Protein C (PC) is a key component in a multiprotein, physiologically relevant pathway that regulates thrombin's procoagulant activity, but which also limits inflammatory responses and provides the vascular endothelium with protection against an array of insults. Delineation of the biochemistry and molecular biology underlying regulation of the PC pathway, complemented by preclinical and clinical studies, has led to major new insights bridging the gap between inflammation and coagulation and resulting in innovative approaches to treat thrombotic disease and sepsis.
DISCOVERY OF PROTEIN C AND A NOVEL NATURAL ANTICOAGULANT PATHWAY
In 1975, Johan Stenflo reported the discovery of a novel vitamin K–dependent factor that revolutionized our view of the molecular mechanisms by which the coagulation system is regulated and provided insights into how coagulation interfaces with other biological systems, including inflammation and cell survival. In the final steps of his strategy to isolate new vitamin K–dependent plasma proteins, Stenflo identified four peaks from a chromatography column, the third of which – “pool C” – was subsequently referred to as protein C (1). Shortly thereafter, Esmon and colleagues (2) recognized that PChas lipid-binding properties and is a zymogen precursor for a serine protease – so-called activated PC (APC). The importance of PC in coagulation rapidly became evidentwhen it was determined that APC is derived from the thrombin-mediated cleavage of PC, that APC proteolytically destroys procoagulant cofactors V/Va and VIII/VIIIa, and finally that familial deficiency of PC in humans results in a hypercoagulable disorder (3–5).
STRUCTURAL FEATURES OF PROTEIN C
PC is synthesized predominantly in the liver as a 461-amino acid, long single-chain precursor, approximately75% of which is subsequently processed prior to and during secretion to yield a two-chain species.
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.
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