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Abstract

IntroductionPROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care).MethodsNineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism.ResultsLevels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin–antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days.ConclusionAbnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups.

Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study

“…In our study, most patients with sepsis exhibited coagulation and fibrinolytic abnormalities at the time of ICU admission, which is consistent with the data from the PROWESS trial [1]. In addition, most hemostatic biomarkers measured on ICU admission were associated with subsequent fulfillment of overt DIC criteria.…”

Interleukin-6 in Surgery, Trauma, and Critical Care Part II: Clinical Implications

“…Nonsurvivors had significantly higher IL-6 concentrations than survivors. 47,48 Similarly, in the Lenercept Trial of a p55 TNF receptor fusion protein, median IL-6 concentrations were higher in nonsurvivors than in survivors. 49 …”

Ex vivo thrombin generation patterns in septic patients with and without disseminated intravascular coagulation

“…Dissemination of inflammatory and procoagulant responses beyond the source of infection is in large part responsible for organ dysfunction and eventually death [2,3]. Coagulation activation can be evidenced in all severe sepsis patients and is associated with poor outcome [4][5][6]. Unfortunately, despite an ever-growing knowledge of hemostasis abnormalities, there has yet to be a breakthrough in any human treatment.…”

“…Thrombin generation is normally finely regulated by the equilibrium between the activation of the coagulation cascade and natural anticoagulants [11]. Protracted activation of the coagulation cascade together with depletion in natural anticoagulants (Protein C, S, antithrombin, tissue factor pathway inhibitor) occasionally culminates in overt disseminated intravascular coagulation (DIC) [4,5]. Despite the central role played by thrombin, no routine diagnostic test enabling to determine thrombin generation has been available in daily practice until recently.…”