Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation

Abstract

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.

Keywords: Activated protein C; Disseminated intravascular coagulation; Sepsis; Thrombomodulin.

Figure 1

Anticoagulant function of TM/APC. TM, thrombomodulin; PC, protein C; APC, activated PC; EPCR, endothelial cell protein C receptor; PAI-1, plasminogen activator inhibitor-1; EGF, epidermal growth factor; Gla, gamma-carboxyglutamic acid.

Figure 2

Anti-inflammatory and cytoprotective functions of TM/APC. HMGB1, high-mobility group box 1; PAR1, protease-activated receptor-1; S1P₁, sphingosine 1-phosphate receptor; TAFIa, active thrombin-activatable fibrinolysis inhibitor; EPCR, endothelial cell protein C receptor; ERK, extracellular signal-regulated kinase; NF-κB, nuclear factor-κ B; Ang1, angiopoietin 1; Tie2, tyrosine kinase with Ig-like loops and epidermal growth factor homology domains-2, ApoER2, apolipoprotein E receptor 2; Dab1, disabled-1; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns.