The results of the present study describe the generalized host response of coagulopathy, inflammation, and endothelial injury in patients with severe sepsis. Differences in the magnitude of abnormality and in the rate of normalization of the markers were clearly observed when parsed by 28-day survival of patients with severe sepsis. Nonsurvivors had greater derangement and less normalization of hemostasis, endothelial injury, and inflammation. These observations, drawn from a large number of patients selected with consistent entry criteria, support the hypothesis that an out-of-control host response of coagulopathy and inflammation in severe sepsis may lead to multiorgan failure syndrome and death. The universal presence of systemic coagulopathy and inflammation in patients with severe sepsis, as observed in this large study, further supports the hypothesis of a tight association between these two host responses [8
The universal coagulopathy observed in patients with severe sepsis is more reflective of activation of coagulation and thrombin generation than of impaired fibrinolysis. Thrombin generation markers TAT and F1.2 were present at study entry in 95.5% and 77.5% of patients, respectively. Elevated PAI-1 was present at study entry in fewer than half of the patients. In spite of elevated thrombin generation in these patients, TAFI levels were decreased in about 18% of patients at baseline. This is consistent with our understanding that TAFI is an acute phase reactant [9
Although 98.5% of patients had detectable levels of IL-6 at baseline, only 9% and 53% of patients had detectable levels of IL-1β and TNF-α, respectively. This is consistent with our understanding that both IL-1β and TNF-α are expressed earlier and are more transient cytokine responses to infection, as compared with IL-6 [10
]. Of the patients in this study, 40% had IL-8 and IL-10 levels above the detection limit at study entry. IL-8 levels in patients with severe sepsis have previously been reported to be mostly below 100 pg/ml, which is the detection limit for the assay used in this study. IL-10 is thought to have anti-inflammatory properties and acts as a temporal regulator of the transition from early sepsis to severe sepsis [11
]. Data from the study suggest that a rise in IL-10 levels is also transient and may rise either before IL-6 or decrease faster than IL-6 levels in response to infection.
A global improvement in coagulation markers was observed in survivors as compared with nonsurvivors. Markers of ongoing thrombin generation, TAT, F1.2, and D-dimer, improved more rapidly in survivors than in nonsurvivors over time. Lorente and coworkers [13
] previously showed a similar difference in TAT trend in survivors compared with nonsurvivors at day 7. The prothrombotic host response to outcome observed in this study is consistent with data reported by Gando and coworkers [14
] indicating that tissue factor antigen levels positively correlated with the number of dysfunctional organs. Higher levels of the anticoagulant factors protein C, protein S, and antithrombin in placebo survivors than in nonsurvivors at baseline, and the statistically significantly higher levels over time during the course of the disease, confirm previous observations from smaller studies [13
]. Finally, survivors exhibited greater normalization of fibrinolytic potential than did nonsurvivors, as indicated by lower levels of PAI-1 and greater increases in plasminogen levels with time. Hesselvik and coworkers [16
] previously showed an association between higher PAI-1 levels and mortality from sepsis, and Lorente and coworkers [13
] showed that sepsis survivors exhibited greater improvements in plasminogen levels.
Of the 13 coagulation markers that correlated with disease severity, PT may be the most clinically useful. Consumption and depletion of endogenous hemostasis factors occurs frequently in patients with severe sepsis, as shown in this and other studies, and may occur before the clinical diagnosis of the first sepsis-associated acute organ dysfunction [17
]. Prolongation of PT was found in more than 90% of the patients with severe sepsis at entry to this large trial. Nonsurviving patients had mean PT values that were significantly greater (more than 2 seconds greater) for a more prolonged period of time than did patients who survived, suggesting reduced consumption of extrinsic coagulation factors, which is also consistent with the decreased levels of markers of thrombin generation observed in patients who survived. Prolongation of PT reflects the depletion of hemostatic factors in patients with severe sepsis and may be an initial indicator of disseminated intravascular coagulopathy [19
]. Similar observations were also made for 12 other biomarkers, but unlike the other biomarkers PT is readily measurable in most clinical settings.
Even though some of the 19 biomarkers were universally outside the normal ranges in patients with severe sepsis at study entry, and the distributions of most of these biomarkers over the next several days were significantly different between survivors and nonsurvivors at 28 days, no biomarker could clearly predict the mortality outcome or correlate with disease severity (APACHE II score). This is probably because of the large variability in the levels of biomarkers between individual patients. The distributions of the levels of the biomarkers in the patients were wide, as indicated by the large interquartile ranges reported in Table and the wide 95% confidence intervals in the figures. Genetic polymorphisms and underlying comorbidities are some of the factors that contribute to the large variability in the distributions of the biomarkers between patients. Age and chronic health points are important contributors to APACHE II scoring, but they may not have any bearing on the levels of these biomarkers. This may explain the rather weak correlation between the baseline levels of these biomarkers with the APACHE II score.
Despite some rather modest differences described in this report, the initial host inflammatory and coagulopathic response to severe sepsis was remarkably similar in Gram-positive, Gram-negative, polymicrobial, and fungal sepsis. This study demonstrates that the clinical syndrome of severe sepsis is characterized by systemic inflammation and coagulopathy that may not be unique to a particular class of microbe.