Thrombomodulin as an intravascular safeguard against inflammatory and thrombotic diseases

Thrombomodulin is a transmembrane protein expressed on the surface of endothelial cells. It plays an important role in regulating inflammation as well as coagulation within blood vessels. Recently, a recombinant form of an extracellular fragment of thrombomodulin (rTM) has been developed and is expected to be useful for patients suffering from inflammatory and thrombotic diseases.

We initially focus on the physiological and biochemical features of thrombomodulin, including its distribution, structure and function. We then discuss potential therapeutic applications of rTM.

Thrombomodulin exerts anticoagulant and anti-inflammatory effects, in part through activated protein C (APC)-dependent mechanisms. Although recombinant human APC (rhAPC) failed to improve the survival of patients with septic shock and has now been withdrawn from the market, rTM may have some advantages over rhAPC. First, rTM may have less risk of bleeding complications than rhAPC, because rTM needs thrombin to act as an anticoagulant and thus its anticoagulant power can be automatically adjusted by the amount of existing thrombin. Second, the APC-independent actions of rTM might confer benefits, including the suppression of complements, endotoxin (representative pathogen-associated molecular pattern) and high-mobility group box 1 protein (prototypical damage-associated molecular pattern) through the lectin-like domain of rTM.