ACTIVATION OF ANTITHROMBIN-III ISOFORMS BY HEPARAN-SULFATE GLYCOSAMINOGLYCANS AND OTHER SULFATED POLYSACCHARIDES

Antithrombin III occurs naturally as two functionally distinct molecul ar species that differ in glycosylation at Asn135. Whereas the predomi nant, glycosylated isoform has high affinity for heparin, a quantitati vely minor isoform lacking glycosylation at that site displays relativ ely higher affinity for both heparins and heparinoids. We characterize d the ability of various sulphated polysaccharides to potentiate the r ates of thrombin inhibition by the isoforms. High-molecular-weight dex tran sulphate was the most effective of those studied, increasing thro mbin inhibition by the higher-affinity antithrombin III isoform up to five-fold more efficiently than did heparin fractions with low-affinit y for antithrombin III. In addition, dextran sulphate activated the hi gher-affinity isoform as much as twelve times more effectively than it did the lower-affinity isoform. Pentosan polysulphate was up to three -fold, and some heparan sulphate fractions up to two-fold, more effect ive with the higher, compared with the lower affinity, isoform. Hepara n sulphate preparations less effectively increased the rate of thrombi n inhibition than did the other low-affinity polysaccharides. Structur e-function studies indicated positive correlations between activity an d both polymer length and anionic group density of low-affinity sulpha ted polysaccharides. The observed effects of the heparan sulphates on this anticoagulant pathway, although of low potency, are consistent wi th the hypotheses that these substances naturally regulate blood homeo stasis in vascular tissues and that much of this function may be media ted by the higher-affinity antithrombin III isoform.