ABSTRACT
This chapter reviews the structure and function of protein C, its mechanistic biology and preclinical pharmacology, as well as the development of recombinant human activated protein C (APC). It discusses the clinical utility as a unique microvascular modulator for the treatment of severe sepsis. The chapter demonstrates that the complete γ-carboxylation of the light chain was required for full functional anticoagulant activity. It argues that the adenovirus transformation of a cell was critical for the secretion of highly functional, correctly modified protein in part because of the induction of the carboxylase enzyme. The chapter also reviews anticoagulant–antithrombotic mechanism of APC, but focus on data describing its role as a modulator of endothelial and leukocyte function. An effective method was reported for expressing recombinant APC directly from cells by replacing the thrombin-cleaved activation peptide with a sequence in the insulin receptor precursor, a substrate for the cellular insulin receptor processing protease.
