Blood, 1 March 2003, Vol. 101, No. 5, pp. 1666-1666
Expanding uses of high-dose factor VIIa
Recombinant FVIIa is approved in many countries as a
"bypassing" agent that promotes hemostasis in patients with
congenital or acquired hemophilia with inhibitors (Hedner,
Adv Exp Med Biol. 2001;489:75-88). In addition, FVIIa has now been used
off label in a range of conditions including thrombocytopenia,
platelet function defects, liver transplantation, and after trauma
or surgery. While few controlled clinical trials have been done, FVIIa
appears to be remarkably safe and effective in a variety of settings.
The mechanism of action of FVIIa has been best studied in models of
hemophilia. Hemophilia is a failure of platelet surface FXa generation.
Our studies and those of others suggest that FVIIa acts
independently of its usual cofactor, tissue factor, to enhance platelet-surface thrombin generation (Hoffman et al, Semin Hematol. 2001;38:6-9). FVIIa does this by partially restoring platelet surface
FX activation that is lacking in the absence of the FIXa/FVIIIa complex. Others have suggested that FVIIa also speeds platelet activation. A platelet-dependent mechanism explains why FVIIa does
not cause systemic activation of coagulation, since the activated platelets on which FVIIa acts localize it to sites of injury.
FVIIa is one of the few treatment options for patients with
Glanzmann thrombasthenia. While the effects of FVIIa in ex
vivo models of thrombocytopenia have been studied to a limited extent, the mechanism by which it improves hemostatic function in Glanzmann patients may or may not be similar (Monroe et al, Semin Thromb Hemost.
2000;26:373-377). The paper by Lisman et al in this issue (page 1864)
provides the first experimental work on a mechanism of action for FVIIa
in platelet function defects. This work shows that FVIIa can enhance
platelet adhesion in a flow chamber model. This effect depends on
thrombin generation but is independent of tissue factor. The authors
provide an experimental rationale for the effectiveness of high-dose
FVIIa in patients with platelet function disorders and suggest that the
mechanism of action may be similar to that in hemophilia.
Maureane Hoffman
Duke University Medical
Center
