ACTIVATED FACTOR-VII ACTIVATES FACTOR-IX AND FACTOR-X ON THE SURFACE OF ACTIVATED PLATELETS - THOUGHTS ON THE MECHANISM OF ACTION OF HIGH-DOSE ACTIVATED FACTOR-VII

High levels of recombinant activated factor VII (rFVIIa; NovoSeven, No vo Nordisk, Bagsvaerd, Denmark) have been found to be effective in pro viding haemostasis in haemophiliacs and in normal individuals with acq uired inhibitors to factor VIII (FVIII) or FIX. However, the mechanism of this therapeutic effect of FVIIa is unclear. Opinion is divided ov er whether high-dose FVIIa therapy works primarily by a tissue factor (TF)-dependent or -independent mechanism. Our group originally favoure d a TF-dependent mechanism; however, we have recently found that, at l evels comparable with those attained therapeutically, FVIIa activates enough FX on activated platelets to restore platelet surface thrombin generation. These data now lead us to favour a primarily (although not necessarily exclusively) TF-independent mechanism for the haemostatic effect of high-dose FVIIa. We believe that a platelet surface localiz ation of FVIIa activity explains both its safety and efficacy, as well as its haemostatic effect in patients with thrombocytopenia and plate let function defects. Localization on activated platelets would tend t o restrict the activity of FVIIa to sites of injury. Activation of FX on the platelet surface in haemophiliacs would provide FXa in a favour able location to escape inhibition by plasma protease inhibitors and b e incorporated into platelet prothrombinase complexes. Activation of F IX and FX on platelet surfaces in thrombocytopenia would result in mor e thrombin generation per platelet, possibly leading to formation of a stable fibrin network even in the absence of an optimal initial plate let plug. Blood Coag Fibrinol 9 (suppl 1):S61-S65 (C) 1998 Lippincott- Raven Publishers