FVIIa: you've come a long way, baby!

In this issue of Blood, Weeterings and colleagues report that binding to the GPIb/ IX/V complex plays a role in mediating the platelet surface procoagulant effects of rFVIIa. I n 1997, our first article on the mechanism of action of recombinant activated factor VII (rFVIIa) in hemophiliacs 1 was summarily rejected by Blood because the reviewers felt that the topic was not of interest to a general hema-tology audience. However, in the ensuing years, FVIIa has become a hot topic, not only in hemophilia but also for its off-label use to manage intractable hemorrhage in a wide variety of clinical settings. Even with all of this interest, the mechanism of its hemostatic effect is still not fully understood. Plasma-derived FVIIa was first used in 1983 to provide hemostasis in 2 hemophiliacs with inhibitors. 2 In 1996, rFVIIa was approved in the European Union and in 1999 in the United States for use as a " bypassing agent " in patients with hemophilia A or B (FVIII or FIX deficiency) and an antibody inhibitor. The rationale for FVIIa use was that FVIIa would drive activation of factor X (FX) by FVIIa/tissue factor (TF) in the absence of the " intrinsic " FX-activating complex (FIXa/ FVIIIa), thus bypassing the need for FVIII or FIX. In light of the " cascade " model of hemo-stasis as shown in the first figure, this seemed a reasonable hypothesis. However, it soon became clear that the situation was not that simple. Very high levels of FVIIa were required for hemostatic efficacy, higher than needed to saturate TF binding. Thus, a debate ensued over whether the mechanism of FVIIa activity was " TF-dependent " or " TF-independent. " Bom and Bertina demonstrated that FVIIa can activate FX on a negatively charged phospholipid surface independent of TF, 3 and Rao and Rapaport initially suggested that this might underlie the hemo-static activity of FVIIa in hemophilia. 4 However, several years later, they reported that FVIIa can compete with zymogen FVII for binding to TF and increase procoagulant activity by forming active FVIIa/TF rather than FVII/TF complexes. 5 This competition could explain why unexpectedly high levels of FVIIa might be needed, even if it acted via a TF-dependent mechanism. During this time, the understanding of hemosta-sis was evolving. 6 While the FVIIa/TF pathway was viewed as critically important to initiating hemostasis, the " intrinsic " pathway was recognized as operating …