Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569].
BACKGROUND
PROWESS (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).


METHODS
Nineteen 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.


RESULTS
Levels 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.


CONCLUSIONS
Abnormalities 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.
Kinasewitz
Gary T
GT
Department of Medicine, Physiology and Biophysics, University of Oklahoma Health Science Center, and Cardiovascular Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Yan
S Betty
SB
Basson
Bruce
B
Comp
Philip
P
Russell
James A
JA
Cariou
Alain
A
Um
Suzane L
SL
Utterback
Barbara
B
Laterre
Pierre-Francois
PF
Dhainaut
Jean-François
JF
D018806:APACHE; D015415:Biomarkers / Q000032:analysis*; D001778:Blood Coagulation Disorders / Q000097:blood / Q000175:diagnosis; D002097:C-Reactive Protein / Q000032:analysis; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000175:diagnosis; D004727:Endothelium / Q000293:injuries; D005337:Fibrin / Q000032:analysis; D005342:Fibrinolysis; D006801:Humans; D007249:Inflammation / Q000097:blood; D010314:Partial Thromboplastin Time; D010919:Placebos; D011379:Prognosis; D011486:Protein C / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D018805:Sepsis / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D012720:Severity of Illness Index; D013514:Surgical Procedures, Operative / Q000009:adverse effects; D013530:Surgical Wound Infection / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality
D015415:Biomarkers; D010919:Placebos; D011486:Protein C; D011994:Recombinant Proteins; D005337:Fibrin; D002097:C-Reactive Protein; C421124:drotrecogin alfa activated