 1,3,4 ; Linda Johnston 2,5 ; Robyn Summerhayes 1,3,4 ; Geoff Lane 6 ; Noel Cranswick 1,7 ; Paul Monagle 1,3,4 1 Department of Paediatrics, The University of Melbourne, Melbourne, Australia; 2 School of Nursing and Social Work, The University of Melbourne, Melbourne, Australia; 3 Clinical Haematology Department, Royal Children’s HospitalMelbourne, Australia; 4 Murdoch Childrens Research Institute, Parkville, Australia; 5 School of Nursing and Midwifery, Queens University, Belfast, UK; 6 Department of Cardiology, Royal Children’s HospitalMelbourne, Australia; 7 Australian Paediatric Pharmacology Research Unit (APPRU), Royal Children’s HospitalMelbourne, Australia Summary 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=55) 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 as- says, respectively. In addition, a trend suggesting a proportional in- crease in anti-Xa and anti-IIa-mediated UFH effect with age was evi- dent. Logistic regression demonstrated an increase in protamine ti- Correspondence to: Fiona Newall Clinical Haematology Department Royal Children’s Hospital Flemington Rd. Parkville, Victoria 3052, Australia Tel.: +61 3 9345 5914, Fax: +61 3 9349 1819 E-mail: fiona.newall@rch.org.au tration of 0.6 IU/ml for every year of age in samples collected 15 min- utes 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 teen- agers in the setting of high UFH concentrations. This study demon- strates that the previously reported age-dependent response to UFH oc- curs in the context of an age-dependent serum concentration of UFH. The trend toward increased UFH serum concentration and anticoagu- lant activity with age may be related to short-term differences in UFH binding to coagulant and competitive plasma proteins in vivo. Keywords Unfractionated heparin, anticoagulant activity, age-related response Received: September 6, 2009 Accepted after major revision: January 5, 2010 Prepublished online: February 19, 2010 doi:10.1160/TH09-09-0624 Thromb Haemost 2010; 103: ■■■ Introduction Evidence supporting an age-dependent response to unfraction- ated heparin (UFH) in vitro and in vivo has increased across the last five years. The relative novelty of this concept no doubt relates to the increased clinical awareness of development haemostasis, and the impact that this has upon response to anticoagulant therapies (1–7). For example, in paediatric populations, baseline activated partial thromboplastin time (APTT) levels are known to be in- creased compared with adult normative values and also change with age. This likely reflects quantitative, and possibly qualitative, developmental differences in various haemostatic proteins. Data arising from in vitro and small in vivo studies investigating UFH therapy in diverse populations of children have reported age- related differences in UFH response with respect to discrete coagu- lation assay response and the correlation between different measures of UFH effect (2, 4, 6, 8, 9). Andrew et al. were the first to report in vivo evidence that infants require increased doses of UFH to achieve a target APTT range compared to older children, who in turn required increased UFH dose compared to adults (2). Since 1994, several researchers have further contributed to the under- standing that UFH has an age-specific effect in infancy and child- hood. Ignjatovic et al. reported that the APTT range corresponding to an anti-Xa assay of 0.35 to 0.7 IU/ml was significantly higher in infants compared to older children (6) whilst Kuhle et al. and Chan et al. have both reported that the correlation between the APTT and anti-Xa assay is reduced in infants compared to older children (4, 8). More recently, Newall and Ignjatovic reported that the ratio of UFH inhibition of IIa versus Xa changes with age (9). Whilst all of this evidence supports the premise of UFH having an age-de- pendent mechanism of action, the data is limited by small sample sizes and the heterogeneity of the populations under investigation. No study to date has examined the impact of age upon UFH concentration, as measured by protamine titration. At present, the mechanism for determining target therapeutic ranges for UFH therapy in children are extrapolated from adult evidence. The APTT range correlating to a protamine titration assay of 0.2 to 0.4 IU/ml is assumed to provide optimal anticoagulant management to infants, children and adults alike (10, 11). If advancing age does impact the serum concentration of UFH achieved by infants and children, current evidence-based guidelines for the determination of target therapeutic ranges for UFH therapy in paediatrics will