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

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=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 as-says, 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.

Keywords

Unfractionated heparin - anticoagulant activity - age-related response

• References

• 1 Monagle P, Barnes C, Ignjatovic V. et al. Developmental haemostasis: Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362-372.
• 2 Andrew M, Marzinotto V, Massicotte P. et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatric Res 1994; 35: 78-83.
• 3 Chan A, Berry L, Monagle P. et al. Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential. Thromb Haemost 2002; 87: 606-613.
• 4 Chan A, Black L, Ing C. et al. Utility of aPTT in monitoring unfractionated heparin in children. Thromb Res 2008; 122: 135-136.
• 5 Ignjatovic V, Furmedge J, Newall F. et al. Age-related differences in heparin response. Thromb Res 2006; 118: 741-745.
• 6 Ignjatovic V, Summerhayes R, Than J. et al. Therapeutic range for unfractionated heparin therapy: age-related differences in response in children. J Thromb Haemost 2006; 04: 2280-2282.
• 7 Schmidt B, Mitchell L, Ofosu F. et al. Standard assays underestimate the concentration of heparin in neonatal plasma. J Lab Clin Med 1988; 112: 641-643.
• 8 Kuhle S, Eulmesekian P, Kavanagh B. et al. Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically ill children. Haematologica 2007; 92: 554-557.
• 9 Newall F, Ignjatovic V, Summerhayes R. et al. In vivo age dependency of unfractionated heparin in infants and children. Thromb Res 2009; 123: 710-714.
• 10 Hirsh J, Bauer K, Donati M. et al. Parenteral anticoagulants. Chest 2008; 133: S141-S159.
• 11 Monagle P, Chalmers E, Chan A. et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133: 887S-968S.
• 12 Refn I, Vestergaard L. The titration of heparin with protamine. Scand J Clin Lab Invest 1954; 06: 284-287.
• 13 Andrew M, Monagle P, Brooker L. Thromboembolic complications during infancy and childhood. Hamilton: BC. Decker; 2000
• 14 Newall F, Johnston L, Ignjatovic V. et al. Refinement and feasibility testing of a manual micro-method for protamine titration. Int J Lab Hematol 2009; 31: 457-461.
• 15 Summerhayes R, Newall F, Monagle P. et al. An automated anti-IIa assay to measure UFH levels in plasma – A method without exogenous antithrombin. Int J Lab Hematol. 2009 epub ahead of print.
• 16 Ignjatovic V, Summerhayes R, Gan A. et al. Monitoring unfractionated heparin (UFH) therapy: which anti factor Xa assay is appropriate?. Thromb Res 2007; 120: 347-351.
• 17 Hirsh J. Heparin. New Engl J Med 1991; 324: 1565-1574.
• 18 Hull R, Raskob G, Hirsh J. et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. New Engl J Med 1986; 315: 1109-1114.
• 19 Kitchen S, Jennings I, Woods T. et al. Wide variability in the sensitivity of APTT reagents for monitoring of heparin dosage. J Clin Pathol 1996; 49: 10-14.
• 20 Kitchen S, Preston F. The therapeutic range for heparin therapy: relationship between six activated partial thromboplastin time reagents and two heparin assays. Thromb Haemost 1996; 75: 734-739.
• 21 Newall F, Ignjatovic V, Johnston L. et al. Unfractionated heparin therapy in infants and children. Pediatrics 2009; 123: e510-e518.