Download PDF
Semin Thromb Hemost 2011; 37(7): 814-825
DOI: 10.1055/s-0031-1297173
© Thieme Medical Publishers

Safety and Efficacy of Low Molecular Weight Heparins in Children: A Systematic Review of the Literature and Meta-Analysis of Single-Arm Studies

Christoph Bidlingmaier1 , Gili Kenet2 , Karin Kurnik1 , Prasad Mathew3 , Daniela Manner4 , Lesley Mitchell5 , Anne Krümpel6 , Ulrike Nowak-Göttl4
  • 1Department of Thrombosis and Hemostasis, Dr. von Hauner's Children's Hospital, University Children's Hospital, Munich, Germany
  • 2Pediatric Coagulation Service, National Hemophilia Centre and Institute of Thrombosis and Hemostasis Sheba Medical Centre, Tel-Hashomer, Israel
  • 3Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico
  • 4Centre for Thrombosis and Hemostasis, Institute for Clinical Chemistry, University of Kiel, Kiel, Germany
  • 5Stollery Children's Hospital, University of Alberta, Edmonton AB, Canada
  • 6Department of Pediatric Hematology/Oncology, University Children's Hospital, University of Münster, Germany
Further Information

Publication History

Publication Date:
20 December 2011 (online)

    Permissions and Reprints

ABSTRACT

Within the last two decades low molecular weight heparins (LMWH) have gained increasing widespread use as anticoagulants in children. The use of LMWH has been implemented into clinical care even though there is a lack of firm evidence on the efficacy and safety of LMWH in this population due to the absence of sufficiently powered randomized controlled trials. In the absence of clinical trials, we performed a meta-analysis of available single-arm studies using LMWH in children. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1980 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients, ethnicity, venous thromboembolic events type, and frequency of recurrence and major bleedings were abstracted. Pooled incidence rates (IR) including 95% confidence intervals (95% CIs) on efficacy and safety data of LMWH administration on primary prophylaxis, as well as on secondary prophylaxis in children following symptomatic thromboembolism (TE) were shown. We included 2251 pediatric patients derived from 35 single-arm studies from 12 study countries who were eligible for analysis in the present systematic review. Pooled incidence rates (95% CI) to develop first TE on primary prophylaxis, further TE event on LMWH secondary prophylaxis, or a major bleeding event on LMWH were 0.047 (0.023 to 0.091), 0.052 (0.037 to 0.073) for efficacy, and 0.054 (0.039 to 0.074) for safety (treatment data only), respectively. Efficacy and safety data are comparable with adult data. The present systematic review suggests that use of LMWH in children as primary prophylaxis and in treatment of symptomatic thrombosis is effective and safe. However, properly designed randomized controlled trials are needed.

KEYWORDS

Low molecular weight heparin - pediatric thrombosis - children - safety and efficacy

REFERENCES

  • 1 Andrew M. Developmental hemostasis: relevance to thromboembolic complications in pediatric patients.  Thromb Haemost. 1995;  74 (1) 415-425
    Google Scholar
  • 2 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood.  Blood. 1992;  80 (8) 1998-2005
    Google Scholar
  • 3 Nowak-Göttl U, Kosch A, Schlegel N. Thromboembolism in newborns, infants and children.  Thromb Haemost. 2001;  86 (1) 464-474
    Google Scholar
  • 4 Nowak-Göttl U, Kurnik K, Krümpel A, Stoll M. Thrombophilia in the young.  Hamostaseologie. 2008;  28 (1–2) 16-20
    Google Scholar
  • 5 Albisetti M, Andrew M. Low molecular weight heparin in children.  Eur J Pediatr. 2002;  161 (2) 71-77
    Google Scholar
  • 6 Monagle P, Chalmers E, Chan A American College of Chest Physicians et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 (6, Suppl) 887S-968S
    Google Scholar
  • 7 Nowak-Göttl U, Bidlingmaier C, Krümpel A, Göttl L, Kenet G. Pharmacokinetics, efficacy, and safety of LMWHs in venous thrombosis and stroke in neonates, infants and children.  Br J Pharmacol. 2008;  153 (6) 1120-1127
    Google Scholar
  • 8 Vandenbroucke J P, von Elm E, Altman D G STROBE initiative et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration.  Ann Intern Med. 2007;  147 (8) W163–94
    Google Scholar
  • 9 Laird N M, Mosteller F. Some statistical methods for combining experimental results.  Int J Technol Assess Health Care. 1990;  6 (1) 5-30
    Google Scholar
  • 10 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 (3) 313-318
    Google Scholar
  • 11 Punzalan R C, Hillery C A, Montgomery R R, Scott C A, Gill J C. Low-molecular-weight heparin in thrombotic disease in children and adolescents.  J Pediatr Hematol Oncol. 2000;  22 (2) 137-142
    Google Scholar
  • 12 Massicotte P, Julian J A, Marzinotto V et al.. Dose-finding and pharmacokinetic profiles of prophylactic doses of a low molecular weight heparin (reviparin-sodium) in pediatric patients.  Thromb Res. 2003a;  109 (2–3) 93-99
    Google Scholar
  • 13 Laporte S, Mismetti P, Piquet P, Doubine S, Touchot A, Decousus H. Population pharmacokinetic of nadroparin calcium (Fraxiparine) in children hospitalised for open heart surgery.  Eur J Pharm Sci. 1999;  8 (2) 119-125
    Google Scholar
  • 14 Kuhle S, Massicotte P, Dinyari M et al.. Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events.  Thromb Haemost. 2005;  94 (6) 1164-1171
    Google Scholar
  • 15 Trame M N, Mitchell L, Krümpel A, Male C, Hempel G, Nowak-Göttl U. Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study.  J Thromb Haemost. 2010;  8 (9) 1950-1958
    Google Scholar
  • 16 Broyer M, Gagnadoux M F, Sierro A et al.. [Prevention of vascular thromboses after renal transplantation using low molecular weight heparin].  Ann Pediatr (Paris). 1991;  38 (6) 397-399
    Google Scholar
  • 17 Nohe N, Flemmer A, Rümler R, Praun M, Auberger K. The low molecular weight heparin dalteparin for prophylaxis and therapy of thrombosis in childhood: a report on 48 cases.  Eur J Pediatr. 1999;  158 (Suppl 3) S134-S139
    Google Scholar
  • 18 Elhasid R, Lanir N, Sharon R et al.. Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia.  Blood Coagul Fibrinolysis. 2001;  12 (5) 367-370
    Google Scholar
  • 19 Hofmann S, Knoefler R, Lorenz N et al.. Clinical experiences with low-molecular weight heparins in pediatric patients.  Thromb Res. 2001;  103 (5) 345-353
    Google Scholar
  • 20 Massicotte P, Julian J A, Gent M PROTEKT Study Group et al. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial.  Thromb Res. 2003b;  109 (2–3) 101-108
    Google Scholar
  • 21 Meister B, Kropshofer G, Klein-Franke A, Strasak A M, Hager J, Streif W. Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia.  Pediatr Blood Cancer. 2008;  50 (2) 298-303
    Google Scholar
  • 22 Mitchell L, Lambers M, Flege S et al.. Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study.  Blood. 2010;  115 (24) 4999-5004
    Google Scholar
  • 23 Harlev D, Zaidman I, Sarig G, Ben Arush M W, Brenner B, Elhasid R. Prophylactic therapy with enoxaparin in children with acute lymphoblastic leukemia and inherited thrombophilia during L-asparaginase treatment.  Thromb Res. 2010;  126 (2) 93-97
    Google Scholar
  • 24 deVeber G, Chan A, Monagle P et al.. Anticoagulation therapy in pediatric patients with sinovenous thrombosis: a cohort study.  Arch Neurol. 1998;  55 (12) 1533-1537
    Google Scholar
  • 25 deVeber G, Andrew M, Adams C et al.. Canadian Pediatric Ischemic Stroke Group. Cerebral sinovenous thrombosis in children.  N Engl J Med. 2001;  345 417-423
    Google Scholar
  • 26 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 (4) 439-445
    Google Scholar
  • 27 Massicotte P, Julian J A, Gent M REVIVE Study Group 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. 2003c;  109 (2–3) 85-92
    Google Scholar
  • 28 Streif W, Goebel G, Chan AKC, 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 (5) F365-F370
    Google Scholar
  • 29 Michaels L A, Gurian M, Hegyi T, Drachtman R A. Low molecular weight heparin in the treatment of venous and arterial thromboses in the premature infant.  Pediatrics. 2004;  114 (3) 703-707
    Google Scholar
  • 30 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;  2 (1) 42-46
    Google Scholar
  • 31 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 (9) 561-566
    Google Scholar
  • 32 Schobess R, Düring C, Bidlingmaier C, Heinecke A, Merkel N, Nowak-Göttl U. Long-term safety and efficacy data on childhood venous thrombosis treated with a low molecular weight heparin: an open-label pilot study of once-daily versus twice-daily enoxaparin administration.  Haematologica. 2006;  91 (12) 1701-1704
    Google Scholar
  • 33 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 (9) 1985-1987
    Google Scholar
  • 34 Malowany J I, Knoppert D C, Chan A K, Pepelassis D, Lee D S. Enoxaparin use in the neonatal intensive care unit: experience over 8 years.  Pharmacotherapy. 2007;  27 (9) 1263-1271
    Google Scholar
  • 35 Kenet G, Kirkham F, Niederstadt T European Thromboses Study Group et al. Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study.  Lancet Neurol. 2007;  6 (7) 595-603
    Google Scholar
  • 36 van Ommen C H, van den Dool E J, Peters M. Nadroparin therapy in pediatric patients with venous thromboembolic disease.  J Pediatr Hematol Oncol. 2008;  30 (3) 230-234
    Google Scholar
  • 37 Sandoval J A, Sheehan M P, Stonerock C E, Shafique S, Rescorla F J, Dalsing M C. Incidence, risk factors, and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk.  J Vasc Surg. 2008;  47 (4) 837-843
    Google Scholar
  • 38 Tousovska K, Zapletal O, Skotakova J, Bukac J, Sterba J. Treatment of deep venous thrombosis with low molecular weight heparin in pediatric cancer patients: safety and efficacy.  Blood Coagul Fibrinolysis. 2009;  20 (7) 583-589
    Google Scholar
  • 39 Cavo M, Wang W, O'Brien S H. Use of low molecular weight heparin for thromboprophylaxis in a pediatric inpatient population: reasons for use and incidence of bleeding complications.  Thromb Res. 2010;  125 (4) 370-372
    Google Scholar
  • 40 Moharir M D, Shroff M, Stephens D et al.. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study.  Ann Neurol. 2010;  67 (5) 590-599
    Google Scholar
  • 41 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 (5) 734-738
    Google Scholar
  • 42 Qureshi A, Mitchell C, Richards S, Vora A, Goulden N. Asparaginase-related venous thrombosis in UKALL 2003- re-exposure to asparaginase is feasible and safe.  Br J Haematol. 2010;  149 (3) 410-413
    Google Scholar
  • 43 Sträter R, Kurnik K, Heller C, Schobess R, Luigs P, Nowak-Göttl U. Aspirin versus low-dose low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study.  Stroke. 2001;  32 (11) 2554-2558
    Google Scholar
  • 44 Burak C R, Bowen M D, Barron T F. The use of enoxaparin in children with acute, nonhemorrhagic ischemic stroke.  Pediatr Neurol. 2003;  29 (4) 295-298
    Google Scholar
  • 45 Bontadelli J, Moeller A, Schmugge M et al.. Enoxaparin therapy for arterial thrombosis in infants with congenital heart disease.  Intensive Care Med. 2007;  33 (11) 1978-1984
    Google Scholar
  • 46 Couturaud F, Julian J A, Kearon C. Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis.  Thromb Haemost. 2001;  86 (4) 980-984
    Google Scholar
  • 47 Merli G, Spiro T E, Olsson C G Enoxaparin Clinical Trial Group et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.  Ann Intern Med. 2001;  134 (3) 191-202
    Google Scholar
  • 48 Crary S E, Van Orden H, Journeycake J M. Experience with intravenous enoxaparin in critically ill infants and children.  Pediatr Crit Care Med. 2008;  9 (6) 647-649
    Google Scholar
  • 49 Blatný J, Fiamoli V. Treatment of deep vein thrombosis with continuous intravenous infusion of LMWH in children—an alternative to subcutaneous application when needed.  Vnitr Lek. 2009;  55 (3) 227-232
    Google Scholar
  • 50 Sharathkumar A, Hirschl R, Pipe S, Crandell C, Adams B, Lin J J. Primary thromboprophylaxis with heparins for arteriovenous fistula failure in pediatric patients.  J Vasc Access. 2007;  8 (4) 235-244
    Google Scholar
  • 51 Greaves M. Control of Anticoagulation Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis . Limitations of the laboratory monitoring of heparin therapy. Scientific and Standardization Committee Communications: on behalf of the Control of Anticoagulation Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis.  Thromb Haemost. 2002;  87 (1) 163-164
    Google Scholar
  • 52 Shojania A M. More on: is laboratory monitoring of low-molecular-weight heparin necessary?.  J Thromb Haemost. 2004;  2 (12) 2276-2277
    Google Scholar
  • 53 Bauman M E, Belletrutti M J, Bajzar L et al.. Evaluation of enoxaparin dosing requirements in infants and children. Better dosing to achieve therapeutic levels.  Thromb Haemost. 2009;  101 (1) 86-92
    Google Scholar

Christoph BidlingmaierM.D. 

Department of Thrombosis and Hemostasis, Dr. von Hauner's Children's Hospital

University Hospital, Lindwurmstr. 4, 80337 Munich

Email: christoph.bidlingmaier@med.uni-muenchen.de

      >