Studies on the Mechanism of the Rate‐Enhancing Effect of Heparin on the Thrombin‐Antithrombin III Reaction

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Abstract
The rate of the reaction between thrombin and antithrombin III was greatly increased with heparin. Several mechanisms for this effect were possible. To study the problems coummercial heparin was fractionated into 1 fraction of high anticoagulant activity and 1 of low anticoagulant activity by affinity chromatography on matrix-bound antithrombin III. The strength of the binding of the 2 heparin fractions to [human] antithrombin III and thrombin, respectively, was determined by a crossed immunoelectrophoresis technique. As was expected, the high activity fraction was strongly bound to antithrombin III while the low activity fraction was weakly bound. Thrombin showed equal binding affinity for both heparin fractions. The ability of the 2 heparin fractions to catalyze the inhibition of thrombin by antithrombin III was determined and was much greater for the high activity heparin fraction. A mechanism for the reaction between thrombin and antithrombin III with small amounts of heparin was suggested, whereby antithrombin III first binds heparin and this complex then inhibits thrombin by interaction with the bound heparin and the antithrombin III.