The Roles of Protein C and Thrombomodulin in the Regulation of Blood Coagulation

The coagulation process presents unusual problems with respect to control mechanisms.To limit the scope of the review, the protein C anticoagulant pathway will serve as a model to illustrate some of the biochemical mechanisms involved in control.It is perhaps worthwhile to consider initiaIly some of the fundamental observations that indicate where and how the system must be regulated.The cascade of zymogen activation events in coagulation provides the potential for explosive amplification (reviewed in Ref. 1) ultimately leading to the formation of thrombin, the serine protease responsible for clot formation, platelet activation, activation of factor XI11 with subsequent cross-linking of the fibrin network, and the feedback activation of the two regulatory proteins, factors V and VI11 (reviewed in Ref. 2).The circulating levels of the thrombin precursor, prothrombin, is at least 100 times greater than that required for rapid and complete clot formation (1, 2).This provides the potential for massive clotting in the face of a triggering event.In healthy individuals, the coagulation system is very effectively controlled, and the balance clearly lies in favor of the negative regulation of this process (3).This contrasts to the observation that when blood is shed into containers, coagulation is complete and relatively rapid.In selected disease states, especially those with an ongoing inflammatory process, the propensity to form blood clots is apparent, suggesting that these individuals might have depressed anticoagulant mechanisms.This hypothesis is supported by the observation that infants born without protein C, a component of a major anticoagulant mechanisms, often die with massive thrombotic complications in infancy (4).