2009
DOI: 10.1161/strokeaha.108.536680
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Differential Neuroprotection and Risk for Bleeding From Activated Protein C With Varying Degrees of Anticoagulant Activity

Abstract: 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 occlu… Show more

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Cited by 51 publications
(80 citation statements)
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References 33 publications
(48 reference statements)
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“…In this study, we used Drotrecogin alfa activated (Xigris; Lilly Deutschland), a human recombinant activated protein C that was shown to be effective in mice. Xigris (Lilly Deutschland) had a neuroprotective effect in murine neuronal and brain endothelial cell injury models (25) and prevented septic-like reactions after injection of histones into mice (26). In sepsis, it was initially thought that activated protein C has antithrombotic and profibrinolytic functions, but recently, it has been postulated that cytoprotective effects are responsible for reduced mortality.…”
Section: Discussionmentioning
confidence: 99%
“…In this study, we used Drotrecogin alfa activated (Xigris; Lilly Deutschland), a human recombinant activated protein C that was shown to be effective in mice. Xigris (Lilly Deutschland) had a neuroprotective effect in murine neuronal and brain endothelial cell injury models (25) and prevented septic-like reactions after injection of histones into mice (26). In sepsis, it was initially thought that activated protein C has antithrombotic and profibrinolytic functions, but recently, it has been postulated that cytoprotective effects are responsible for reduced mortality.…”
Section: Discussionmentioning
confidence: 99%
“…Therefore, both neuronal-protective and vascular-protective effects are fully preserved in 3K3A-APC mutant. In fact, recent studies using a permanent distal middle cerebral occlusion model of stroke in mice have demonstrated that 3K3A-APC has superior neuroprotection and reduced risk for bleeding (Guo et al, 2009a;Wang et al, 2009). Although, it is difficult to determine the exact contributions of direct neuroprotection and vasculoprotection versus reduced risk for bleeding in the overall beneficial effects of 3K3A-APC therapy compared to wt-APC in stroke and TBI models in vivo, it has been reported that 3K3A-APC has superior cytoprotective effects compared to wt-APC in cultured neurons challenged by N-methy-Daspratate and brain endothelial cells subjected to oxygen/glucose deprivation (Guo et al, 2009a).…”
Section: Discussionmentioning
confidence: 99%
“…The mechanism(s) for the augmented cytoprotection of 3K3A-APC versus wt-APC remains to be elucidated. In addition to the altered amino acid composition in the loop 37, different post-translational modifications of the mutant protein can occur that could change contents of negatively charged sialic acid and/or the distribution and branching of the Nlinked glycan species causing an increased ability of mutant 3K3A-APC to interact with PAR-1 and/or other putative APC receptors (Wang et al, 2009;Guo et al, 2009a). Thus, enhanced neuroprotective and/or vasculoprotective direct activities may contribute to the observed protection in vivo after TBI in addition to elimination of the bleeding risk.…”
Section: Discussionmentioning
confidence: 99%
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