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Kinetics of the Heparin-enhanced Antithrombin III / Thrombin Reaction

The heparin-enhanced antithrombin III/thrombin reaction was studied under a variety of conditions designed to determine the validity of kinetic models for the mechanism of action of heparin. The observed second order rate constant k& values for thrombin inhibition by antithrombin I11 were determined as a function of heparin concentration in the presence and absence of varying amounts of active site-blocked thrombin. In the absence of active site-blocked thrombin, the kZb. value increased as the concentration of heparin was increased to approximately M. With higher heparin concentration, the k:bb. value progressively decreased. In the presence of active site-blocked thrombin, the heparin concentration dependence curve was shifted to the right at low heparin concentration (less than M). With higher heparin concentration (greater than 5.0 X lo-’ M) there was no measurable effect of active site-blocked thrombin on the rate of thrombin inhibition. Experiments were also conducted in the presence and absence of active site-blocked thrombin to determine the antithrombin I11 concentration dependence for the heparin-enhanced antithrombin III/thrombin reaction. The results suggested that the enhanced rate of thrombin inhibition by antithrombin I11 in the presence of heparin is due to the simultaneous binding of both proteins to the same heparin molecule. Of the previously reported models for the mechanism of action of heparin, only the template (ternary complex) model appeared to describe the experimental results. The template model was, therefore, derived in mathematical terms and theoretical data calculated to test the possible validity of the model. Using heparin-thrombin and heparin-antithrombin I11 dissociation constant values of 3.5 X lo-’ M and 1.0 X M, respectively, a very reasonable correlation between theoretical data and experimental data was obtained. With this model, the reaction is first order with respect to the concentration of the ternary (antithrombin IIIheparin-thrombin) complex, with an apparent first order rate constant k’ value of 800 min”. It was concluded that, at the present time, the template model provides the simplest working model for the mechanism of action of heparin in accelerating thrombin inhibition by antithrombin 111.