Protein S is a vitamin K–dependent plasma glycoprotein with anticoagulant properties (1–3). It is mainly synthesized in the liver and, to a lesser degree, in several other cell types including endothelium. Protein S binds to negatively charged phospholipid membranes, where it functions as a cofactor to activated protein C (APC) in the degradation of coagulation factors Va and VIIIa, cofactors in the prothrombinase and tenase complexes, respectively. In addition, protein S has APC-independent anticoagulant activities, which directly inhibit both the prothrombinase and the tenase complexes. In vivo, endothelium presumably promotes the anticoagulant activity of protein S by providing a suitable phospholipid membrane for interaction with APC. Protein S normally circulates in human plasma at a concentration of 0.30 µM. In human plasma, 60% to 70% of protein S is bound to the high-molecular- weight C4b-binding protein (C4BP), a regulator of the classical complement pathway (3,4). The remaining 30% to 40% of protein S circulates as free protein. Thus, protein S functions as a link between the protein C anticoagulant system and the complement system.

PROTEIN S GENE AND SYNTHESIS

Protein S in plasma is mainly derived from synthesis in the liver. In addition, endothelial cells (ECs), testicular Leydig cells, and osteoblasts synthesize protein S (3). Platelets contain protein S, but it is not known whether this is derived from megakaryocytic synthesis or from uptake of plasma protein S. However, protein S synthesis has been demonstrated in a megakaryocytic cell line, suggesting megakaryocytes have the capacity to synthesize the protein. Two protein S genes (PROS1 and PROSP) are found in the human genome, but only PROS1 is expressed, where as PROSP is a pseudogene.