title: Covalent antithrombin-heparin complexes with high anticoagulant activity. Intravenous, subcutaneous, and intratracheal administration.
abstract: 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 x 10(9) M-1 s-1 and 3.1 x 10(9) M-1 s-1, 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.
authors.affiliation: Research Institute of the Hospital for Sick Children, Toronto, Ontario M5G 1X8.
authors.forename: A
authors.initials: A
authors.lastname: Chan
authors.forename: L
authors.initials: L
authors.lastname: Berry
authors.forename: H
authors.initials: H
authors.lastname: O'Brodovich
authors.forename: P
authors.initials: P
authors.lastname: Klement
authors.forename: L
authors.initials: L
authors.lastname: Mitchell
authors.forename: B
authors.initials: B
authors.lastname: Baranowski
authors.forename: P
authors.initials: P
authors.lastname: Monagle
authors.forename: M
authors.initials: M
authors.lastname: Andrew
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D000990:Antithrombin III / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006493:Heparin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007700:Kinetics; D046911:Macromolecular Substances; D011817:Rabbits
chemical_list: D000925:Anticoagulants; D046911:Macromolecular Substances; D000990:Antithrombin III; D006493:Heparin