Combined effect of a direct oral anticoagulant edoxaban and an inhibitor of activated thrombin-activatable fibrinolysis inhibitor on clot lysis

Fibrinolysisis regulated by the thrombin/thrombin-activatable fibrinolysisinhibitor (TAFI) system. Thus, anticoagulants and inhibitors of TAFI are expected to accelerate fibrinolysis. The combined effects of an anticoagulant and a TAFIa inhibitor on fibrinolysisremain unknown. The aim of this study was to evaluate the combined effect of edoxaban, an oral direct factor Xa (FXa) inhibitor, and a TAFIa inhibitor, potato tuber carboxypeptidaseinhibitor (PCI) on tissue-type plasminogen activator (t-PA)-induced clot lysisin human plasma in vitro. Pooled human plasma( containing180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxabanand/or PCI. Clot formationwas induced by 2.5 pM tissue factorand 4 µM phospholipids and clot lysistime was examined. Plasma plasmin-α2 antiplasmin complex (PAP) concentration was measured as a marker of plasmingeneration. Edoxabanor PCI alone significantly shortened the t-PA-induced clot lysistime and plasma PAP concentration. The combination of these compounds significantly accelerated the clot lysiscompared with the inhibitors alone. Addition of PCI (0.3, 1, and 3 μg/mL) to 75 ng/mL edoxabanincreased plasma PAP concentration compared with edoxabanalone; however, compared with PCI alone only the combination of 0.3 μg/mL PCI + 75 ng/mL edoxabanshowed the significant increase in PAP concentration. Concomitant use of an oral direct FXa inhibitor, edoxaban, and a TAFIa inhibitor, PCI, significantly accelerate fibrinolysisvia enhancement of plasmingeneration. These results suggest that the combination of edoxabanand a TAFIa inhibitor might be beneficial for the treatment of thromboembolic diseases.