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 activated clotting factors. In addition, their activity can further be curtailed by proteolytic inactivation. Loss of antithrombin III and protein C activity blocks the endogenous control mechanism for thrombin generation resulting in a state of systemic activation of coagulation and inflammatory processes. Levels of tissue factor pathway inhibitor, a third endogenous coagulation inhibitor, are increased in sepsis rather than decreased, probably reflecting a depletion of the endothelial cell bound tissue factor pathway inhibitor pool with loss of its endothelial protective function. Administration of any of these three inhibitors in various animal species and sepsis models reduces morbidity and mortality. In addition to their anticoagulant effects, these inhibitors also have various anti-inflammatory activities that may contribute to their protective effects. Phase II studies in patients with severe sepsis using coagulation inhibitors have indicated that this therapeutic approach may be useful. Large-scale phase III trials will ultimately decide whether adjunctive coagulation inhibitor replacement will have a place in the treatment of patients with severe sepsis.