Thrombomodulin and disseminated intravascular coagulation

Thrombomodulin (TM) is a thrombin-binding anticoagulant cofactor, which is extensively expressed on the surface of endothelial cells. Human TM is a single-chain type 1 transmembrane glycoprotein containing five extracellular domains. TM is an important endogenous anti-coagulant protein. Thrombin-TM complexes transform the inactive from of protein C into an activated protein C (APC). APC subsequently inactivate the coagulation factors Va and VIIIa, thereby suppressing further thrombin generation. In addition, TM also plays an important role in attenuation of inflammatory responses through inhibition of leukocyte adhesion to endothelial cells, inhibition of complement pathways, neutralization of lipopolysaccharide (LPS) as well as sequestration and degradation of proinflammatory high-mobility group box 1 protein (HMGB1). Thus, the endothelial surface bounded TM prevents dissemination of pro-coagulant and pro-inflammatory molecules and allows these molecules to act locally at the site of injury. In patients with sepsis and disseminated intravascular coagulation (DIC), TM expression is down regulated resulting in dissemination of pro-coagulant and pro-inflammatory molecules throughout the systemic circulation. The dual ability of TM to suppress both coagulation and inflammation makes this molecule a possible drug candidate for the treatment for DIC. A soluble form of recombinant human TM (rhsTM) has been shown to be more effective and safer than heparin in treatment of patients with DIC. In fact, rhsTM has been approved for the treatment of DIC in Japan. This chapter focuses on the critical roles of TM in the cross talk between inflammation and coagulation. Furthermore, this chapter provides a rationale for the clinical application of TM for treatment of DIC.