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 109 M-1 s-1 and 3.1 x 109 M-1 s-1, respectively. The intravenous half-life..