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 specifically inhibiting thrombin and is facilitated by the binding of glycosaminoglycans such as heparin and dermatan sulfate. In vivo, heparin cofactor II-glycosaminoglycan complexes dissociate, leaving the inhibitor less active in its ability to function as a component of the anticoagulation pathway. We have produced permanently activated heparin cofactor II molecules by covalent linkage to either heparin or dermatan sulfate. Covalent heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate complexes had catalytic antithrombin activities similar to those of the corresponding starting heparin and dermatan sulfate (86% and 110% of standard heparin and dermatan sulfate activity, respectively). Both heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate had fast bimolecular rate constants of 1.4 x 10(7) M-1 s-1 and 1.3 x 10(7) M-1 s-1, respectively, for reaction with thrombin. The intravenous half-life of the covalent complexes in rabbits was significantly longer than that of free heparin or dermatan sulfate (4.4, 3.4, 0.33, and 0.50 h for heparin cofactor II-heparin, heparin cofactor II-dermatan sulfate, heparin, and dermatan sulfate, respectively). Given their unique properties, these conjugates may have a clinical application for long term, selective inhibition of thrombin.
Monagle
P
P
Hamilton Civic Hospitals Research Centre, Hamilton, Ontario L8V 1C3, Canada.
Berry
L
L
O'Brodovich
H
H
Andrew
M
M
Chan
A
A
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002852:Chromatography, Ion Exchange; D003871:Dermatan Sulfate / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D006493:Heparin / Q000737:chemistry*; D015844:Heparin Cofactor II / Q000737:chemistry*; D011817:Rabbits
D000925:Anticoagulants; D003871:Dermatan Sulfate; D015844:Heparin Cofactor II; D006493:Heparin