Severe sepsis is associated with three integrated components:

Infection with the systemic activation of inflammation. During progression of sepsis, a wide variety of proinflammatory cytokines is released. Endotoxin induces rapid increases in the levels of tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) in experimental models of sepsis. These proinflammatory cytokines are linked to the development of the clinical signs of sepsis. Release of proinflammatory cytokines is associated with endothelial injury and vascular bed-specific changes in the thrombogenicity of the endothelium.These can include increased tissue factor (TF) expression in a subset of endothelial cells and release of plasminogen activator inhibitor-1 (PAI-1).

Activation of coagulation. Inflammatory changes trigger the extrinsic pathway of coagulation. Activation of coagulation in patients with sepsis is not always disseminated intravascular coagulation. Instead, in most patients, it is a subclinical activation of the hemostatic system as indicated by changes in commonly measured hemostatic parameters. Experimentally, there are increases in thrombin-antithrombin (TAT) complexes. Clinical laboratory findings include significant increases in D-dimer, a marker of coagulation and associated fibrinolysis.

Impairment of fibrinolysis. In patients with sepsis, plasminogen levels fall rapidly while antiplasmin levels remain normal. This decreases the normal fibrinolytic response. Fibrinolysis is further impaired by release of PAI-1 and the generation of increased amounts of thrombin-activatable fibrinolysis inhibitor (TAFI). Although plasminogen/antiplasmin ratio and PAI-1 levels remain abnormal in nonsurviving patients, they tend to normalize in survivors.

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