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W2050997077 abstract "Enoxaparin is frequently used now in pediatric and neonatal care due to an increase in invasive procedures with secondary thrombotic episodes [[1]Nowak-Gottl U. Kosch A. Schlegel N. Thromboembolism in newborns, infants and children.Thromb Haemost. 2001; 86: 464-474PubMed Google Scholar]. The two peaks of enoxaparin use in pediatrics are in newborns and adolescents [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 3Monagle P. Newall F. Campbell J. Anticoagulation in neonates and children: Pitfalls and dilemmas.Blood Rev. 2010; 24: 151-162Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 4Payne J.H. Aspects of anticoagulation in children.Br J Haematol. 2010; 150: 259-277Crossref PubMed Scopus (31) Google Scholar]. Enoxaparin is easier to monitor than standard unfractionated heparin [[5]Ho S.H. Wu J.K. Hamilton D.P. Dix D.B. Wadsworth L.D. An assessment of published pediatric dosage guidelines for enoxaparin: a retrospective review.J Pediatr Hematol Oncol. 2004; 26: 561-566Crossref PubMed Scopus (38) Google Scholar] but little is known about neonatal enoxaparin pharmacokinetics, dosing and target anti-Xa levels specific to neonates. Knowledge about pharmacokinetics in neonatal overdose is more limited [6Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 7Volz S. Schinzel H. Keune N. Neukirch M. Schmidtke S. Stopfkuchen H. Low Molecular Heparin for Treatment of Venous Thrombosis in Two Very Low-Birth-Weight Pre-Term Infants with Genetic Risk Factors.Klin Padiatr. 2006; 218: 226-229Crossref PubMed Scopus (2) Google Scholar]. Neonates are a vulnerable group for medication drug errors [[8]Fortescue E.B. Kaushal R. Landrigan C.P. McKenna K.J. Clapp M.D. Federico F. et al.Prioritizing strategies for preventing medication errors and adverse drug events in pediatric inpatients.Pediatrics. 2003; 111: 722-729Crossref PubMed Scopus (340) Google Scholar]. There is a large potential for enoxaparin overdose in neonates, as dilutions and smaller volumes can lead to mistakes [[9]Bauman M.E. Black K.L. Bauman M.L. Belletrutti M. Bajzar L. Massicotte M.P. Novel uses of insulin syringes to reduce dosing errors: A retrospective chart review of enoxaparin whole milligram dosing.Thromb Res. 2009; 123: 845-847Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. We report a case of a newborn given an accidental supratherapeutic dose of enoxaparin, which permitted calculation of a half-life of the agent in the neonate.A healthy 3.865 kg, term female neonate, born by Ventouse-assisted delivery, received a supratherapeutic dose of enoxaparin of 40 mg in error. The enoxaparin dose was intended for the infant’s mother, but was mistaken for a drawn-up vial of hepatitis B vaccine and administered subcutaneously to the neonate. A cephalhematoma was present after birth, prior to enoxaparin administration. No bleeding was noted subsequent to the dosing. Serial anti-Xa levels, coagulation and full blood count studies were performed. The anti-Xa level at hour +5.70 was 3.16 units/ml (U/ml) with an APTT of 132 seconds. Decision regarding management was complicated by the presence of the scalp cephalhematoma. A decision was made not to give protamine as it was felt that there was insufficient safety data for protamine use in neonates, and reports of cardiovascular side effects [[10]Pugsley M.K. Kalra V. Froebel-Wilson S. Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle.Life Sci. 2002; 72: 293-305Crossref PubMed Scopus (21) Google Scholar]. At hour +13, the anti-Xa level was 1.43 and at hour +38 was 0.10, with a normalised APTT of 35.8 at hour +38. A mild transaminitis (GGT 341U/L, ALT 53U/L, AST 96U/L, normal ALP 185U/L) was noted post-enoxaparin administration. The mild transaminitis was still present one week later. The baby remained well.Using observed data from this patient, pharmacokinetic parameters for neonatal enoxaparin metabolism following a supratherapeutic dose were derived (Fig. 1). The calculated elimination half-life was 4.8 hours, using a one-compartment model with non-linear kinetics. Limited time points do not permit further pharmacokinetic analysis. The half-life of 4.8 hours derived in our patient following supratherapeutic dosing is consistent with the half-life of enoxaparin in adults (for therapeutic dosing), which is 4.5 hours after a single subcutaneous dose of 40 mg and about 7 hours for repeated dosing [[11]Product Information Lovenox.http://products.sanofi.us/lovenox/lovenox.htmlDate: 2011Google Scholar]. One-compartment [[12]Dunaway K.K. Gal P. Ransom J.L. Use of enoxaparin in a preterm infant.Ann Pharmacother. 2000; 34: 1410-1413Crossref PubMed Google Scholar] and two-compartment models [[13]Trame M.N. Mitchell L. Krumpel A. Male C. Hempel G. Nowak-Gottll U. Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study.J Thromb Haemost. 2010; 8: 1950-1958Crossref PubMed Scopus (45) Google Scholar] have both been used to describe enoxaparin pharmacokinetics in children. A one-compartment model in a preterm infant was used to derive a half-life of 4 hours [[12]Dunaway K.K. Gal P. Ransom J.L. Use of enoxaparin in a preterm infant.Ann Pharmacother. 2000; 34: 1410-1413Crossref PubMed Google Scholar]. A two-compartment model with linear kinetics is described in enoxaparin product information for adults when doses in the higher end (73.8-132 mg/dose) of the therapeutic range are administered [[14]MIMS Online Product Information Clexane.https://www.mimsonline.com.auDate: 2012Google Scholar]. A recent case report of enoxaparin overdose in an adult demonstrated non-linear pharmacokinetics, although protamine and recombinant Factor VIIa were used to control bleeding after 24 hours in this case [[15]Byrne M. Zumberg M. Intentional low-molecular-weight heparin overdose: a case report and review.Blood Coagul Fibrinolysis. 2012; 23: 772-774Crossref PubMed Scopus (12) Google Scholar].Enoxaparin use in children is a non-licensed indication, therefore there is no pediatric product information providing guidance in supratherapeutic dosing. In addition, there are no published guidelines or half-life calculations following overdose in children. Amongst reported cases of adult enoxaparin overdose, only one determined an approximate half-life (of 25 hours) [[15]Byrne M. Zumberg M. Intentional low-molecular-weight heparin overdose: a case report and review.Blood Coagul Fibrinolysis. 2012; 23: 772-774Crossref PubMed Scopus (12) Google Scholar].Pediatric dosing of enoxaparin has been extrapolated from adult populations and then further informed by a dose-finding study of 25 children [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Therapeutic doses recommended for neonates are 1.5 mg/kg/dose twice daily and 0.75 mg/kg/dose twice daily for prophylaxis under age 2 months [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 16Monagle P. Chalmers E. Chan A. deVeber G. Kirkham F. Massicotte P. et al.Antithrombotic Therapy in Neonates and Children*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2008; 133: 887S-968SCrossref PubMed Scopus (560) Google Scholar, 17Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar]. The dose administered in our patient was 10.3 mg/kg/dose, which is nearly 7 times the current standard therapeutic starting dose in neonates [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 3Monagle P. Newall F. Campbell J. Anticoagulation in neonates and children: Pitfalls and dilemmas.Blood Rev. 2010; 24: 151-162Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 18Malowany J.I. Monagle P. Knoppert D.C. Lee D.S.C. Wu J. McCusker P. et al.Enoxaparin for neonatal thrombosis: a call for a higher dose for neonates.Thromb Res. 2008; 122: 826-830Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 20O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar]. Neonatal patients may require doses higher than current recommended starting doses [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 5Ho S.H. Wu J.K. Hamilton D.P. Dix D.B. Wadsworth L.D. An assessment of published pediatric dosage guidelines for enoxaparin: a retrospective review.J Pediatr Hematol Oncol. 2004; 26: 561-566Crossref PubMed Scopus (38) Google Scholar, 17Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar, 19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar] as evidenced by more dose adjustments to achieve therapeutic anti-Xa levels [[5]Ho S.H. Wu J.K. Hamilton D.P. Dix D.B. Wadsworth L.D. An assessment of published pediatric dosage guidelines for enoxaparin: a retrospective review.J Pediatr Hematol Oncol. 2004; 26: 561-566Crossref PubMed Scopus (38) Google Scholar]. A recent pediatric study showed a 2-3 fold variation in individual dose requirements for low-molecular weight heparin in children ≤ 5 years of age [[17]Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar]. Randomized control trials in neonates and children are required to establish exact dosage requirements [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 3Monagle P. Newall F. Campbell J. Anticoagulation in neonates and children: Pitfalls and dilemmas.Blood Rev. 2010; 24: 151-162Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 17Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar, 18Malowany J.I. Monagle P. Knoppert D.C. Lee D.S.C. Wu J. McCusker P. et al.Enoxaparin for neonatal thrombosis: a call for a higher dose for neonates.Thromb Res. 2008; 122: 826-830Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar]. Age-dependent variation in pharmacokinetic parameters and in hemostatic function result in altered behaviour of enoxaparin in the neonatal population. Neonatal clearance (hepatic and renal) and volume of distribution alter with physiological maturation processes [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Neonates have physiologically lower anti-thrombin concentrations [[22]Monagle P. Ignjatovic V. Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas.Blood Rev. 2010; 24: 63-68Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar] which results in relative heparin resistance [[4]Payne J.H. Aspects of anticoagulation in children.Br J Haematol. 2010; 150: 259-277Crossref PubMed Scopus (31) Google Scholar]. Clinical correlation or significance of these differences is not well understood [[22]Monagle P. Ignjatovic V. Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas.Blood Rev. 2010; 24: 63-68Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar].Target anti-Xa levels are extrapolated from adult studies. There are few pediatric studies correlating enoxaparin dose and anti-Xa levels with clinical efficacy or adverse outcomes [20O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar, 23Revel-Vilk S. Sharathkumar A. Massicotte P. Marzinotto V. Daneman A. Dix D. 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; 2: 42-46Crossref PubMed Scopus (64) Google Scholar, 24Bontadelli J. Moeller A. Schmugge M. Schraner T. Kretschmar O. Bauersfeld U. et al.Enoxaparin therapy for arterial thrombosis in infants with congenital heart disease.Intensive Care Med. 2007; 33: 1978-1984Crossref PubMed Scopus (39) Google Scholar, 25Lulic-Botica M. Rajpurkar M. Sabo C. Tutag-Lehr V. Natarajan G. Fluctuations of anti-Xa concentrations during maintenance enoxaparin therapy for neonatal thrombosis.Acta Paediatr. 2012; 101: e147-e150Crossref PubMed Scopus (14) Google Scholar]. Recommended target anti-Xa levels for therapeutic enoxaparin are 0.5-1.0 Units/ml at 4-6 hours post-dose, and 0.1-0.3 Units/ml for prophylactic administration [[16]Monagle P. Chalmers E. Chan A. deVeber G. Kirkham F. Massicotte P. et al.Antithrombotic Therapy in Neonates and Children*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2008; 133: 887S-968SCrossref PubMed Scopus (560) Google Scholar]. The largest neonatal cohort studied used target anti-Xa levels of 0.5-1.0 Units/ml for therapeutic dosing and noted a complete thrombus resolution rate of 53% [[23]Revel-Vilk S. Sharathkumar A. Massicotte P. Marzinotto V. Daneman A. Dix D. 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; 2: 42-46Crossref PubMed Scopus (64) Google Scholar]. This is equivalent to studies in adults. O’Brien et al. found that most children are subtherapeutic at 12 hours post dose (anti-Xa level <0.5 Units/ml), and that levels are undetectable at 18 hours [[20]O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar]. The peak anti-Xa level in neonates 4 hours post dose was 0.58 Units/ml [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Therefore, if neonatal clearance is faster than older children, a level at 4-6 hours post dose may actually be after the peak onset of activity [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Neonates may also have a lower anti-Xa therapeutic index [[24]Bontadelli J. Moeller A. Schmugge M. Schraner T. Kretschmar O. Bauersfeld U. et al.Enoxaparin therapy for arterial thrombosis in infants with congenital heart disease.Intensive Care Med. 2007; 33: 1978-1984Crossref PubMed Scopus (39) Google Scholar].There is no clear correlation between anti-Xa levels and risk of bleeding. In adults, anti-Xa levels greater than 2 Units/mL correlate with an increased bleeding risk [[6]Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. Our patient had at least 13 hours with a significantly raised anti-Xa level >1, but without bleeding, despite the presence of an established cephalhematoma. Major bleeding was observed in neonates receiving secondary prophylaxis with enoxaparin, even when the anti-Xa level was in the therapeutic range (0.5-1.0 Units/ml) [19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar]. In addition, no major bleeding episodes were reported in several neonatal and pediatric studies when the anti-Xa level was greater than 1.0 IU/ml [19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 20O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar, 25Lulic-Botica M. Rajpurkar M. Sabo C. Tutag-Lehr V. Natarajan G. Fluctuations of anti-Xa concentrations during maintenance enoxaparin therapy for neonatal thrombosis.Acta Paediatr. 2012; 101: e147-e150Crossref PubMed Scopus (14) Google Scholar, 26Streif W. Goebel G. Chan A.K.C. Massicotte M.P. 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-F370Crossref PubMed Google Scholar, 27Malowany J.I. Knoppert D.C. Chan A.K.C. Pepelassis D. Lee D.S.C. Enoxaparin use in the neonatal intensive care unit: experience over 8 years.Pharmacotherapy. 2007; 27: 1263-1271Crossref PubMed Scopus (72) Google Scholar].The elevated APTT in this case was higher than expected, based on pooled plasma in vitro studies of enoxaparin in children [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar], and may reflect immaturity of the liver. The peak APTT in this case was 132.7 at hour +5.7 (INR 1.2, anti-Xa 3.16) and normalised at hour +38. We observed a transaminitis 5.7 hours post dose, which was still present one week later. There were no baseline liver function tests. Transaminitis is a potential common effect of enoxaparin [[11]Product Information Lovenox.http://products.sanofi.us/lovenox/lovenox.htmlDate: 2011Google Scholar]. Other common side effects such as bleeding, thrombocytopenia and gastrointestinal effects [[11]Product Information Lovenox.http://products.sanofi.us/lovenox/lovenox.htmlDate: 2011Google Scholar] were not noted in the case.Enoxaparin errors are potentially life-threatening. Unlike unfractionated heparin, protamine does not completely reverse low-molecular weight heparin [[28]Crowther M.A. Berry L.R. Monagle P.T. Chan A.K.C. Mechanisms responsible for the failure of protamine to inactivate low molecular weight heparin.Br J Haematol. 2002; 116: 178-186Crossref PubMed Scopus (165) Google Scholar]. Protamine use in pediatric populations has been described, using guidelines extrapolated from adult guidelines [[6]Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. The risk/benefit ratio for protamine administration needs to be considered, as it has a narrow therapeutic range [[28]Crowther M.A. Berry L.R. Monagle P.T. Chan A.K.C. Mechanisms responsible for the failure of protamine to inactivate low molecular weight heparin.Br J Haematol. 2002; 116: 178-186Crossref PubMed Scopus (165) Google Scholar] and its use in children in this scenario is off-label [[29]Product Information Protamine Sulphate.http://www.medicines.ie/medicine/12799/SPC/Protamine+sulphate+LEO+PharmaDate: 2010Google Scholar]. Possible protamine side-effects include bleeding, cardiovascular instability, QT prolongation and anaphylactic reactions [[29]Product Information Protamine Sulphate.http://www.medicines.ie/medicine/12799/SPC/Protamine+sulphate+LEO+PharmaDate: 2010Google Scholar]. Alternatives to protamine are recombinant VIIa (“Novoseven”) [[30]Vavra K.A. Lutz M.F. Smythe M.A. Recombinant factor VIIa to manage major bleeding from newer parenteral anticoagulants.Ann Pharmacother. 2010; 44: 718-726Crossref PubMed Scopus (31) Google Scholar] fresh frozen plasma (FFP), and cryoprecipitate [[31]Monte A.A. Bodmer M. Schaeffer T.H. Low-molecular-weight heparin overdose: Management by observation.Ann Pharmacother. 2010; 44: 1836-1839Crossref PubMed Scopus (16) Google Scholar]. Wiernikowski et al. reported a 40 mg (ten–times enoxaparin overdose) in an ex-preterm neonate being treated for superior vena cava thrombosis, nearly 2 months after starting therapy. They used protamine in small aliquots, and a total protamine dose of 35 mg was given without adverse event. The anti-Xa level at hour +4 was 3.8 units/ml, and fell gradually to <1.0 units/ml at hour +12 with protamine use. A drug half-life could not be derived in the patient reported by Wiernikowski as the patient received protamine [[6]Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. Our case had an anti-Xa level of 3.16 at hour +5.7 and 1.43 at hour +13, without use of protamine. Another case of a 100-times overdose has been reported, without adverse consequences to the pre-term neonate [[7]Volz S. Schinzel H. Keune N. Neukirch M. Schmidtke S. Stopfkuchen H. Low Molecular Heparin for Treatment of Venous Thrombosis in Two Very Low-Birth-Weight Pre-Term Infants with Genetic Risk Factors.Klin Padiatr. 2006; 218: 226-229Crossref PubMed Scopus (2) Google Scholar].To our knowledge, this is the first reported case of supratherapeutic enoxaparin administration in a term neonate that has allowed half-life determination. Age-related variations make it difficult to confirm a pharmacokinetic model for enoxaparin. In our case, we found a trend towards non-linear pharmacokinetics. In term neonates, with no other significant comorbidities or presence of bleeding, clinical and laboratory monitoring may be a safe management option.Conflict of interestNone declared. Enoxaparin is frequently used now in pediatric and neonatal care due to an increase in invasive procedures with secondary thrombotic episodes [[1]Nowak-Gottl U. Kosch A. Schlegel N. Thromboembolism in newborns, infants and children.Thromb Haemost. 2001; 86: 464-474PubMed Google Scholar]. The two peaks of enoxaparin use in pediatrics are in newborns and adolescents [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 3Monagle P. Newall F. Campbell J. Anticoagulation in neonates and children: Pitfalls and dilemmas.Blood Rev. 2010; 24: 151-162Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 4Payne J.H. Aspects of anticoagulation in children.Br J Haematol. 2010; 150: 259-277Crossref PubMed Scopus (31) Google Scholar]. Enoxaparin is easier to monitor than standard unfractionated heparin [[5]Ho S.H. Wu J.K. Hamilton D.P. Dix D.B. Wadsworth L.D. An assessment of published pediatric dosage guidelines for enoxaparin: a retrospective review.J Pediatr Hematol Oncol. 2004; 26: 561-566Crossref PubMed Scopus (38) Google Scholar] but little is known about neonatal enoxaparin pharmacokinetics, dosing and target anti-Xa levels specific to neonates. Knowledge about pharmacokinetics in neonatal overdose is more limited [6Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 7Volz S. Schinzel H. Keune N. Neukirch M. Schmidtke S. Stopfkuchen H. Low Molecular Heparin for Treatment of Venous Thrombosis in Two Very Low-Birth-Weight Pre-Term Infants with Genetic Risk Factors.Klin Padiatr. 2006; 218: 226-229Crossref PubMed Scopus (2) Google Scholar]. Neonates are a vulnerable group for medication drug errors [[8]Fortescue E.B. Kaushal R. Landrigan C.P. McKenna K.J. Clapp M.D. Federico F. et al.Prioritizing strategies for preventing medication errors and adverse drug events in pediatric inpatients.Pediatrics. 2003; 111: 722-729Crossref PubMed Scopus (340) Google Scholar]. There is a large potential for enoxaparin overdose in neonates, as dilutions and smaller volumes can lead to mistakes [[9]Bauman M.E. Black K.L. Bauman M.L. Belletrutti M. Bajzar L. Massicotte M.P. Novel uses of insulin syringes to reduce dosing errors: A retrospective chart review of enoxaparin whole milligram dosing.Thromb Res. 2009; 123: 845-847Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. We report a case of a newborn given an accidental supratherapeutic dose of enoxaparin, which permitted calculation of a half-life of the agent in the neonate. A healthy 3.865 kg, term female neonate, born by Ventouse-assisted delivery, received a supratherapeutic dose of enoxaparin of 40 mg in error. The enoxaparin dose was intended for the infant’s mother, but was mistaken for a drawn-up vial of hepatitis B vaccine and administered subcutaneously to the neonate. A cephalhematoma was present after birth, prior to enoxaparin administration. No bleeding was noted subsequent to the dosing. Serial anti-Xa levels, coagulation and full blood count studies were performed. The anti-Xa level at hour +5.70 was 3.16 units/ml (U/ml) with an APTT of 132 seconds. Decision regarding management was complicated by the presence of the scalp cephalhematoma. A decision was made not to give protamine as it was felt that there was insufficient safety data for protamine use in neonates, and reports of cardiovascular side effects [[10]Pugsley M.K. Kalra V. Froebel-Wilson S. Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle.Life Sci. 2002; 72: 293-305Crossref PubMed Scopus (21) Google Scholar]. At hour +13, the anti-Xa level was 1.43 and at hour +38 was 0.10, with a normalised APTT of 35.8 at hour +38. A mild transaminitis (GGT 341U/L, ALT 53U/L, AST 96U/L, normal ALP 185U/L) was noted post-enoxaparin administration. The mild transaminitis was still present one week later. The baby remained well. Using observed data from this patient, pharmacokinetic parameters for neonatal enoxaparin metabolism following a supratherapeutic dose were derived (Fig. 1). The calculated elimination half-life was 4.8 hours, using a one-compartment model with non-linear kinetics. Limited time points do not permit further pharmacokinetic analysis. The half-life of 4.8 hours derived in our patient following supratherapeutic dosing is consistent with the half-life of enoxaparin in adults (for therapeutic dosing), which is 4.5 hours after a single subcutaneous dose of 40 mg and about 7 hours for repeated dosing [[11]Product Information Lovenox.http://products.sanofi.us/lovenox/lovenox.htmlDate: 2011Google Scholar]. One-compartment [[12]Dunaway K.K. Gal P. Ransom J.L. Use of enoxaparin in a preterm infant.Ann Pharmacother. 2000; 34: 1410-1413Crossref PubMed Google Scholar] and two-compartment models [[13]Trame M.N. Mitchell L. Krumpel A. Male C. Hempel G. Nowak-Gottll U. Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study.J Thromb Haemost. 2010; 8: 1950-1958Crossref PubMed Scopus (45) Google Scholar] have both been used to describe enoxaparin pharmacokinetics in children. A one-compartment model in a preterm infant was used to derive a half-life of 4 hours [[12]Dunaway K.K. Gal P. Ransom J.L. Use of enoxaparin in a preterm infant.Ann Pharmacother. 2000; 34: 1410-1413Crossref PubMed Google Scholar]. A two-compartment model with linear kinetics is described in enoxaparin product information for adults when doses in the higher end (73.8-132 mg/dose) of the therapeutic range are administered [[14]MIMS Online Product Information Clexane.https://www.mimsonline.com.auDate: 2012Google Scholar]. A recent case report of enoxaparin overdose in an adult demonstrated non-linear pharmacokinetics, although protamine and recombinant Factor VIIa were used to control bleeding after 24 hours in this case [[15]Byrne M. Zumberg M. Intentional low-molecular-weight heparin overdose: a case report and review.Blood Coagul Fibrinolysis. 2012; 23: 772-774Crossref PubMed Scopus (12) Google Scholar]. Enoxaparin use in children is a non-licensed indication, therefore there is no pediatric product information providing guidance in supratherapeutic dosing. In addition, there are no published guidelines or half-life calculations following overdose in children. Amongst reported cases of adult enoxaparin overdose, only one determined an approximate half-life (of 25 hours) [[15]Byrne M. Zumberg M. Intentional low-molecular-weight heparin overdose: a case report and review.Blood Coagul Fibrinolysis. 2012; 23: 772-774Crossref PubMed Scopus (12) Google Scholar]. Pediatric dosing of enoxaparin has been extrapolated from adult populations and then further informed by a dose-finding study of 25 children [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Therapeutic doses recommended for neonates are 1.5 mg/kg/dose twice daily and 0.75 mg/kg/dose twice daily for prophylaxis under age 2 months [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 16Monagle P. Chalmers E. Chan A. deVeber G. Kirkham F. Massicotte P. et al.Antithrombotic Therapy in Neonates and Children*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2008; 133: 887S-968SCrossref PubMed Scopus (560) Google Scholar, 17Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar]. The dose administered in our patient was 10.3 mg/kg/dose, which is nearly 7 times the current standard therapeutic starting dose in neonates [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 3Monagle P. Newall F. Campbell J. Anticoagulation in neonates and children: Pitfalls and dilemmas.Blood Rev. 2010; 24: 151-162Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 18Malowany J.I. Monagle P. Knoppert D.C. Lee D.S.C. Wu J. McCusker P. et al.Enoxaparin for neonatal thrombosis: a call for a higher dose for neonates.Thromb Res. 2008; 122: 826-830Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 20O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar]. Neonatal patients may require doses higher than current recommended starting doses [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 5Ho S.H. Wu J.K. Hamilton D.P. Dix D.B. Wadsworth L.D. An assessment of published pediatric dosage guidelines for enoxaparin: a retrospective review.J Pediatr Hematol Oncol. 2004; 26: 561-566Crossref PubMed Scopus (38) Google Scholar, 17Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar, 19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar] as evidenced by more dose adjustments to achieve therapeutic anti-Xa levels [[5]Ho S.H. Wu J.K. Hamilton D.P. Dix D.B. Wadsworth L.D. An assessment of published pediatric dosage guidelines for enoxaparin: a retrospective review.J Pediatr Hematol Oncol. 2004; 26: 561-566Crossref PubMed Scopus (38) Google Scholar]. A recent pediatric study showed a 2-3 fold variation in individual dose requirements for low-molecular weight heparin in children ≤ 5 years of age [[17]Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar]. Randomized control trials in neonates and children are required to establish exact dosage requirements [2Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 3Monagle P. Newall F. Campbell J. Anticoagulation in neonates and children: Pitfalls and dilemmas.Blood Rev. 2010; 24: 151-162Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 17Ignjatovic V. Najid S. Newall F. Summerhayes R. Monagle P. Dosing and monitoring of enoxaparin (Low molecular weight heparin) therapy in children.Br J Haematol. 2010; 149: 734-738Crossref PubMed Scopus (62) Google Scholar, 18Malowany J.I. Monagle P. Knoppert D.C. Lee D.S.C. Wu J. McCusker P. et al.Enoxaparin for neonatal thrombosis: a call for a higher dose for neonates.Thromb Res. 2008; 122: 826-830Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar]. Age-dependent variation in pharmacokinetic parameters and in hemostatic function result in altered behaviour of enoxaparin in the neonatal population. Neonatal clearance (hepatic and renal) and volume of distribution alter with physiological maturation processes [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Neonates have physiologically lower anti-thrombin concentrations [[22]Monagle P. Ignjatovic V. Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas.Blood Rev. 2010; 24: 63-68Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar] which results in relative heparin resistance [[4]Payne J.H. Aspects of anticoagulation in children.Br J Haematol. 2010; 150: 259-277Crossref PubMed Scopus (31) Google Scholar]. Clinical correlation or significance of these differences is not well understood [[22]Monagle P. Ignjatovic V. Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas.Blood Rev. 2010; 24: 63-68Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. Target anti-Xa levels are extrapolated from adult studies. There are few pediatric studies correlating enoxaparin dose and anti-Xa levels with clinical efficacy or adverse outcomes [20O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar, 23Revel-Vilk S. Sharathkumar A. Massicotte P. Marzinotto V. Daneman A. Dix D. 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; 2: 42-46Crossref PubMed Scopus (64) Google Scholar, 24Bontadelli J. Moeller A. Schmugge M. Schraner T. Kretschmar O. Bauersfeld U. et al.Enoxaparin therapy for arterial thrombosis in infants with congenital heart disease.Intensive Care Med. 2007; 33: 1978-1984Crossref PubMed Scopus (39) Google Scholar, 25Lulic-Botica M. Rajpurkar M. Sabo C. Tutag-Lehr V. Natarajan G. Fluctuations of anti-Xa concentrations during maintenance enoxaparin therapy for neonatal thrombosis.Acta Paediatr. 2012; 101: e147-e150Crossref PubMed Scopus (14) Google Scholar]. Recommended target anti-Xa levels for therapeutic enoxaparin are 0.5-1.0 Units/ml at 4-6 hours post-dose, and 0.1-0.3 Units/ml for prophylactic administration [[16]Monagle P. Chalmers E. Chan A. deVeber G. Kirkham F. Massicotte P. et al.Antithrombotic Therapy in Neonates and Children*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest. 2008; 133: 887S-968SCrossref PubMed Scopus (560) Google Scholar]. The largest neonatal cohort studied used target anti-Xa levels of 0.5-1.0 Units/ml for therapeutic dosing and noted a complete thrombus resolution rate of 53% [[23]Revel-Vilk S. Sharathkumar A. Massicotte P. Marzinotto V. Daneman A. Dix D. 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; 2: 42-46Crossref PubMed Scopus (64) Google Scholar]. This is equivalent to studies in adults. O’Brien et al. found that most children are subtherapeutic at 12 hours post dose (anti-Xa level <0.5 Units/ml), and that levels are undetectable at 18 hours [[20]O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar]. The peak anti-Xa level in neonates 4 hours post dose was 0.58 Units/ml [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Therefore, if neonatal clearance is faster than older children, a level at 4-6 hours post dose may actually be after the peak onset of activity [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Neonates may also have a lower anti-Xa therapeutic index [[24]Bontadelli J. Moeller A. Schmugge M. Schraner T. Kretschmar O. Bauersfeld U. et al.Enoxaparin therapy for arterial thrombosis in infants with congenital heart disease.Intensive Care Med. 2007; 33: 1978-1984Crossref PubMed Scopus (39) Google Scholar]. There is no clear correlation between anti-Xa levels and risk of bleeding. In adults, anti-Xa levels greater than 2 Units/mL correlate with an increased bleeding risk [[6]Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. Our patient had at least 13 hours with a significantly raised anti-Xa level >1, but without bleeding, despite the presence of an established cephalhematoma. Major bleeding was observed in neonates receiving secondary prophylaxis with enoxaparin, even when the anti-Xa level was in the therapeutic range (0.5-1.0 Units/ml) [19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar]. In addition, no major bleeding episodes were reported in several neonatal and pediatric studies when the anti-Xa level was greater than 1.0 IU/ml [19Dix D. Andrew M. Marzinotto V. Charpentier K. Bridge S. Monagle P. et al.The use of low molecular weight heparin in pediatric patients: a prospective cohort study.J Pediatr. 2000; 136: 439-445Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 20O'Brien S.H. Lee H. Ritchey A.K. Once-daily enoxaparin in pediatric thromboembolism: a dose finding and pharmacodynamics/pharmacokinetics study.J Thromb Haemost. 2007; 5: 1985-1987Crossref PubMed Scopus (32) Google Scholar, 21Bauman M.E. Belletrutti M.J. Bajzar L. Black K.L. Kuhle S. Bauman M.L. et al.Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.Thromb Haemost. 2009; 101: 86-92PubMed Google Scholar, 25Lulic-Botica M. Rajpurkar M. Sabo C. Tutag-Lehr V. Natarajan G. Fluctuations of anti-Xa concentrations during maintenance enoxaparin therapy for neonatal thrombosis.Acta Paediatr. 2012; 101: e147-e150Crossref PubMed Scopus (14) Google Scholar, 26Streif W. Goebel G. Chan A.K.C. Massicotte M.P. 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-F370Crossref PubMed Google Scholar, 27Malowany J.I. Knoppert D.C. Chan A.K.C. Pepelassis D. Lee D.S.C. Enoxaparin use in the neonatal intensive care unit: experience over 8 years.Pharmacotherapy. 2007; 27: 1263-1271Crossref PubMed Scopus (72) Google Scholar]. The elevated APTT in this case was higher than expected, based on pooled plasma in vitro studies of enoxaparin in children [[2]Massicotte P. Adams M. Marzinotto V. Brooker L.A. Andrew M. Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.J Pediatr. 1996; 128: 313Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar], and may reflect immaturity of the liver. The peak APTT in this case was 132.7 at hour +5.7 (INR 1.2, anti-Xa 3.16) and normalised at hour +38. We observed a transaminitis 5.7 hours post dose, which was still present one week later. There were no baseline liver function tests. Transaminitis is a potential common effect of enoxaparin [[11]Product Information Lovenox.http://products.sanofi.us/lovenox/lovenox.htmlDate: 2011Google Scholar]. Other common side effects such as bleeding, thrombocytopenia and gastrointestinal effects [[11]Product Information Lovenox.http://products.sanofi.us/lovenox/lovenox.htmlDate: 2011Google Scholar] were not noted in the case. Enoxaparin errors are potentially life-threatening. Unlike unfractionated heparin, protamine does not completely reverse low-molecular weight heparin [[28]Crowther M.A. Berry L.R. Monagle P.T. Chan A.K.C. Mechanisms responsible for the failure of protamine to inactivate low molecular weight heparin.Br J Haematol. 2002; 116: 178-186Crossref PubMed Scopus (165) Google Scholar]. Protamine use in pediatric populations has been described, using guidelines extrapolated from adult guidelines [[6]Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. The risk/benefit ratio for protamine administration needs to be considered, as it has a narrow therapeutic range [[28]Crowther M.A. Berry L.R. Monagle P.T. Chan A.K.C. Mechanisms responsible for the failure of protamine to inactivate low molecular weight heparin.Br J Haematol. 2002; 116: 178-186Crossref PubMed Scopus (165) Google Scholar] and its use in children in this scenario is off-label [[29]Product Information Protamine Sulphate.http://www.medicines.ie/medicine/12799/SPC/Protamine+sulphate+LEO+PharmaDate: 2010Google Scholar]. Possible protamine side-effects include bleeding, cardiovascular instability, QT prolongation and anaphylactic reactions [[29]Product Information Protamine Sulphate.http://www.medicines.ie/medicine/12799/SPC/Protamine+sulphate+LEO+PharmaDate: 2010Google Scholar]. Alternatives to protamine are recombinant VIIa (“Novoseven”) [[30]Vavra K.A. Lutz M.F. Smythe M.A. Recombinant factor VIIa to manage major bleeding from newer parenteral anticoagulants.Ann Pharmacother. 2010; 44: 718-726Crossref PubMed Scopus (31) Google Scholar] fresh frozen plasma (FFP), and cryoprecipitate [[31]Monte A.A. Bodmer M. Schaeffer T.H. Low-molecular-weight heparin overdose: Management by observation.Ann Pharmacother. 2010; 44: 1836-1839Crossref PubMed Scopus (16) Google Scholar]. Wiernikowski et al. reported a 40 mg (ten–times enoxaparin overdose) in an ex-preterm neonate being treated for superior vena cava thrombosis, nearly 2 months after starting therapy. They used protamine in small aliquots, and a total protamine dose of 35 mg was given without adverse event. The anti-Xa level at hour +4 was 3.8 units/ml, and fell gradually to <1.0 units/ml at hour +12 with protamine use. A drug half-life could not be derived in the patient reported by Wiernikowski as the patient received protamine [[6]Wiernikowski J.T. Chan A.K.C. Lo G. Reversal of anti-thrombin activity using protamine sulfate. Experience in a neonate with 10-fold overdose of enoxaparin.Thromb Res. 2007; 120: 303-305Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. Our case had an anti-Xa level of 3.16 at hour +5.7 and 1.43 at hour +13, without use of protamine. Another case of a 100-times overdose has been reported, without adverse consequences to the pre-term neonate [[7]Volz S. Schinzel H. Keune N. Neukirch M. Schmidtke S. Stopfkuchen H. Low Molecular Heparin for Treatment of Venous Thrombosis in Two Very Low-Birth-Weight Pre-Term Infants with Genetic Risk Factors.Klin Padiatr. 2006; 218: 226-229Crossref PubMed Scopus (2) Google Scholar]. To our knowledge, this is the first reported case of supratherapeutic enoxaparin administration in a term neonate that has allowed half-life determination. Age-related variations make it difficult to confirm a pharmacokinetic model for enoxaparin. In our case, we found a trend towards non-linear pharmacokinetics. In term neonates, with no other significant comorbidities or presence of bleeding, clinical and laboratory monitoring may be a safe management option. Conflict of interestNone declared. None declared. Personal communication with Dr Anthony Chan (1800-No Clots service) assisted safe decision-making in our reported case. Thank you to Professor Andrew McLachlan (BPharm PhD), University of Sydney, for his help with data analysis." @default.
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W2050997077 title "Pharmacokinetic analysis of enoxaparin in a term neonate and review of literature" @default.
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W2050997077 cites W1545662671 @default.
W2050997077 cites W1569239833 @default.
W2050997077 cites W1577721739 @default.
W2050997077 cites W1976249987 @default.
W2050997077 cites W1982028161 @default.
W2050997077 cites W2007428852 @default.
W2050997077 cites W2015275814 @default.
W2050997077 cites W2032757997 @default.
W2050997077 cites W2042052132 @default.
W2050997077 cites W2043765279 @default.
W2050997077 cites W2044866522 @default.
W2050997077 cites W2056646475 @default.
W2050997077 cites W2064827504 @default.
W2050997077 cites W2067353872 @default.
W2050997077 cites W2071896716 @default.
W2050997077 cites W2076592624 @default.
W2050997077 cites W2096610078 @default.
W2050997077 cites W2098266168 @default.
W2050997077 cites W2100610911 @default.
W2050997077 cites W2108043885 @default.
W2050997077 cites W2132950616 @default.
W2050997077 cites W2144575923 @default.
W2050997077 cites W2146288546 @default.
W2050997077 cites W2166137806 @default.
W2050997077 cites W2409911587 @default.
W2050997077 cites W4249969546 @default.
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