C4b-binding protein: a forgotten factor in thrombosis and hemostasis

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.