The role of thrombin activatable fibrinolysis inhibitor and factor XI in platelet-mediated fibrinolysis resistance: a thromboelastographic study in whole blood

Background: The resistance of platelet-rich thrombi to fibrinolysis is generally attributed to clot retraction and platelet PAI-1 release. The role of TAFI in platelet-mediated resistance to lysis is unclear. Objective: We investigated the contribution of TAFI to the antifibrinolytic effect of platelets in whole blood by thromboelastography. Methods: Platelet-poor (PP-WB, < 40 x 103 mu L-1) and platelet-rich (PR-WB, > 400 x 103 mu L-1) blood samples were obtained from normal human blood (N-WB, 150-220 x 103 mu L-1). Clot lysis time was measured by thromboelastography in recalcified blood supplemented with t-PA (100 ng mL-1) and tissue factor (1:1000 Recombiplastin). Results: t-PA-induced lysis time increased in parallel with platelet concentration (up to 3-fold). Neutralization of TAFI, but not of PAI-1, shortened the lysis time by similar to 50% in PR-WB and by < 10% in PP-WB. Accordingly, prothrombin F1+2 and TAFIa accumulation was greater in PR-WB than in PP-WB. A similar TAFI-dependent inhibition of fibrinolysis was observed when clot retraction was prevented by cytochalasin D or abciximab, or when platelet membranes were tested. Moreover, in blood with an intact contact system, platelet-mediated fibrinolysis resistance was attenuated by an anti-FXI but not by an anti F-XII antibody. Finally, platelets made the clots resistant to the profibrinolytic effect of heparin concentrations displaying a strong anticoagulant activity. Conclusions: Our data indicate that TAFI activation is one major mechanism whereby platelets make clots resistant to fibrinolysis and underscore the importance of TAFI inhibitors as new antithrombotic agents.