Scientific Publications by FDA Staff

Blood 2012 Jul 26;120(4):891-9

Unifying the mechanism of recombinant FVIIa action: dose-dependence is regulated differently by tissue factor and phospholipids.

Shibeko AM, Woodle SA, Lee TK, Ovanesov MV

Recombinant Factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors, as well for off-label treatment of severe bleeding in trauma and surgery. Effective bleeding control requires supraphysiological doses of rFVIIa, posing both high expense and uncertain thrombotic risk. Two major competing theories offer different explanations for the supraphysiological rFVIIa dosing requirement: 1) the need to overcome competition between FVIIa and FVII zymogen for tissue factor (TF)-binding or 2) a high-dose requiring phospholipid-related pathway of FVIIa action. In this study, we found experimental conditions in which both mechanisms contribute simultaneously and independently to rFVIIa-driven thrombin generation in FVII-deficient human plasma. From mathematical simulations of our model of FX activation confirmed by thrombin generation experiments, we conclude that the action of rFVIIa at pharmacological doses is dominated by the TF-dependent pathway, with minor contribution by the phospholipid-dependent mechanism. We established a dose-response curve for rFVIIa that is useful to explain dosing strategies. In summary, we offer a pathway to reconcile the two major mechanisms of rFVIIa action, a necessary step to understanding future dose optimization and evaluation of new rFVIIa analogues that are currently under development.