Evaluation of enoxaparin dosing requirements in infants and children

Summary

Increasing the starting dose of enoxaparin results in the early achievement of therapeutic anti-factor Xa levels in children receiving enoxaparin which is critical for effective therapy and the reduction of venipunctures. The aim of this study was: i) to determine the enoxaparin dose required to achieve therapeutic anti-factor Xa levels in infants and children, and ii) to establish whether increasing the starting dose of enoxaparin influenced the time required to reach the therapeutic range and the number of venipunctures required for dose-adjustment, and iii) the radiographic outcome of the thrombosis, where applicable. A retrospective chart review of children who received enoxaparin was carried out at the Stollery Children’s Hospital, Edmonton, Alberta, Canada. Patients treated with standard-dose enoxaparin (1.5 mg/kg for children ≤3 months of age, 1.0 mg/kg for children ≥3 months of age), were compared with children who received a higher initial starting dose of enoxaparin (1.7 mg/kg for children ≥3 months of age, 1.2 mg/kg for children ≥3 months of age). Infants <3 months required an enoxaparin dose of 1.83 mg/kg, and those who received an increased initial enoxaparin dose resulted in faster attainment of therapeutic anti-factor Xa levels requiring significantly fewer venipunctures. Similarly, infants ≥3–12 months, 1–5 years, and 6–18 years, require enoxaparin 1.48 mg/kg, 1.23 mg/kg and 1.13 mg/kg, respectively, in order to achieve a therapeutic anti-factor Xa level. In conclusion, increasing the starting dose of enoxaparin may result in more rapid attainment of therapeutic range with fewer venipunctures, dose adjustments, and without an increase in adverse events.

Keywords

Enoxaparin - children - infants - anti-factor Xa levels - anticoagulation - dosage/adverse effects

• References

• 1 Monagle P, Adams M, Mahoney M. et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000; 47: 763-766.
• 2 Andrew M, David M, Adams M. et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83: 1251-1257.
• 3 Massicotte MP, Dix D, Monagle P. et al. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133: 770-776.
• 4 Bomgaars L. International Society for Thrombosis and Hemostasis Pediatric Perinatal Subcommittee. 2005 Sydney, Australia.:
• 5 Dix D, Andrew M, Marzinotto V. et al. The use of low molecular weight heparin in pediatric patients: a prospective cohort study. J Pediatr 2000; 136: 439-445.
• 6 Revel-Vilk S, Sharathkumar A, Massicotte P. et al. Natural history of arterial and venous thrombosis in children treated with low molecular weight heparin: a longitudinal study by ultrasound. J Thromb Haemost 2004; 02: 42-46.
• 7 Streif W, Goebel G, Chan AKC. et al. Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients. Arch Dis Child Fetal Neonatal Ed 2003; 88: F365-70.
• 8 Massicotte MP. Low-molecular-weight heparin therapy in children.[comment]. J Pediatr Hematol Oncol 2000; 22: 98-99.
• 9 Dix D, Andrew M, Marzinotto V. et al. The use of low molecular weight heparin in pediatric patients: a prospective cohort study [see comment]. J Pediatr 2000; 136: 439-445.
• 10 Massicotte P, Adams M, Marzinotto V. et al. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study. J Pediatr 1996; 128: 313-318.
• 11 Verso M, Agnelli G, Bertoglio S. et al. Enoxaparin for the prevention of venous thromboembolism associated with central vein catheter: a double-blind, placebo-controlled, randomized study in cancer patients [see comment]. J Clin Oncol 2005; 23: 4057-4062.
• 12 Dager WE, Gosselin RC, King JH. et al. Anti-Xa stability of diluted enoxaparin for use in pediatrics. Ann Pharmacother 2004; 38: 569-573.
• 13 Ho SH, Wu JK, Hamilton DP. et al. An assessment of published pediatric dosage guidelines for enoxaparin: a retrospective review. J Pediatr Hematol Oncol 2004; 26: 561-566.
• 14 Monagle P, Chan A, Massicotte P. et al. Antithrombotic therapy in children: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 645S-87S.
• 15 Nowak-Gottl U, Bidlingmaier C, Krumpel A. et al. Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children. Br J Pharmacol 2008; 153: 1120-1127.
• 16 Michaels LA, Gurian M, Hegyi T. et al. Low molecular weight heparin in the treatment of venous and arterial thromboses in the premature infant. Pediatrics 2004; 114: 703-707.
• 17 Bauman M, Black K, Bauman M. et al. Novel uses of insulin syringes to reduce dosing errors: A retrospective chart review of Enoxparin whole milligram dosing. Thromb Res. 2008 [In press].
• 18 D’Agostino Jr R. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. . Stat Med 1998; 17: 2265-2281.
• 19 Malowany J, Knoppert D, Chan A. et al. Enoxaparin use in the neonatal intesnive care unit: Experience over 8 years. Pharmacotherapy 2007; 27: 1263-1271.
• 20 Manco-Johnson MJ. How I treat thrombosis in children. Blood 2006; 107: 21-29.
• 21 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72: 1651-1657.
• 22 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165-172.
• 23 Andrew M, Vegh P, Johnston M. et al. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998-2005.
• 24 Kearns G, Abdel-Rahman S, Alander S. et al. Developmental Pharmacology-Drug Disposition, Action, and Therapy in Infants and children. N Eng J Med 2003; 349: 1157-1167.
• 25 O’Brien SH, Lee H, Ritchey AK. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study. J Thromb Haemost 2007; 05: 1985-1987.
• 26 Marzinotto V, Monagle P, Chan A. et al. Capillary whole blood monitoring of oral anticoagulants in children in outpatient clinics and the home setting. Pediatr Cardiol 2000; 21: 347-352.
• 27 Marzinotto V, Monagle P, Chan A. et al. Capillary whole blood monitoring of oral anticoagulants in children in outpatient clinics and the home setting. Pediatr Cardiol 2000; 21: 347-352.
• 28 Massicotte P, Julian JA, Gent M. et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res 2003; 109: 85-92.
• 29 Streif W, Andrew M, Marzinotto V. et al. Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients. Blood 1999; 94: 3007-3014.
• 30 deVeber G, Chan A, Monagle P. et al. Anticoagulation therapy in pediatric patients with sinovenous thrombosis: a cohort study. Arch Neurol 1998; 55: 1533-1537.
• 31 Nowak-Gottl U, Kosch A. Factor VIII, D-Dimer, and thromboembolism in children.[comment]. N Engl J Med 2004; 351: 1051-1053.
• 32 Alhenc-Gelas M, Jestin-Le GC, Vitoux J. et al. Adjusted versus fixed doses of the low-moleuclar-weight heparin Fragmin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 71: 698-702.
• 33 Levine M, Planes A, Hirsch J. et al. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparine low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 1989; 62: 940-944.