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.