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 (APC), but also for tissue factor pathway inhibitor alpha (TFPIα). In addition, protein S exhibit so-called direct anticoagulant activity. i.e. inhibition of tenase (Xase, factor IXa/VIIIa) and prothrombinase (IIase, factor Xa/Va) 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 that includes upregulation by kinases and downregulation by limited proteolysis or even complete degradation. Enzymatic modification of protein S is a largely unrecognized phenomenon that not only may have substantial impact on the diagnostics of protein S deficiencies and on the preparation and clinical utility of pooled plasma products, but it may also provide opportunities for drug development. This review provides historical background, state-of-the-art knowledge and future perspectives on the enzymatic modification of the anticoagulant properties of protein S.