Thrombin has far-reaching effects in a variety of biological systems, including coagulation, inflammation, cell survival, and cell proliferation. Modulation of the dynamic production of this key protease is essential to maintain homeostasis during development and, in adults, under a variety of pathophysiological conditions. The crucial importance of thrombin has prompted intense studies over the past few decades to characterize the molecular pathways that regulate its functional expression. The remarkable insight of several scientists led to the discovery of thrombomodulin (TM) (1), a key regulator of thrombin's activities, a predominantly vascular endothelial cell (EC) cofactor in a physiologically relevant natural anticoagulant system, and a modulator of inflammation and cell proliferation, with links to innate immunity.

THROMBOMODULIN IS A MASTER SWITCH THAT PREVENTS BLOOD CLOTTING

The discovery of TM (1,2), elegantly recounted by Esmon and Owen (1), emanated from evidence in the 1960s of the existence of a circulating thrombin-activated protein – now referred to as activated protein C (APC) – and the identification and isolation of its precursor, protein C (PC) (3). PC is a vitamin-K–dependent plasma protein, synthesized in the liver and circulating as a biologically inactive species. Activation of PC by thrombin requires TM as a cofactor (4) (Figure 105.1), which accelerates the reaction over 1,000-fold. APC, in turn, suppresses further thrombin generation through the proteolysis of coagulation factors Va and VIIIa, facilitated by the cofactor, protein S (PS). Not only does TM affect the generation of APC but, when complexed with TM, thrombin's entire substrate specificity is changed such that it no longer functions as a procoagulant molecule. For example, thrombin-TM is not able to activate platelets or factor V, or to cleave fibrinogen.