Effect of warfarin treatment on thrombin activatable fibrinolysis inhibitor ( TAFI ) activation and TAFI ‐mediated inhibition of fibrinolysis

Summary Background Severe clotting deficiencies are associated with enhanced in vitro fibrinolysis due to insufficient thrombin activatable fibrinolysis inhibitor (TAFI) activation. Because oral anticoagulant therapy ( OAT ) with warfarin causes a partial deficiency of vitamin K‐dependent factors, its effect on clot lysability remains unclear. Objectives To evaluate plasma and blood fibrinolytic capacity in patients under stable OAT ( n  = 221) as compared with controls ( n  = 132). Methods Fibrinolysis resistance of plasma (turbidimetry) and blood (thromboelastography) clots was calculated as the lysis time of tissue factor‐induced clots exposed to 30 and 100 ng mL −1 t‐PA, respectively. Results Plasma PAI‐1 was similar in the two groups, whereas TAFI was slightly lower in patients. OAT plasma clots lysed faster than controls ( P  = 0.001). The addition of the TAFI a inhibitor PTCI reduced lysis time by 14% in OAT and 34% in controls, and the difference between the groups disappeared. Similar data were obtained with blood clots. Thrombin and TAFIa generation in OAT plasma amounted to roughly 50% of controls, supporting a reduced thrombin‐dependent TAFI activation. Clot resistance of OAT plasma was normalized by Ba‐citrate plasma eluate or prothrombin but not by BaSO 4 serum eluate, rFVII a or FX . Surprisingly, circulating levels of TAFI a and its inactive derivative TAFI ai were higher in warfarin patients ( P  < 0.0001) and correlated with plasmin‐antiplasmin ( P  = 0.0001) but not with prothrombin F 1   +   2 . Conclusions OAT enhances both plasma and blood fibrinolysis by reducing thrombin‐dependent TAFI activation, a phenomenon largely determined by low prothrombin levels. At variance with in vitro data, ‘basal’ in vivo TAFI a/ai levels seem related to plasmin rather than thrombin generation.