Mechanism of action of high-dose factor VIIa: points of agreement and disagreement.

In an article in this issue of the Arteriosclerosis, Thrombosis, and Vascular Biology,1 Butenas and colleagues report studies looking at pharmacologic levels of factor VIIa in a model system of hemophilia. Understanding the mechanism by which high-dose factor VIIa increases thrombin generation and enhances hemostasis is important because it is currently being used very effectively in treatment of patients with hemophilia, especially those with inhibitors.2 Factor VIIa is also being tested in other clinical settings of uncontrolled bleeding.3 Previously, Mann and coworkers4 developed a model for studying coagulation that involved reassembling purified coagulation factors with phospholipid vesicles. They examined not only thrombin generation but also the precise sequence of events leading to thrombin generation. Subsequently, this group has looked at the mechanisms of coagulation using tissue factor initiation and surfaces of: phospholipid vesicles,5 isolated platelets,6 and platelets in whole blood.7 These studies provided the impetus for many of the current studies on the mechanisms of coagulation being done by Mann’s group and many other groups, including ours.8–11 This body of work has resulted in important observations that have helped define the mechanisms of the hemostatic process including demonstration of: the pivotal role of the tissue factor complex in initiating coagulation, the important role of initial thrombin generation in activating platelets, and the role of coagulation cofactor interactions.