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 µL-1) and platelet-rich (PR-WB, > 400 x 103 µL-1) blood samples were obtained from normal human blood (N-WB, 150-220 x 103 µL-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 to platelet concentration (up to 3-fold). Neutralization of TAFI, but not of PAI-1, shortened the lysis time by ~ 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.
The role of thrombin activatable fibrinolysis inhibitor and factor XI in platelet-mediated fibrinolysis resistance: a thromboelastographic study in whole blood
SEMERARO F;COLUCCI, Mario
2011-01-01
Abstract
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 µL-1) and platelet-rich (PR-WB, > 400 x 103 µL-1) blood samples were obtained from normal human blood (N-WB, 150-220 x 103 µL-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 to platelet concentration (up to 3-fold). Neutralization of TAFI, but not of PAI-1, shortened the lysis time by ~ 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
