Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology

Severe sepsis, defined as sepsis associated with acute organ dysfunction, r esults from a generalized inflammatory and procoagulant host response to in fection. Coagulopathy in severe sepsis is commonly associated with multiple organ dysfunction, and often results in death. The molecule that is centra l to these effects is thrombin, although it may also have anticoagulant and antithrombotic effects through the activation of Protein C and induction o f prostacyclin. In recent years, it has been recognized that chemicals prod uced by endothelial cells play a key role in the pathogenesis of sepsis. Th rombomodulin on endothelial cells coverts Protein C to Activated Protein C, which has important antithrombotic, profibrinolytic and anti-inflammatory properties. A number of studies have shown that Protein C levels are reduce d in patients with severe infection, or even in inflammatory states without infection. Because coagulopathy is associated with high mortality rates, a nd animal studies have indicated that therapeutic intervention may result i n improved outcomes, it was rational to initiate clinical studies.