Antithrombotic agents in the treatment of severe sepsis.

Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with multiple organ dysfunction is termed severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading microorganisms may be considered as a balance between a pro-inflammatory and an anti-inflammatory reaction. While an inadequate pro-inflammatory reaction and a strong anti-inflammatory response could lead to overwhelming infection and the death of the patient, a strong and uncontrolled pro-inflammatory response, manifested by the release of pro-inflammatory mediators may lead to microvascular thrombosis and multiple organ failure. Endotoxin triggers sepsis via the release of various mediators such as tumour necrosis factor-alpha and interleukin-1 (IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen species and nitric oxide. Other mediators involved in the sepsis syndrome include IL-1, -6 and -8; arachidonic acid metabolites; platelet activating factor; histamine; bradykinin; angiotensin; complement components and vasoactive intestinal peptide. These pro-inflammatory responses are counteracted by IL-10. Most of the trials targeting the different mediators of the pro-inflammatory response have failed due to a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable more advanced treatment options. Targeting the coagulation system with various anticoagulant agents including, activated protein C, and tissue factor pathway inhibitor (TFPI) is a rational approach. Many clinical trials have been conducted to evaluate these agents in severe sepsis. While trials on antithrombin and TFPI were not so successful, the double-blind, placebo-controlled, Phase III trial of recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) was successful, creating a significant decrease in mortality when compared to the placebo group. A better understanding of the pathophysiologic mechanism of severe sepsis will provide better treatment options, and combination antithrombotic treatment may provide a multipronged approach for the treatment of severe sepsis.