title: Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study.
abstract: BACKGROUND
  Patients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage. Given the critical role of the endothelium in balancing hemostasis, we investigated single-point associations between whole blood coagulopathy by thrombelastography (TEG) and plasma/serum markers of endothelial activation and damage in patients with severe sepsis.
  
  
  METHODS
  A post-hoc multicenter prospective observational study in a subgroup of 184 patients from the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial. Study patients were admitted to two Danish intensive care units. Inclusion criteria were severe sepsis, pre-intervention whole blood TEG measurement and a plasma/serum research sample available from baseline (pre-intervention) for analysis of endothelial-derived biomarkers. Endothelial-derived biomarkers were measured in plasma/serum by enzyme-linked immunosorbent assay (syndecan-1, thrombomodulin, protein C (PC), tissue-type plasminogen activator and plasminogen activator inhibitor-1). Pre-intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database.
  
  
  RESULTS
  Most patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. The median (IQR) age was 67 years (59 to 75), and 55% were males. The median SOFA and SAPS II scores were 8 (6 to 10) and 56 (41 to 68), respectively, with 7-, 28- and 90-day mortality rates being 21%, 39% and 53%, respectively. Pre-intervention (before treatment with different fluids), TEG reaction (R)-time, angle and maximum amplitude (MA) and FF MA all correlated with syndecan-1, thrombomodulin and PC levels. By multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at the same time-point: 100 ng/ml higher syndecan-1 predicted 0.64 minutes higher R-time (SE 0.25), 1.78 mm lower TEG MA (SE 0.87) and 0.84 mm lower FF MA (SE 0.42; all P < 0.05), and 10% lower protein C predicted 1.24 mm lower TEG MA (SE 0.31).
  
  
  CONCLUSIONS
  In our cohort of patients with severe sepsis, higher circulating levels of biomarkers of mainly endothelial damage were independently associated with hypocoagulability assessed by TEG and FF. Endothelial damage is intimately linked to coagulopathy in severe sepsis.
  
  
  BACKGROUND
  Clinicaltrials.gov number: NCT00962156. Registered 13 July 2009.
authors.affiliation: Section for Transfusion Medicine, Capital Region Blood Bank, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. sisse.ostrowski@gmail.com.
authors.forename: Sisse Rye
authors.initials: SR
authors.lastname: Ostrowski
authors.affiliation: Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet Blegdamsvej 9, DK-2100, Copenhagen, Denmark. nicolai.rosenkrantz.segelcke.haase@regionh.dk.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Haase
authors.affiliation: Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet Blegdamsvej 9, DK-2100, Copenhagen, Denmark. rasmus.muller@regionh.dk.
authors.forename: Rasmus Beier
authors.initials: RB
authors.lastname: Müller
authors.affiliation: Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet Blegdamsvej 9, DK-2100, Copenhagen, Denmark. mortenhylander@gmail.com.
authors.forename: Morten Hylander
authors.initials: MH
authors.lastname: Møller
authors.affiliation: Department of Intensive Care, Copenhagen University Hospital, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark. frank.christian.pott@regionh.dk.
authors.forename: Frank Christian
authors.initials: FC
authors.lastname: Pott
authors.affiliation: Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet Blegdamsvej 9, DK-2100, Copenhagen, Denmark. anders.perner@regionh.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Perner
authors.affiliation: Department of Surgery, Division of Acute Care Surgery, Centre for Translational Injury Research (CeTIR), University of Texas Medical School at Houston, 6410 Fannin Street UPB 1100, Houston, TX, 77030, USA. per.johansson@regionh.dk.
authors.forename: Pär Ingemar
authors.initials: PI
authors.lastname: Johansson
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015415:Biomarkers / Q000097:blood; D001778:Blood Coagulation Disorders / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies; D018805:Sepsis / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D013916:Thrombelastography / Q000379:methods
chemical_list: D015415:Biomarkers