Activated factor VII activates factors IX and 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, Novo Nordisk, Bagsvaerd, Denmark) have been found to be effective in providing haemostasis in haemophiliacs and in normal individuals with acquired inhibitors to factor VIII (FVIII) or FIX. However, the mechanism of this therapeutic effect of FVIIa is unclear. Opinion is divided over whether high-dose FVIIa therapy works primarily by a tissue factor (TF)-dependent or -independent mechanism. Our group originally favoured a TF-dependent mechanism; however, we have recently found that, at levels 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 localization of FVIIa activity explains both its safety and efficacy, as well as its haemostatic effect in patients with thrombocytopenia and platelet function defects. Localization on activated platelets would tend to restrict the activity of FVIIa to sites of injury. Activation of FX on the platelet surface in haemophiliacs would provide FXa in a favourable location to escape inhibition by plasma protease inhibitors and be incorporated into platelet prothrombinase complexes. Activation of FIX and FX on platelet surfaces in thrombocytopenia would result in more thrombin generation per platelet, possibly leading to formation of a stable fibrin network even in the absence of an optimal initial platelet plug.
Hoffman
M
M
Department of Pathology, Durham Veterans Affairs Medical Center, NC 27705, USA. maureane@med.unc.edu
Monroe
D M
DM
Roberts
H R
HR
D004305:Dose-Response Relationship, Drug; D015949:Factor IXa / Q000378:metabolism*; D015942:Factor VIIa / Q000627:therapeutic use*; D015951:Factor Xa / Q000378:metabolism*; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use
D008565:Membrane Proteins; D011994:Recombinant Proteins; D015942:Factor VIIa; D015949:Factor IXa; D015951:Factor Xa