Effect of activated human protein c on experimental venous thrombosis induced by stasis with operative invasion in mice

Protein C (PC) is the zymogen of an anticoagulant serine protease and is co nverted to its active form (activated protein C: APC) by thrombin in the pr esence of thrombomodulin. APC plays an important role in regulating blood c oagulation and fibrinolysis by inhibiting not only blood coagulation factor s Va and VIIIa but also type-1 plasminogen activator inhibitor In this study, it was reported that the antithrombotic effect of a human AP C product (designated as CTC-111) compared with that of heparin and human P C on the deep venous thrombosis (DVT) model induced in mice by stasis cause d by inferior vena cava ligation and operative invasion. Drugs were injecte d into a tail vein at -2, 30, 60, and 120 min after the inferior vena cava ligation. One-fifth amount of the total dosage of a given drug was injected at each time point. The wet weight of thrombus formed was reduced by APC o r heparin administration, however, PC, which was equal to APC in protein am ount, did not show any antithrombotic effect. To confirm whether human PC could be activated by mouse thrombin, PC was tr eated with mouse or human thrombin to measure the amount of APC formed. Mou se thrombin could activate human PC at a similar activation rate as human t hrombin. These results suggest that externally administrated PC cannot exhibit antit hrombotic effect in this DVT model due to slow activation rate to APC and t hat APC is a better antithrombic agent than PC for treating thrombotic dise ases.