Endotoxemia and sepsis mortality reduction by non-anticoagulant–activated protein C

Kerschen, E. J., et al. 2007. JEM. 204, 2439-2448

Speaker: Juin-Wei Chen (陳君瑋)                                  Time: 13:00~14:00, Nov. 14, 2007

Commentator: Dr. Chiou-Feng Lin (林秋烽博士)          Place: Room 601

Abstract:

    Activated protein C (APC) plays an important role on anticoagulation resulted from proteolysis of factor Va/VIIIa and also triggers anti-inflammatory and anti-apoptotic effects which are through endothelial cell receptors (EPCR) as well as protease activated receptor-1 (PAR1) signaling. Clinically, APC treatment can reduce mortality of severe sepsis, but the side effect is bleeding. In this study, the authors wanted to clarify the protective mechanism of APC in sepsis, and generated more proper APC variants devoid of causing bleeding. First of all, the authors found a recombinant APC variant lacking enzymatic proteolytic activity but anticoagulant potency didn’t reduce mortality in septic mice showing that enzymatic proteolytic activity is essential. They consecutively noted that APC reduces apoptosis in liver but not in lymphocytes and reduces LPS-induced vascular permeability, especially in small vessels. In addition, EPCR and PAR1 were also proved to be required for the therapeutic efficacy of APC. The authors further generated several APC variants diminished with anticoagulant activity but preserved with EPCR- and PAR1-dependent effects. Among these variants, 5A-APC was found to be the most efficient one to decrease anticoagulation and induce cytoprotective activities. Moreover, 5A-APC could prevent mortality of lethal gram-negative or –positive bacterial sepsis in mice. It is considered that APC variants have a much greater dose range without raising bleeding risk, and 5A-APC is the particularly safer alternative for treating patients with severe sepsis.

References:

1. Mosnier, L.O., et al. 2004. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood. 104, 740–1744.

2. Dahlbäck, B., and Villoutreix, B. O., 2005. Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway: Novel Insights Into Structure-Function Relationships and Molecular Recognition. Arterioscler. Thromb. Vasc. Biol. 25, 1311-1320.