The
thrombomodulin (TM)/activated
protein C (APC) system plays an important role in maintaining the homeostasis of
thrombosis and hemostasis and maintaining vascular integrity in vivo. TM expressed on vascular endothelium binds to
thrombin, forming a 1:1 complex and acts as an
anticoagulant. In addition, the
thrombin-TM complex activates
protein C to produce APC, which inactivates factors VIIIa and Va in the presence of
protein S, thereby inhibiting further
thrombin formation. Intriguingly, APC possesses anti-inflammatory as well as cytoprotective activities. Moreover, the extracellular domain of TM also possesses APC-independent anti-inflammatory and cytoprotective activities. Of note, the TM/APC system is compromised in
disseminated intravascular coagulation (
DIC) caused by
sepsis due to various mechanisms, including cleavage of cell-surface TM by exaggerated
cytokines and
proteases produced by activated inflammatory cells. Thus, it is reasonable to assume that reconstitution of the TM/APC system by
recombinant proteins would alleviate
sepsis and
DIC. On the basis of the success of the
Protein C Worldwide Evaluation in
Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (
rhAPC) for
severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for
rhAPC, and an increased incidence of
hemorrhage-related adverse events was noted, which prompted the industry to withdraw
rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with
DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in
severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. This review article discusses the molecular mechanisms by which the TM/APC system produces
anticoagulant as well as anti-inflammatory and cytoprotective activities in septic
DIC patients.