[The role of thrombomodulin in sepsis-associated DIC]

Thrombosis is generally considered to be harmful because it compromises the blood supply to organs. However, recent studies have suggested that thrombosis during infection might play a physiological role in the early immune defense against invading microorganisms. This defensive role of thrombosis is now referred to as immunothrombosis. Detection of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by immune cells triggers tissue factor expression and neutrophil extracellular trap (NET) release, promoting immunothrombosis. Sepsis-associated disseminated intravascular coagulation (DIC) is considered to be an advanced stage of pathological immunothrombosis, in which the immune system is no longer able to restrict the spread of pathogens, inflammation, and coagulation. In this stage, thrombosis is detrimental in part because it causes multiple organ failure. Recombinant thrombomodulin (rTM) is a therapeutic option for the treatment of sepsis-associated DIC in Japan. rTM binds thrombin, and switches its substrate specificity from coagulation factors V, VIII, and XIII to anticoagulant protein C. In addition to the activated protein C (APC)-dependent anticoagulant action, rTM has APC-independent anti-inflammatory actions, i.e., the sequestration of PAMPs and DAMPs. Thus, rTM is useful for resolving PAMP-and DAMP-mediated DIC, although further studies are needed to confirm the effectiveness of rTM in terms of clinical outcomes.