APC provides extensive PAR1-dependent neuroprotective effects after murine ischemia-induced stroke in the absence or presence of tPA. When APC was given 10 minutes after onset of murine middle cerebral artery occlusion (MCAO), it had beneficial effects on motor neurologic score (A), total brain infarct volume (B), and postischemic cerebral blood flow (C). (D) In MCAO studies, recombinant human (rh)-tPA was given, and tPA-induced brain hemorrhage was visualized as hemoglobin leakage at 24 hours (tPA, 0.2 mg/kg). (E) For other studies, mice received either 0.2 mg/kg APC with tPA or 2.0 mg/kg APC at 3 hours post-tPA, and bleeding in the ischemic hemisphere was quantified. Results showed that APC decreased tPA-induced bleeding. (F) Similar studies using PAR1 null mice (PAR1^−/−) showed that PAR1 was required for the ability of APC to prevent tPA-induced bleeding. Panels A-C reprinted from Cheng et al⁵⁷  with permission; panels D-F reprinted from Cheng et al⁵⁸  with permission.