5Īfter 10 years of clinical experience with rFVIIa in the treatment of hemophilia, it is increasingly evident that the dosing must be individualized to achieve an optimal treatment outcome. 5,6 Furthermore, rFVIIa improves fibrin clot formation in a fibrinolytic environment, suggesting that rFVIIa may improve hemostasis by improving formation of the primary clot, as well as formation of subsequent clots if the primary clot fails. 2,3,5 RFVIIa also shortens the time to onset of fibrin clot formation and normalizes the fibrin structure and porosity of clots formed under hemophilic conditions (absence of factors VIII and/or IX). We and others have previously shown that rFVIIa shortens the time to onset and increases the rate of thrombin generation. 1 RFVIIa exerts its effects via both tissue factor (TF)-dependent 2 and independent 3,4 activities. Recombinant factor VIIa (rFVIIa, NovoSeven Novo Nordisk A/S, Copenhagen, Denmark) is effective in treating bleeding in hemophilic patients with inhibitors, and is in trials to expand its application to traumatic bleeding and intracerebral hemorrhage. In fibrinolytic conditions, both rFVIIa and NN1731 increased fibrin formation and stability however, NN1731 was effective at 50-fold lower concentrations than were required of rFVIIa.Ĭonclusions- By increasing factor Xa generation, NN1731 promotes the formation of thrombin and a stable clot to a greater degree than rFVIIa. Both rFVIIa and NN1731 shortened clotting times in the absence of factors IX and VIII however, NN1731 did so at 50-fold lower concentrations than were required of rFVIIa. NN1731 produced 4- to 10-fold higher maximal thrombin generation rates than equal rFVIIa concentrations. NN1731-mediated thrombin generation depended on platelet activation, but NN1731 did not directly activate platelets. Methods and Results- In a cell-based in vitro model of hemophilia, rFVIIa and NN1731 similarly increased factor X activation on tissue factor–bearing cells however, NN1731 exhibited 30-fold higher factor Xa generation on platelets than similar rFVIIa concentrations. The aim of this work was to define the effects of NN1731 toward factor X activation, platelet activation, thrombin generation, and fibrin clot formation and stability. A rFVIIa analog with mutations V158D/E296V/M298Q (NN1731) exhibits increased procoagulant activity in in vitro and in vivo models. Objective- Recombinant factor VIIa (rFVIIa, NovoSeven) has proven efficacy in treating bleeding in hemophilia patients with inhibitors.
Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).
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