Modulation of the Enzymatic Activity of α-Thrombin by Polyanions: Consequences on Intrinsic Activation of Factor V and Factor VIII

The polyanions heparin and dermatan sulfate catalyze α-thrombin inhibition and can delay the onset of factor VIII and factor V necessary for intrinsic prothrombin activation to begin in plasma. These polyanions bind α-thrombin at its anion-binding exosite(s), structural domain(s) occupancy of which may alter the properties of the fibrin(ogen) recognition exosite of α-thrombin. We compared how such four polyanions influenced factor VIII and factor V activation during intrinsic coagulation. A pentasaccharide with high affinity for antithrombin III and the C-terminal docedapeptide fragment of hirudin (hirugen) which occupy the anion-binding and fibrin(ogen) recognition exosites of α-thrombin, respectively, could not significantly inhibit factor VIII and factor V activation. In contrast, heparin and a bis-lactobionic acid, both of which catalyzed α-thrombin inhibition, could effectively inhibit factor VIII and factor V activation. These results suggest that occupancy of fibrin(ogen) or anionbinding exosites by itself does not provide a necessary and sufficient condition for catalysis of thrombin inhibition or the inhibition thrombin-mediated amplification reactions.

Modulation of the Enzymatic Activity of α-Thrombin by Polyanions: Consequences on Intrinsic Activation of Factor V and Factor VIII Journal Articles