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(Stroke. 2009;40:1864.)
© 2009 American Heart Association, Inc.

Original Contributions

Differential Neuroprotection and Risk for Bleeding From Activated Protein C With Varying Degrees of Anticoagulant Activity

Yaoming Wang, MD, PhD; Meenakshisundaram Thiyagarajan, PhD; Nienwen Chow, PhD; Itender Singh, PhD; Huang Guo, MD, PhD; Thomas P. Davis, PhD Berislav V. Zlokovic, MD, PhD

From the Center for Neurodegenerative and Vascular Brain Disorders (Y.W., M.T., I.S., H.G., B.V.Z.), Departments for Neurosurgery and Neurology, University of Rochester Medical Center, Rochester, NY; ZZ Biotech Research Laboratory (N.C.), Rochester, NY; and the Department of Medical Pharmacology (T.P.D.), Blood Brain Barrier Research Laboratory, College of Medicine, University of Arizona, Tucson, Ariz.

Correspondence to Berislav V. Zlokovic, MD, PhD, Center for Neurodegenerative and Vascular Brain Disorders, 601 Elmwood Avenue, Box 670, Rochester, NY 14642. E-mail berislav_zlokovic{at}urmc.rochester.edu

Background and Purpose— Activated protein C (APC), a protease with anticoagulant and cytoprotective activities, protects neurons and endothelium from ischemic injury. Drotrecogin-alfa activated, a hyperanticoagulant form of human recombinant APC, is currently being studied in patients with ischemic stroke. How changes in APC anticoagulant activity influence APC’s neuroprotection and risk for bleeding is not clear.

Methods— We used neuronal and brain endothelial cell injury models and middle cerebral artery occlusion in mice to compare efficacy and safety of drotrecogin-alfa activated and human 3K3A-APC, an APC nonanticoagulant mutant.

Results— Drotrecogin-alfa activated and 3K3A-APC exhibited 148% and 10% of plasma-derived APC’s anticoagulant activity and differ in the carbohydrate content. 3K3A-APC protected mouse neurons from N-methyl-D-aspartate-induced apoptosis and human brain endothelial cell from oxygen-glucose deprivation with 1.8- and 3.1-fold greater efficacy than drotrecogin-alfa activated. Given 5 minutes before transient middle cerebral artery occlusion, 3K3A-APC and drotrecogin-alfa activated (0.5 and 2 mg/kg intravenously) reduced comparably and dose-dependently the infarction lesion up to 85%. 3K3A-APC, but not drotrecogin-alfa activated, improved neurological score dose-dependently (P<0.05). 3K3A-APC did not cause bleeding. In contrast, drotrecogin-alfa activated dose-dependently increased hemoglobin content in postischemic brain. After permanent middle cerebral artery occlusion, 3K3A-APC multidose therapy (1 mg/kg intravenously at 12 hours and 1, 3, 5, and 7 days) improved functional recovery and reduced infarction by 60% with no risk for bleeding, whereas drotrecogin-alfa activated increased hemoglobin deposition in the postischemic brain and showed relatively modest neuroprotection.

Conclusions— Nonanticoagulant 3K3A-APC exhibits greater neuroprotective efficacy with no risk for bleeding compared with drotrecogin-alfa activated, a hyperanticoagulant form of APC.

Key Words: anticoagulant activity • brain ischemia • intracerebral microhemorrhage • neuroprotection • proteases