The antiheparin effect of a heparinoid, pentosan polysulphate. Investigation of a mechanism

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Abstract
A pentosan polysulfate [a fully sulfated (1-4)-.beta.-D-xylopyranose with a single laterally positioned 4-O-methyl-.alpha.-D-glucuronic acid] inhibited anticoagulant activity of high-affinity heparin in [human] plasma, and when purified enzyme and inhibitor were used. The activity was concentration-dependent with an apparent Ki of .apprx. 2 .mu.M. The antiheparin property was not shown by a number of other anionic carbohydrates when tested. The rate of thrombin inhibition at 0.33 .mu.M-heparin was reduced from 7.1 .times. 108 M-1 .cntdot. min-1 in the absence of pentosan polysulphate to 2.3 .times. 108 M-1 .cntdot. min-1 at 2 .mu.M-pentosan polysulfate and to 0.3 .times. 108 M-1 .cntdot. min-1 at 20 .mu.M. Use of the random bireactant model of heparin action showed that the pentosan polysulfate had no effect on the Km for antithrombin III (150 nM) but increased the Km for thrombin from 25 to 450 nM. A 17.3-fold reduction in the inhibition rate predicted by substitution of these values into the general 2-substrate reaction-rate equation was confirmed experimentally.

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