Regulation of blood coagulation

The protein C anticoagulant pathway converts the coagulation signal generat ed by thrombin into an anticoagulant response through the activation of pro tein C by the thrombin-thrombomodulin (TM) complex. The activated protein C (APC) thus formed interacts with protein S to inactivate two critical coag ulation cofactors, factors Va and VIIIa, thereby dampening further thrombin generation. The proposed mechanisms by which TM switches the specificity o f thrombin include conformational changes in thrombin, blocking access of n ormal substrates to thrombin and providing a binding site for protein C. Th e function of protein S appears to be to alter the cleavage site preference s of APC in factor Va, probably by changing the distance of the active site of APC relative to the membrane surface. The clinical relevance of this pa thway is now established through the identification of deficient individual s with severe thrombotic complications and through the analysis of families with partial deficiencies in these components and an increased thrombotic tendency. One possible reason that even partial deficiencies are a thrombot ic risk is that the function of the pathway can be down-regulated by inflam matory mediators. For instance, clinical studies have shown that the extent to which protein C levels decrease in patients with septic shock is predic tive of a negative outcome. Initial clinical studies suggest that supplemen tation with protein C may be useful in the treatment of acute inflammatory diseases such as sepsis. (C) 2000 Elsevier Science B.V. All rights reserved .