SYNERGISTIC COFACTOR FUNCTION OF FACTOR-V AND PROTEIN-S TO ACTIVATED PROTEIN-C IN THE INACTIVATION OF THE FACTOR VIIIA - FACTOR IXA COMPLEX- SPECIES-SPECIFIC INTERACTIONS OF COMPONENTS OF THE PROTEIN-C ANTICOAGULANT SYSTEM

Human factor V has been shown not only to be a precursor to procoagula nt factor Va but also to express anticoagulant properties. Thus, facto r V was recently found to potentiate the effect of protein S as cofact or to activated protein C (APC) in the inactivation of the factor VIII a-factor IXa complex. The purpose of this study was to determine wheth er the APC-cofactor function of factor V was also expressed in the bov ine protein C system and to elucidate the molecular background for the species specificity of APC. For this purpose, the effects of protein S and factor V on APC-mediated inactivation of factor VIIIa were studi ed using purified APC, protein S and factor V of human and bovine orig in, The factor Vma investigated here was part of a Xase complex (i.e. factor IXa, factor Vma, phospholipid and calcium and the APC-mediated inhibition of factor VIIIa was monitored by the ability of the Xase co mplex to activate factor X. Synergistic APC-cofactor function of facto r V and protein S was demonstrated in the bovine system. The effect of bovine APC was potentiated by bovine protein S but not by human prote in S, whereas both human or bovine protein S stimulated the function o f human APC. Factor V did not express species specificity in its APC-c ofactor activity even though bovine factor V was more potent than its human counterpart. Recombinant human/bovine protein S chimeras were us ed to demonstrate that the thrombin sensitive region and first epiderm al growth factor-like module of protein S determine the species specif icity of the APC-protein S interaction. In conclusion, both human and bovine factor V were found to express APC-cofactor activity which depe nds on the presence of protein S. The species specificity of APC was s hown to be caused by the interaction between APC and protein S.