Low-molecular-weight heparin in pediatric patients with thrombotic disease: A dose finding study,☆☆,,★★

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Abstract

OBJECTIVE: To compare low-molecular-weight preparations of heparin (LMWH) with standard heparin in children requiring anticoagulant treatment for thromboembolic disease. METHODS: We treated 25 children who required heparin, but were at significant risk of bleeding, with LMWH (enoxaparin, Rhone-Poulenc Rorer). The median age was 4 years (range, newborn to 17 years), with nine infants less than 2 months of age. Fourteen children had a deep vein thrombosis or pulmonary embolism, nine had thrombotic complications in the central nervous system, and two had complex congenital heart disease, for which they received prophylaxis at a lower dosage (0.5 mg/kg given subcutaneously twice a day). The remaining 23 children received an initial dose of 1 mg/kg, every 12 hours subcutaneously, with subsequent doses adjusted to achieve a 4-hour anti-factor Xa level between 0.5 and 1.0 unit/ml. RESULTS: Newborn infants had increased dose requirements; an average of 1.60 units/kg was required to achieve therapeutic heparin levels. For the remaining children, the initial dose of 1.0 mg/kg was sufficient. After the initial dose adjustment, LMWH was administered with twice-weekly monitoring. The median duration of therapy with LMWH was 14 days. Two children with previously documented gastrointestinal ulcers bled and required transfusion therapy. Therapy with LMWH was continued without further events. There were no new thrombotic events during the treatment with LMWH. The cost of administering LMWH compared with heparin was reduced by 30% because of decreased laboratory monitoring, blood sampling times, intravenous starts, and nursing time. Needle punctures were reduced with LMWH therapy by the placement of a subcutaneous catheter. CONCLUSION: These results provide the basis for a randomized, controlled trial comparing LMWH with standard heparin in pediatric patients. (J PEDIATR 1996; 128:313-8)

Section snippets

Patient population

From January to December 1994, consecutive pediatric patients from two institutions, the Hospital for Sick Children, Toronto, Canada, and the Children's Hospital at Chedoke/McMaster University Medical Centre, were eligible to receive LMWH if they required anticoagulation therapy but had an increased risk of bleeding with standard heparin. Many children also had limited venous access for administering and monitoring heparin.

Radiologic evaluation

All pediatric patients with suspected deep vein thrombosis, pulmonary

Patient population

Twenty-five consecutive pediatric patients were treated with LMWH; 14 were female. The underlying disorders were cancer (4 patients), infection (3), surgery or other trauma (5), systemic lupus erythematosus (2), Wegener granulomatosis (2), nephrosis (3), congenital heart disease (3), and dehydration (3). Nine patients were less than 2 months of age.

Indications for LMWH therapy

All 25 children received LMWH because their responsible physician assessed the risk of bleeding with standard heparin as excessive or because they

DISCUSSION

Thromboembolic complications are one of the most serious new complications of tertiary care in children.15, 16, 17, 18, 19, 20 Our results show that LMWH is easily administered to children, the dose is age dependent, and the pharmacokinetics are reproducible; minimal monitoring is required. A randomized, controlled trial comparing standard heparin with LMWH to determine safety and efficacy is justified by the results of our study.

The LMWHs are prepared by a variety of methods, including

Acknowledgements

We acknowledge the technical assistance of Mrs. P. Vegh and Mrs. L. Brooker.

References (53)

  • DA Lane et al.

    Molecular weight dependence of the anticoagulant properties of heparin: intravenous and subcutaneous administration of fractionated heparins to man

    Thromb Res

    (1979)
  • M Palm et al.

    Pharmacokinetics of Fragmin: a comparative study in the rabbit of its high and low affinity forms for antithrombin

    Thromb Res

    (1987)
  • CJ Carter et al.

    The relationship between the hemorrhagic and antithrombotic properties of a low molecular weight heparin in rabbits

    Blood

    (1982)
  • P Hartl et al.

    Prophylaxis of thromboembolism in general surgery: comparison between standard heparin and Fragmin

    Thromb Res

    (1990)
  • M Andrew et al.

    The use of heparin in newborn infants

    Semin Thromb Haemost

    (1988)
  • MM McDonald et al.

    Anticoagulant therapy by continuous heparinization in newborn and older infants

    J PEDIATR

    (1982)
  • M Andrew et al.

    Heparin therapy in pediatric patients: a prospective cohort study

    Pediatr Res

    (1994)
  • MM McDonald et al.

    Heparin clearance in the newborn

    Pediatr Res

    (1981)
  • S Turner Gomes et al.

    Heparin is cleared faster in children with congenital heart disease than adults

    J Am Coll Cardiol

    (1993)
  • RD Hull et al.

    Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis

    N Engl J Med

    (1992)
  • G Simmoneau et al.

    Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis

    Arch Intern Med

    (1993)
  • MK Cruickshank et al.

    A standard heparin nomogram for the management of heparin therapy

    Arch Intern Med

    (1991)
  • DR Barnard et al.

    Coagulation studies in extremely premature infants

    Pediatr Res

    (1979)
  • DR Barnard et al.

    Neonatal thrombosis

    Am J Pediatr Hematol/Oncol

    (1979)
  • VT Turrito et al.

    Red blood cells: their dual role in thrombus formation

    Science

    (1980)
  • A Linker et al.

    Isolation and characterization of oligosaccharides obtained from heparin by the action of heparinase

    Biochem

    (1972)
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    From the Department of Paediatrics, McMaster University, Hamilton, Ontario, and the Divisions of Haematology, Cardiology, Surgery, and Radiology and Department of Haematology, Hospital for Sick Children, Toronto, Ontario, Canada

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    Supported by a grant in aid from the Medical Research Council of Canada. Dr. Andrew is a Career Scientist with the Heart and Stroke Foundation of Canada. Dr. Massicotte is a Research Fellow of the Heart and Stroke Foundation.

    Reprint requests: Maureen Andrew, MD, Hamilton Civic Hospitals Research Centre, 711 Concession St., Hamilton, Ontario L8V 1C3, Canada.

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