Enzymatic modifications of protein S: cause and impact on diagnostics, plasma processing, and anticoagulant properties.

Coagulation processes are under critical control of anticoagulation mechanisms. Protein S is a multifunctional natural anticoagulant in plasma that downregulates coagulation at different crucial points in the coagulation process. Protein S is not only cofactor for activated protein C, but also for tissue factor pathway inhibitor-α. In addition, protein S exhibits so-called direct anticoagulant activity, ie, inhibition of tenase (factor [F]IXa/FVIIIa) and prothrombinase (FXa/FVa) complex assembly and activity. Being a multifunctional anticoagulant, stringent regulation of its functions seems essential. Protein S is susceptible to enzymatic modulation of its anticoagulant properties, which includes upregulation by kinases and downregulation by limited proteolysis or even complete degradation. Enzymatic modification of protein S is a largely unrecognized phenomenon that may have substantial impact on the diagnostics of protein S deficiencies and the preparation and clinical utility of pooled plasma products, but may also provide opportunities for drug development. This review provides historic background, state-of-the-art knowledge, and future perspectives on the enzymatic modification of the anticoagulant properties of protein S.