Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity

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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1864-1869
Number of pages6
JournalStroke
Volume40
Issue number5
DOIs
StatePublished - May 1 2009

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Protein C
Anticoagulants
Hemorrhage
Middle Cerebral Artery Infarction
Brain
Neuroprotection
Infarction
Hemoglobins
Endothelial Cells
drotrecogin alfa activated
Neurons
Wounds and Injuries
Recombinant Proteins
Aspartic Acid
Endothelium
Peptide Hydrolases
Stroke
Carbohydrates
Apoptosis
Oxygen

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing
  • Medicine(all)

Cite this

Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity. / Wang, Yaoming; Thiyagarajan, Meenakshisundaram; Chow, Nienwen; Singh, Itender; Guo, Huang; Davis, Thomas P; Zlokovic, Berislav V.

In: Stroke, Vol. 40, No. 5, 01.05.2009, p. 1864-1869.

Research output: Contribution to journalArticle

Wang, Yaoming ; Thiyagarajan, Meenakshisundaram ; Chow, Nienwen ; Singh, Itender ; Guo, Huang ; Davis, Thomas P ; Zlokovic, Berislav V. / Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity. In: Stroke. 2009 ; Vol. 40, No. 5. pp. 1864-1869.
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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 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.",
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AU - Wang, Yaoming

AU - Thiyagarajan, Meenakshisundaram

AU - Chow, Nienwen

AU - Singh, Itender

AU - Guo, Huang

AU - Davis, Thomas P

AU - Zlokovic, Berislav V.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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.

AB - 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.

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