Activated protein
C (APC) is a serine protease with anticoagulant, anti-inflammatory and
anti-apoptotic functions. The active protein is generated from its precursor
zymogen protein C (PC) on the surface of endothelial cells by an activation
complex formed by thrombin and thrombomodulin (TM). APC released from the
endothelial cell surface down-regulates thrombin formation by cleavage of the
activated cofactors V and VIII, whereas APC still bound to the cell surface
induces anti-inflammatory and cytoprotective signaling responses in endothelial
cells.
A failure to
generate sufficient amounts of APC is associated with a prothrombotic and a
hyperinflammatory phenotype. The severity of the clinical symptoms depends on
the residual APC activity. The prothrombotic phenotype is the leading symptom
in milder forms of APC deficiency such as in heterozygous PC deficiency,
whereas more severe forms of APC deficiency such as in homozygous PC deficiency
are characterized by a thromboinflammatory phenotype. Acquired APC dysfunction
is critically involved in the pathogenesis of several thromboinflammatory
diseases including severe sepsis.