Severe sepsis is a devastating disorder with high morbidity and mortality. Even with advances in supportive care, severe sepsis carries a mortality rate of 30 to 50% [136-142], and the incidence is expected to increase over the next decade [143,144]. In considering a role for protein C in sepsis pathogenesis and treatment, it is instructive to review briefly the pathophysiology of sepsis and septic shock. In-depth reviews on this topic can be found in many sources [72,145-153]. Severe sepsis results from a complex host response to insult following infection. Figure 4.9 depicts a simplified schematic representation of the series of events from insult (e.g., infection), through the release of various inflammatory and cytotoxic mediators, to vascular dysfunction, end-organ dysfunction, and death.
In the early events leading to severe sepsis, the host response results in the activation of a number of systems aimed at getting rid of the infection. The elucidation of cytokines such as TNFa following insult initiates cell surface activation, affecting a number of pathways (e.g., oxidation, adhesion, cytokine release, apoptosis, and nitric oxide production) as well as releasing a tissue factor that further contributes to inflammation through throm-bin-induced activation of endothelium, platelets, and vascular smooth muscle . These responses, however, can directly damage the vascular endothelium [146,155], resulting in neutrophil-endothelial cell adhesion, mononuclear cell adhesion, and tissue-factor-dependent activation of the coagulation cascade [150,156]. These responses can set in play a cycle
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