Mechanisms of action of recombinant human activated protein C

Human activated protein C (APC) is a serine-protease and one of the most important physiological inhibitors of the coagulation system. Apart from anticoagulative effects, profibrinolytic and anti-inflammatory modes of action have been reported for APC The administration of recombinant human activated protein C (rhAPC) drotrecogin alfa (activated), Xigris((R)), to patients with severe sepsis and sepsis-induced multi-organ failure reduced mortality in large clinical trials. Antiapoptotic and immunomodulatory effects of rhAPC have been examined in in vitro experiments and in experimental animal studies. Moreover, a reduction of endothelial cell permeability, enhanced endothelial cell survival as well as improvements of microcirculatory disorders have been proposed for rhAPC. The manifold mechanisms of action of APC may give reasons for its application in diseases other than sepsis, which are characterized by endothelial and microcirculatory dysfunction, e.g. acute pulmonary or renal failure, ischemic stroke, ischemia-reperfusion injury and acute pancreatitis. A better understanding of the anti-inflammatory, anti-apoptotic and immunomodulatory modes of action of APC could be relevant for dosing and mode of application and may lead to a broadening of the indication field for rhAPC.