ArticleThe Journal of experimental medicine2007
Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C.
Article in The Journal of experimental medicine, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 156 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
156 citing papers in PubMed, 304 citations in OpenAlex.
- Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant.Thrombosis and haemostasis · 2015Trial
- Targeting PAR1 biased signaling with parmodulin reduces thromboinflammation and acute lung injury in sickle cell disease.Blood advances · 2026Article
- Review
- Article
- An orthosteric/allosteric bivalent peptide agonist comprising covalently linked protease-activated receptor-derived peptides mimics in vitro and in vivo activities of activated protein C.Journal of thrombosis and haemostasis : JTH · 2024Article
- Characterizing Modulators of Protease-activated Receptors with a Calcium Mobilization Assay Using a Plate Reader.Journal of visualized experiments : JoVE · 2024Article
- Review
- Endothelial APC/PAR1 distinctly regulates cytokine-induced pro-inflammatory VCAM-1 expression.Frontiers in molecular biosciences · 2023Article
- Hemostatic and protein C pathway dysfunction in the pathogenesis of experimental cerebral malaria.Haematologica · 2022Article
- aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Signaling pathways and intervention therapies in sepsis.Signal transduction and targeted therapy · 2021Review
- Endothelial Cell Protein C Receptor Deficiency AttenuatesAmerican journal of respiratory cell and molecular biology · 2021Article
- Coagulopathy in COVID-19.Lung India : official organ of Indian Chest Society · 2021Review
- Different DOACs Control Inflammation in Cardiac Ischemia-Reperfusion Differently.Circulation research · 2021Article
- Targeting coagulation activation in severe COVID-19 pneumonia: lessons from bacterial pneumonia and sepsis.European respiratory review : an official journal of the European Respiratory Society · 2020Review
- COVID-19 hypothesis: Activated protein C for therapy of virus-induced pathologic thromboinflammation.Research and practice in thrombosis and haemostasis · 2020Article
- Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation.Cell host & microbe · 2020Article
- A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection.Nature microbiology · 2019Article
- Advance in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation.Journal of clinical medicine · 2019Review
- Activated protein C inhibits lipopolysaccharide-mediated acetylation and secretion of high-mobility group box 1 in endothelial cells.Journal of thrombosis and haemostasis : JTH · 2019Article
96 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Activated protein C (APC) reduces mortality of severe sepsis patients but increases the risk of serious bleeding. APC exerts anticoagulant activity by proteolysis of factors Va/VIIIa. APC also exerts antiinflammatory and antiapoptotic effects and stabilizes endothelial barrier function by APC-initiated cell signaling that requires two receptors, endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR1). The relative importance of APC's various activities for efficacy in sepsis is unknown. We used protein engineering of mouse APC and genetically altered mice to clarify mechanisms for the efficacy of APC in mouse sepsis models. Mortality reduction in LPS-induced endotoxemia required the enzymatic active site of APC, EPCR, and PAR-1, highlighting a key role for APC's cytoprotective actions. A recombinant APC variant with normal signaling but <10% anticoagulant activity (5A-APC) was as effective as wild-type APC in reducing mortality after LPS challenge, and enhanced the survival of mice subjected to peritonitis induced by gram-positive or -negative bacteria or to polymicrobial peritoneal sepsis triggered by colon ascendens stent implantation. Thus, APC's efficacy in severe sepsis is predominantly based on EPCR- and PAR1-dependent cell signaling, and APC variants with normal cell signaling but reduced anticoagulant activities retain efficacy while reducing the risk of bleeding.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.