Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study

Sisse Rye Ostrowski, Nicolai Haase, Rasmus Beier Müller, Morten Hylander Møller, Frank Christian Pott, Anders Perner, Pär Ingemar Johansson

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. 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 and 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, plasminogen activator inhibitor-1). Pre-intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database. Most patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. Median (IQR) age was 67 years (59-75), 55% were males. Median SOFA and SAPS II scores were 8 (6-10) and 56 (41-68), 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 MA and FF MA all correlated with syndecan-1, thrombomodulin and PC levels and by multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at this single time-point: 100 ng/ml higher syndecan-1 predicted 0.64 min higher R-time (SE 0.25), 1.78 mm lower (SE 0.87) TEG MA and 0.84 mm lower (SE 0.42) FF MA, all p < 0.05 and 10% lower protein C predicted 1.24 mm lower (SE 0.31) TEG MA. 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. ClinicalTrials.gov number: NCT00962156 . Registered 13 July 2009.