Journal of thrombosis and haemostasis vol:3 issue:12 pages:2745-2753
Objective: To elucidate the mechanism and the binding regions of monoclonal antibodies (MA) that interfere with thrombin-activatable fibrinolysis inhibitor (TAFI)/activated thrombin-activatable fibrinolysis inhibitor (TAFIa) activity. Results: Of 42 MA, 19 interfere with the TAFI activation/TAFIa activity resulting in an inhibition of up to 92%. Characterization of the mechanism of inhibition revealed that 14 MA blocked the activation of TAFI by thrombin/thrombomodulin completely whereas five MA interfered directly with the enzymatic activity of TAFIa. Surprisingly, the former, except one, induced a significant reduction of clot lysis time whereas the latter did not. Affinity studies using a human/murine TAFI chimer revealed that the binding region of the 14 activation blocking MA is located between AA1 and AA67. MA that inhibit exclusively the activation of TAFI by thrombin/thrombomodulin bind to Gly(66). A MA that inhibits the activation of TAFI by both thrombin/thrombomodulin and plasmin binds to Val(41). The MA that interfere with the enzymatic activity bind to the TAFIa moiety. Conclusions: The current study reveals at least three different putative molecular targets in the search for pharmacologically active compounds to modulate TAFIa activity.