Tissue-type plasminogen activator transgenic rats for evaluating inhibitors of the activated form of thrombin-activatable fibrinolysis inhibitor

摘要

No rodent models are currently available for evaluating inhibitors of the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa) without exogenous supplementation of tissue-type plasminogen activator (tPA). Characterization of tPA transgenic rats as a tool for the nonclinical evaluation of TAFIa inhibitors is the objective of the current study. tPA transgenic rats were subjected to rat models of tissue-factor-induced thromboembolism, FeCl3-induced deep vein thrombosis (DVT) and arterial thrombosis, and tail bleeding. Potato tuber carboxypeptidase inhibitor (PCI), a selective TAFIa inhibitor, was used as an experimental compound at doses of 0.1, 1, or 10mg/kg, and its antithrombotic effects and bleeding prolongation effect were compared with nontransgenic rats. Intravenous PCI showed significant and dose-related increase in plasma d-dimer levels in the tissue-factor-induced thromboembolism model. Intravenous PCI also significantly and dose-dependently reduced thrombus weights in the two thrombosis models only in the tPA transgenic rats. These results suggest that sensitive in-vivo evaluation of TAFIa inhibitors can be achieved using tPA transgenic rats without exogenous supplementation of recombinant tPA. On the other hand, no statistically significant prolongation of bleeding times by PCI was observed in either strain, whereas increased bleeding times were observed with 10mg/kg of intravenous recombinant tPA, suggesting that the low bleeding risk of TAFIa inhibitors is further confirmed in the tPA transgenic rats whose basal tPA levels are elevated. tPA transgenic rats may be beneficial for the pharmacological and toxicological evaluation of TAFIa inhibitors and further confirm that TAFIa is a promising target for various thrombotic disorders.