Dose-dependent thrombolytic activity of ADAMTS13 on large t-PA–resistant MCA occlusions. A large thrombus was generated in the right MCA of C57Bl/6J mice. This thrombus was resistant to spontaneous dissolution. Five minutes after occlusion, vehicle, t-PA, or different doses of rhADAMTS13 were IV administered (arrow), and MCA blood flow was monitored for 60 minutes. (A) Average blood flow profiles show that rhADAMTS13 restores MCA blood flow in a dose-dependent way, whereas t-PA was unable to restore blood vessel patency. (B) The proportion of animals in which blood flow is restored to more than 25%, 50%, or 75% increases with rhADAMTS13 dose. (C) When ischemic brain injury was assessed 24 hours after occlusion, a dose-dependent reduction of infarct size was observed with increasing amounts of rhADAMTS13. Quantification of the infarct sizes is shown in the left panel, and representative brain sections are shown in the right panel. (n = 10 and 8 mice for vehicle and 3500 U/kg rhADAMTS13, respectively, n = 5 for the lower doses of rhADAMTS13 and t-PA; *P < .05; **P < .01; ***P < .005; ****P < .001; compared with vehicle.)