Pathogenesis of disseminated intravascular coagulation in sepsis.
OBJECTIVE
To review new insights in the pathogenetic mechanisms involved in the development of disseminated intravascular coagulation (DIC) in septic patients, in order to develop new directions for therapeutic intervention.


METHODS
Articles and published peer-reviewed abstracts on the mechanism of the initiation of DIC in sepsis.


METHODS
Studies selected for detailed review were those reporting specifics about the mechanism of activation of coagulation and fibrinolysis in experimental human and animal models of sepsis. Data extraction guidelines for assessing data quality included validity of the model, quality of the laboratory assessment of activation of coagulation and fibrinolysis, and methodological considerations, such as the presence of control experiments and statistical analysis.


RESULTS
After the presence of endotoxin in the circulation, significant coagulation activation can be detected. This activation is preceded by an increase in the serum levels of various cytokines, such as tumor necrosis factor and interleukins. Inhibition of the increase in tumor necrosis factor results in inhibition of coagulation activation. Measurement of molecular markers for the activation of coagulation proteins at various levels indicates that the activation of coagulation is mediated by the tissue factor-dependent pathway, which is further confirmed by experiments in which the inhibition of the tissue factor-dependent pathway resulted in complete inhibition of coagulation activation. The activation of coagulation seems to be amplified by impaired function of the protein C-protein S inhibitory pathway. An imbalance between coagulation and fibrinolysis, ultimately leading to plasminogen activator inhibitor type 1-mediated inhibition of fibrinolysis, may further promote the procoagulant state.


CONCLUSIONS
The increased knowledge of the various pathogenetic mechanisms of coagulation activation and fibrinolysis in sepsis may have therapeutic implications; however, their efficacy needs to be assessed in appropriate clinical trials.
Levi
M
M
Center for Haemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Center, Amsterdam, The Netherlands.
ten Cate
H
H
van der Poll
T
T
van Deventer
S J
SJ
D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D004211:Disseminated Intravascular Coagulation / Q000209:etiology*; D004731:Endotoxins / Q000502:physiology; D005342:Fibrinolysis / Q000502:physiology; D006801:Humans; D007239:Infections / Q000150:complications / Q000503:physiopathology*; D011486:Protein C / Q000502:physiology; D017293:Protein S / Q000502:physiology; D018805:Sepsis / Q000150:complications / Q000503:physiopathology
D016207:Cytokines; D004731:Endotoxins; D011486:Protein C; D017293:Protein S