In the plasma model, M298Q-rFVIIa had a moderately increased procoagulant and
antifibrinolytic potential, whereas V158D/E296V/M298Q/K337A-
rFVIIa had a strongly increased procoagulant and
antifibrinolytic activity compared with wild-type
rFVIIa. The increased
antifibrinolytic potential of the
rFVIIa variants was completely dependent on enhancement of TAFI activation. In the platelet-rich plasma model similar results were obtained. The presence of TF was mandatory for clot formation in the absence of exogenous
rFVIIa. At lower concentrations of
rFVIIa (wild-type or variants), clot formation did occur but was significantly slower when TF activity was blocked. At increasing concentrations of
rFVIIa, clotting times were no longer dependent on TF. In conclusion, should a TF-independent mechanism be involved in the efficacy of
rFVIIa in patients with
hemophilia, the superactive
rFVIIa variants studied here might be clinically advantageous, as both procoagulant and
antifibrinolytic potencies are significantly enhanced compared with those of wild-type
rFVIIa. This ought to result in more efficient cessation of
bleeding episodes and reduced risk of rebleeding.