thrombomodulin

Thrombomodulin is a large, endothelial cell–surface glycoprotein that acts as a key regulator of coagulation. By forming a complex with thrombin, it changes thrombin’s substrate specificity, enabling the activation of protein C to activated protein C (APC). APC, with its cofactor protein S, cleaves and inactivates coagulation factors Va and VIIIa, shifting the system toward anticoagulation. In addition to its anticoagulant role, thrombomodulin has anti-inflammatory and cytoprotective effects on the endothelium, in part through APC signaling via the endothelial protein C receptor and related pathways. A soluble form of thrombomodulin can be produced by shedding from the cell surface and serves as a biomarker of endothelial injury.

Structure and distribution: Thrombomodulin is a type I transmembrane glycoprotein expressed predominantly on vascular endothelial cells, with a large extracellular domain containing several epidermal growth factor–like repeats, a mucin-like region, a single transmembrane segment, and a short cytoplasmic tail. The THBD gene encodes the protein. While mainly endothelial, thrombomodulin can be detected in other tissues at lower levels, and soluble forms are present in plasma.

Mechanism of action: The thrombomodulin–thrombin complex reduces thrombin’s procoagulant activities while steering its proteolytic activity toward protein C activation. APC then inactivates factors Va and VIIIa, decreasing thrombin generation. APC–EPCR signaling can induce cytoprotective and anti-inflammatory responses, helping to preserve endothelial integrity. Thrombomodulin function can be modulated by inflammatory stimuli, and proteolytic shedding increases soluble thrombomodulin in circulation.

Clinical significance: Thrombomodulin participates in coagulation regulation and vascular homeostasis. Elevated levels of soluble thrombomodulin reflect endothelial injury and have been associated with sepsis, disseminated intravascular coagulation, and acute lung injury. Recombinant human soluble thrombomodulin has been used in treating DIC in some countries, notably Japan, but its use and approval status vary by regulatory jurisdiction due to safety concerns such as bleeding risk.