Coagulation inhibitor replacement in sepsis is a potentially useful clinical approach

In sepsis, levels of the endogenous coagulation inhibitors antithrombin III and protein C are lowered as a result of complex formation with multiple a ctivated clotting factors. In addition, their activity can further be curta iled by proteolytic inactivation. Loss of antithrombin III and protein C ac tivity blocks the endogenous control mechanism for thrombin generation resu lting in a state of systemic activation of coagulation and inflammatory pro cesses. Levels of tissue factor pathway inhibitor, a third endogenous coagu lation inhibitor, are increased in sepsis rather than decreased, probably r eflecting a depletion of the endothelial cell bound tissue factor pathway i nhibitor pool with loss of its endothelial protective function. Administrat ion of any of these three inhibitors in various animal species and sepsis m odels reduces morbidity and mortality. In addition to their anticoagulant e ffects, these inhibitors also have various anti-inflammatory activities tha t may contribute to their protective effects. Phase II studies in patients with severe sepsis using coagulation inhibitors have indicated that this th erapeutic approach may be useful. Large-scale phase III trials will ultimat ely decide whether adjunctive coagulation inhibitor replacement will have a place in the treatment of patients with severe sepsis.