Volume 272, Number 35, Issue of August 29, 1997 pp. 22111-22117
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Covalent Antithrombin-Heparin Complexes with High Anticoagulant Activity
INTRAVENOUS, SUBCUTANEOUS, AND INTRATRACHEAL ADMINISTRATION

(Received for publication, February 28, 1997, and in revised form, May 19, 1997)

Anthony Chan , Leslie Berry ^§ , Hugh O'Brodovich ^¶ , Petr Klement ^§ , Lesley Mitchell ^§ , Bryan Baranowski ^§ , Paul Monagle ^§ and Maureen Andrew ^§

From the  Research Institute of the Hospital for Sick Children, Toronto, Ontario M5G 1X8, the ^§ Hamilton Civic Hospitals Research Centre, Hamilton, Ontario L8V 1C3, and the ^¶ Medical Research Council Group in Developmental Lung Biology, Respiratory Research Division, Department of Pediatrics, University of Toronto Hospital for Sick Children's Research Institute, Ontario M5G 1X8, Canada

Although heparin has been used clinically for prophylaxis and treatment of thrombosis, it has suffered from problems such as short duration within compartments in vivo that require long term anticoagulation. A covalent antithrombin-heparin complex has been produced with high anticoagulant activity and a long half-life relative to heparin. The product had high anti-factor Xa and antithrombin activities compared with noncovalent mixtures of antithrombin and heparin (861 and 753 units/mg versus 209 and 198 units/mg, respectively). Reaction with thrombin was rapid with bimolecular and second order rate constants of 1.3 × 10⁹ M¹ s¹ and 3.1 × 10⁹ M¹ s¹, respectively. The intravenous half-life of the complex in rabbits was 2.6 h as compared with 0.32 h for similar loads of heparin. Subcutaneous injection of antithrombin-heparin resulted in plasma levels (peaking at 24-30 h) that were still detectable 96 h post-injection. Given the increased lifetime in these vascular and intravascular spaces, use of the covalent complex in the lung was investigated. Activity of antithrombin-heparin instilled into rabbit lungs remained for 48 h with no detection of any complex systemically. Thus, this highly active agent has features required for pulmonary sequestration as a possible treatment for thrombotic diseases such as respiratory distress syndrome.

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