Covalent heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate complexes - Characterization of novel anticoagulants

Heparin cofactor II is a naturally occurring anticoagulant that acts by spe cifically inhibiting thrombin and is facilitated by the binding of glycosam inoglycans such as heparin and dermatan sulfate. In vivo, heparin cofactor II-glycosaminoglycan complexes dissociate, leaving the inhibitor less activ e in its ability to function as a component of the anticoagulation pathway. We have produced permanently activated heparin cofactor II molecules by co valent linkage to either heparin or dermatan sulfate. Covalent heparin cofa ctor II-heparin and heparin cofactor II dermatan sulfate complexes had cata lytic antithrombin activities similar to those of the corresponding startin g heparin and dermatan sulfate (86% and 110% of standard heparin and dermat an sulfate activity, respectively). Both heparin cofactor II-heparin and he parin cofactor II-dermatan sulfate had fast bimolecular rate constants of 1 .4 x 10(7) M-1 s(-1) and 1.3 x 107 M-1 s(-1), respectively, for reaction wi th thrombin, The intravenous half-life of the covalent complexes in rabbits was significantly longer than that of free heparin or dermatan sulfate (4. 4, 8.4, 0.33, and 0.50 h for heparin cofactor II-heparin, heparin cofactor II-dermatan sulfate, heparin, and dermatan sulfate, respectively). Given th eir unique properties, these conjugates may have a clinical application for long term, selective inhibition of thrombin.