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Open Access 01-04-2011 | Research

Activation of factor VII-activating protease in human inflammation: a sensor for cell death

Authors: Femke Stephan, Jan A Hazelzet, Ingrid Bulder, Marja A Boermeester, JW Olivier van Till, Tom van der Poll, Walter A Wuillemin, Lucien A Aarden, Sacha Zeerleder

Published in: Critical Care | Issue 2/2011

Abstract

Introduction

Cell death is a central event in the pathogenesis of sepsis and is reflected by circulating nucleosomes. Circulating nucleosomes were suggested to play an important role in inflammation and were demonstrated to correlate with severity and outcome in sepsis patients. We recently showed that plasma can release nucleosomes from late apoptotic cells. Factor VII-activating protease (FSAP) was identified to be the plasma serine protease responsible for nucleosome release. The aim of this study was to investigate FSAP activation in patients suffering from various inflammatory diseases of increasing severity.

Methods

We developed ELISAs to measure FSAP-C1-inhibitor and FSAP-α₂-antiplasmin complexes in plasma. FSAP-inhibitor complexes were measured in the plasma of 20 adult patients undergoing transhiatal esophagectomy, 32 adult patients suffering from severe sepsis and 8 from septic shock and 38 children suffering from meningococcal sepsis.

Results

We demonstrate plasma FSAP to be activated upon contact with apoptotic and necrotic cells by an assay detecting complexes between FSAP and its target serpins α₂-antiplasmin and C1-inhibitor, respectively. By means of that assay we demonstrate FSAP activation in post-surgery patients, patients suffering from severe sepsis, septic shock and meningococcal sepsis. Levels of FSAP-inhibitor complexes correlate with nucleosome levels and correlate with severity and mortality in these patients.

Conclusions

These results suggest FSAP activation to be a sensor for cell death in the circulation and that FSAP activation in sepsis might be involved in nucleosome release, thereby contributing to lethality.

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Title: Activation of factor VII-activating protease in human inflammation: a sensor for cell death
Authors: Femke Stephan
Jan A Hazelzet
Ingrid Bulder
Marja A Boermeester
JW Olivier van Till
Tom van der Poll
Walter A Wuillemin
Lucien A Aarden
Sacha Zeerleder
Publication date: 01-04-2011
Publisher: BioMed Central
Published in: Critical Care / Issue 2/2011
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/cc10131

At a glance: The STEP trials

Springer Medicine

Activation of factor VII-activating protease in human inflammation: a sensor for cell death

Abstract

Introduction

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

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