DETERMINANTS OF PLASMA FACTOR VIIA LEVELS IN HUMANS

Several enzymes can activate factor VII in vitro, but the protease res ponsible for generating factor VIIa in vivo has not been determined. U sing recombinant tissue factor that has undergone a COOH-terminal trun cation, a sensitive functional assay has been established for measurin g plasma factor VIIa levels. To evaluate the mechanism responsible for the generation of factor VIIa in vivo, we measured the levels of this enzyme after administering purified concentrates of factor IX and fac tor VIII to patients with severe deficiencies of these clotting factor s. In patients with hemophilia B, factor VIIa levels were initially re duced to 0.5 +/- 0.1 ng/mL and gradually increased to normal after inf using 100 U/kg of body weight (BW) of factor IX. Despite these increas es, there were no significant changes in the generation of factor Xa o r thrombin. In patients with hemophilia A, only a slight reduction in factor VIIa levels (2.5 +/- 1.3 ng/mL) was observed as compared with c ontrols (3.3 +/- 1.1 ng/mL) and no significant changes were observed a fter factor VIII levels were normalized. The administration of recombi nant factor VIIa (10 mu g/kg BW) to patients with factor VII deficienc y increased the mean circulating level of the enzyme to 118 ng/mL, but this only resulted in normalization of the levels of the activation p eptides of factor IX and factor X. The above data indicate that factor IXa is primarily responsible for the basal levels of free factor VIIa generated in vivo (ie, in the absence of thrombosis or provocative st imuli) and that changes in the plasma concentrations of free factor VI Ia in the blood do not necessarily lead to alterations in the extent o f factor X activation. (C) 1995 by The American Society of Hematology.