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Sepsis with acute organ dysfunction (severe sepsis) is common, frequently fatal, and associated with a significant national health/economic burden. In addition to standard care, investigators have focused on interrupting the inflammatory and anti-inflammatory cascade associated with this disease. Unfortunately, despite promising preclinical results, interventions directed at the inflammatory elements have not reduced the morbidity and mortality associated with this disease. Inflammation and coagulation are tightly linked. In fact, sepsis-associated coagulopathy is almost universal in patients with severe sepsis. Preclinical observations indicate that antithrombotic-targeted therapy has the potential to reduce morbidity and mortality in patients with this disease. Treatment with recombinant human activated protein C (drotrecogin α [activated]) was the first antithrombotic-targeted therapy to significantly reduce 28-day all-cause mortality in patients with severe sepsis. The pathophysiological and clinical significance of this evidence and the relationship of coagulation to inflammation are discussed, as are positive and negative results of clinical trials of antithrombotic therapy.