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Background  Protein S ( PS ) is an anticoagulant molecule that functions as a cofactor for activated protein C ( APC ) in the inactivation of activated coagulation factors Va ( FV a) and  VIII a. It also serves as a cofactor for tissue factor pathway inhibitor ( TFPI ) in the efficient inhibition of factor Xa ( FX a). The Lys 196 ‐to‐Glu (K196E, Tokushima) mutation in the  EGF ‐2 domain of  PS  is a genetic risk factor for venous thromboembolism ( VTE ) in the Japanese population.    Objectives  To investigate the molecular basis of the thrombophilic phenotype of Japanese patients carrying the  PS  K196E mutation.    Methods  We expressed recombinant human  PS  wild‐type ( PS ‐K) and K196E‐mutant ( PS ‐E) in  CHO  cells, and purified them by Ni 2+ ‐affinity and anion exchange column chromatography. We investigated the anticoagulant functions of  PS ‐K and  PS ‐E by measuring  APC  cofactor activity,  TFPI  cofactor activity, affinity for the β chain of complement component C4b‐binding protein (C4 BP ), and cleavage by thrombin.    Results   PS ‐E had approximately 40%  APC  cofactor activity compared with  PS ‐K in a clotting‐based assay and a  FV a inactivation assay. The  TFPI  cofactor activity of  PS ‐E in the  FX a inactivation assay was equivalent to that of  PS ‐K in the absence and presence of coagulation factor V. The strengths of  PS ‐E and  PS ‐K binding to the β chain of C4 BP  were comparable, and both were equally cleaved by thrombin.    Conclusions  The  PS  K196E mutation increases the risk of  VTE  because of reduced  APC  cofactor activity but does not alter various other properties, including the  TFPI  cofactor activity.

Protein S K196E mutation reduces its cofactor activity for APC but not for TFPI