SYNERGY OF TRANEXAMIC ACID AND FIBRIN IN THE ENHANCEMENT OF THE ACTIVATION OF GLU-PLASMINOGEN BY UROKINASE

The activation rate of Glu-plasminogen (Glu-plg) by urokinase (UK) was enhanced in the presence of either tranexamic acid or fibrin with increase in catalytic rate constant (k_cat) without change in Km. The values of kcat increased almost linearly up to 0.5 mM of tranexamic acid concentration and reached a plateau. On the other hand, the presence of increasing concentrations of fibrin resulted in almost hyperbolic increase in k_cat values, reaching the plateau level at 0.04 μM. The values of k_cat increased three fold at 0.5 mM of tranexamic acid and at 0.04 μM of fibrin. Fibrinogen was less effective and k_cat increased two fold in the presence of 1 μM of fibrinogen. Similar kinetic parameters suggest that basic mechanisms underlying the enhanced activation of Glu-plg by UK may be similar between in the presence of tranexamic acid and fibrin. Possibly conformational changes of Glu-plg upon interaction of its lysine binding sites (LBS)< with tranexamic acid or fibrin may be reasons for the enhanced activation. The addition of fibrin to 1 mM tranexamic acid resulted in further increase in kcat of the UK activation of Glu-plg. On the other hand, the addition of tranexamic acid to 0.1 μM of fibrin further increased kcat of the UK activation of Glu-plg. Thus synergy was observed in the activation of Glu-plg by UK between tranexamic acid and fibrin. Fibrin binding site on kringle 5 of Glu-plg may be involved in further increase in the activation rate of Glu-plg by UK in the presence of both fibrin and tranexamic acid in comparison to that in the presence of tranexamic acid alone. Possibly, Glu-plg bound with both tranexamic acid and fibrin (at kringle 5) may be most effectively activated by UK. From the concentrations of fibrin to show 50 % changes of k_cat, it is also suggested that two molecules of Glu-plg should bind to one molecule of fibrin monomer.