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The rate of inhibition of thrombin and Factor Xa by antithrombin III has been investigated as a function of heparin concentration. Three general observations were made. First, the amount of heparin required to maximally enhance the inhibition of thrombin is much less than the amount of heparin required for Factor Xa inhibition by anti thrombin III. Second, the maximum rate of thrombin inhibition was approximately 5-fold higher than the maximum rate of Factor Xa inhibition with optimal heparin levels. Third, heparin concentrations greater than 10-6M decreased the rates of inhibition of both Factor Xa and thrombin. Mathematical modeling was attempted to describe the mechanism of action of heparin. At low heparin concentrations (&lt; 10-6M) the inhibition of thrombin and Factor Xa could best be described by a model which presumed that binding of heparin to the enzyme accelerates enzyme inhibition by antithrombin III. The effect of heparin at concentrations &lt; 10-6 on the rates of enzyme inhibition could not be explained by direct binding of heparin to either antithrcmbin III or thrombin (Factor Xa). This observation has led to the hypothesis that the interaction of thrombin and Factor Xa with heparin is altered at relatively high heparin concentration which results in a decrease in the effectiveness of heparin in accelerating enzyme inhibition by anti thrombin III.

Effects Of Heparin On The Rates Of Inhibition Of Thrombin And Factor Xa By Antithrqmbin III