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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3161-3172. Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-09-003004. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-09-003004v1 109/8/3161    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mosnier, L. O. Articles by Griffin, J. H. Search for Related Content PubMed PubMed Citation Articles by Mosnier, L. O. Articles by Griffin, J. H. Related Collections Review Articles Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  REVIEW IN TRANSLATIONAL HEMATOLOGY The cytoprotective protein C pathway Laurent O. Mosnier1, Berislav V. Zlokovic2, and John H. Griffin1 1 Department of Molecular and Experimental Medicine (MEM-180), The Scripps Research Institute, La Jolla, CA; 2 Department of Neurosurgery, University of Rochester, NY Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions. 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