Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects

Background-In view of the central role of the tissue factor-factor VIIa pat hway in the initiation of blood coagulation, novel therapeutic strategies a imed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an approp riate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated w ith recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor-factor VIIa complex, in a double-blind randomized crossov er study. Methods and Results-Administration of nematode anticoagulant protein c2 (3. 5 mug/kg) caused a prolongation of the prothrombin time from 13.7+/-0.6 to 16.9+/-1.2 seconds. The subsequent injection of rVIIa (90 mug/kg) resulted in an immediate and complete correction of the prothrombin time and a marke d generation of thrombin, reflected by increased levels of prothrombin acti vation fragment F1+2 and thrombin-antithrombin complexes from 0.75+/-0.64 t o 3.29+/-6.3 nmol/L and from 2.4+/-0.6 to 10.7+/-3.9 mug/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increa se, respectively, after the administration of rVIIa in the presence of nema tode anticoagulant protein c2. Conclusions-During treatment with an inhibitor of the tissue factor-factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our re sults indicate that rVIIa may be a good candidate as an antidote for inhibi tors of tissue factor.