Abstract
IntroductionPatients 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.MethodsA 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.ResultsMost 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).ConclusionsIn 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.Trial registrationClinicaltrials.gov number: NCT00962156. Registered 13 July 2009.
Highlights
Patients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage
Study patients The present study is a sub-study of The Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial [38], restricted to patients enrolled from March 2010 to November 2011 in two intensive care units (ICUs) at university hospitals in Denmark (Rigshospitalet, Bispebjerg Hospital)
We recently proposed that the coagulopathy observed in severe trauma and other types of acute critical illness reflects a universal response mounted to counterbalance emerging systemic microvascular and endothelial disruption and damage inflicted by the ‘injurious hit’, that is, the tissue injury, infection and/or ischemia-reperfusion injury and its concurrent activation of the neurohumoral, inflammatory and hemostatic systems [37]
Summary
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. The endothelium plays a key role in balancing hemostasis [23,24,25,26,27], and there is emerging evidence that endothelial activation and damage are critical drivers of coagulopathy in acute critical illness, including severe sepsis [5,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. The study confirmed our hypothesis by demonstrating that single time-point measurements of plasma markers of endothelial damage and, to a lesser degree, endothelial activation, were independently associated with concurrent whole blood hypocoagulability by TEG in patients with severe sepsis and septic shock. Endothelial protective interventions would be expected to attenuate the sepsis-induced hypocoagulability
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