Successful administration of thrombolytic agents is associated with vessel reocclusion in a high proportion of cases. We have previously established an animal model to investigate platelet-rich thrombolytic mechanisms in vivo and demonstrated that recombinant staphylokinase (rSAK)-induced thrombolysis was enhanced by the concomitant administration of the direct thrombin inhibitor argatroban. The present study expanded the use of this model by comparing arterial and venous thrombolysis using advanced image analysis software. Mural thrombi were formed by Helium-Neon laser irradiation in mesenteric arterioles and were shown to be lysed, dose-dependently, by smaller amounts of rSAK than those required in venules. Activated protein C (APC), as well as argatroban, enhanced the rSAK-induced thrombolysis. APC or argatroban also induced thrombolysis in the absence of rSAK, and the effect was inhibited by tranexamic acid. The enhanced thrombolysis induced by APC or argatroban in the presence or absence of rSAK may be due to increased endogenous thrombolysis mediated by the inhibition of thrombin activity or delayed thrombin generation.