The process of blood coagulation is mediated by activation of a series of
serine-protease zymogens. The
protein C (PC)
anticoagulant pathway, one of the important pathways related to physiological
thrombosis formation, includes PC,
thrombomodulin (TM), endothelial PC receptor (
EPCR),
protein S (PS) and
C4b-binding protein (C4BP). TM, mainly present in endothelial cells, is a cofactor for
thrombin-catalyzed activation of PC, and the resulting activated PC (aPC) inactivates the blood coagulation cofactors
factor Va and
factor VIIIa in the presence of PS. PS, mainly synthesized in hepatocytes and endothelial cells, plays a critical role as a cofactor of
anticoagulant aPC in the regulation of blood coagulation. The cofactor activity of PS for aPC is regulated by C4BP, a multimeric
protein whose structure consists of seven α-chains (C4BPα) and a β-chain (C4BPβ).
Sepsis is generally caused by
infection by microorganisms, and patients with
sepsis undergo drastic
hemostatic changes, thought to be induced by
lipopolysaccharide (LPS) and inflammatory
cytokines. In this review, based primarily on our previous studies, we describe the LPS- and
cytokine-induced changes in various
proteins in the PC
anticoagulant pathway that are related to the increased risk of
thrombosis under
sepsis. Furthermore, we discuss the potential of recombinant soluble TM (rsTM) as a possible remedy for
sepsis.