Blood coagulation and
complement pathways are two important natural defense systems. The high affinity interaction between the
anticoagulant vitamin K-dependent protein S and the
complement regulator
C4b-binding protein (C4BP) is a direct physical link between the two systems. In human plasma, ~70% of total
protein S circulates in complex with C4BP; the remaining is free. The
anticoagulant activity of
protein S is mainly expressed by the free form, although the
protein S-C4BP complex has recently been shown to have some
anticoagulant activity. The high affinity binding of
protein S to C4BP provides C4BP with the ability to bind to negatively charged
phospholipid membranes, which serves the purpose of localizing
complement regulatory activity close to the membrane. Even though C4BP does not directly affect the coagulation system, it still influences the regulation of blood coagulation through its interaction with
protein S. This is particularly important in states of inherited deficiency of
protein S where the tight binding of
protein S to C4BP results in a pronounced and selective drop in concentration of free
protein S, whereas the concentration of
protein S in complex with C4BP remains relatively unchanged. This review summarizes the current knowledge on C4BP with respect to its association with
thrombosis and hemostasis.