Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage

Brain hemorrhage is a serious complication of tissue plasminogen activator (tPA) therapy for ischemic stroke. Here we report that activated protein C (APC), a plasma serine protease with systemic anticoagulant, anti- inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, blocks tPA- mediated brain hemorrhage after transient brain ischemia and embolic stroke in rodents. We show that APC inhibits a pro- hemorrhagic tPA- induced, NF-kappa B-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1. The present findings suggest that APC may improve thrombolytic therapy for stroke, in part, by reducing tPA- mediated hemorrhage.