Molecular basis for the susceptibility of fibrin-bound thrombin to inactivation by heparin cofactor II in the presence of dermatan sulfate but not heparin

Although fibrin-bound thrombin is resistant to inactivation by heparin anti thrombin and heparin.heparin cofactor II complexes, indirect studies in pla sma systems suggest that the dermatan sulfate.heparin cofactor II complex c an inhibit fibrin-bound thrombin, Herein we demonstrate that fibrin monomer produces a 240-fold decrease in the heparin-catalyzed rate of thrombin inh ibition by heparin cofactor II but reduces the dermatan sulfate-catalyzed r ate only 3-fold. The protection of fibrin-bound thrombin from inhibition by heparin.heparin co-factor II reflects heparin-mediated bridging of thrombi n to fibrin that results in the formation of a ternary heparin.thrombin.fib rin complex. This compiler, formed as a result of three binary interactions (thrombin. fibrin, thrombin.heparin, and heparin.fibrin), limits accessibi lity of heparin-catalyzed inhibitors to thrombin and induces conformational changes at the active site of the enzyme, In contrast, dermatan sulfate bi nds to thrombin but does not bind to fibrin. Although a ternary dermatan su lfate.thrombin.fibrin complex forms, without dermatan sulfate-mediated brid ging of thrombin to fibrin, only two binary interactions exist (thrombin.fi brin and thrombin.dermatan sulfate). Consequently, thrombin remains suscept ible to inactivation by heparin cofactor II. This study explains why fibrin -bound thrombin is susceptible to inactivation by heparin cofactor II in th e presence of dermatan sulfate but not heparin.