A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an In Vitro Model of Hemophilia

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 27 Số 3 - Trang 683-689 - 2007
Geoffrey Allen1, Egon Persson1, Robert A. Campbell1, Mirella Ezban1, Ulla Hedner1, Alisa S. Wolberg1
1From the Department of Pediatrics (G.A.A.), University of North Carolina, Chapel Hill; Novo Nordisk A/S (E.P., M.E., U.H.), Novo Nordisk Park, Maaloev, Denmark; and the Department of Pathology and Laboratory Medicine (R.A.C., A.S.W.), University of North Carolina, Chapel Hill. Current address for G.A.A.: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Ill.

Tóm tắt

Objective— Recombinant factor VIIa (rFVIIa, NovoSeven) has proven efficacy in treating bleeding in hemophilia patients with inhibitors. A rFVIIa analog with mutations V158D/E296V/M298Q (NN1731) exhibits increased procoagulant activity in in vitro and in vivo models. 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. 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. NN1731-mediated thrombin generation depended on platelet activation, but NN1731 did not directly activate platelets. NN1731 produced 4- to 10-fold higher maximal thrombin generation rates than equal rFVIIa concentrations. 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. 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. Conclusions— By increasing factor Xa generation, NN1731 promotes the formation of thrombin and a stable clot to a greater degree than rFVIIa.

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Tài liệu tham khảo

10.1056/NEJMoa042991

10.1182/blood.V99.3.923

10.1046/j.1365-2141.1997.4463256.x

10.1111/j.1538-7836.2004.01015.x

10.1111/j.1365-2141.2005.05820.x

10.1046/j.1538-7836.2003.00242.x

10.1046/j.1538-7836.2003.00059.x

10.1046/j.1365-2516.2001.00553.x

10.1055/s-0037-1613160

10.1053/j.seminhematol.2003.11.011

10.1073/pnas.241339498

10.1046/j.1538-7836.2003.00444.x

10.1182/blood-2003-05-1369

10.1182/blood-2002-08-2527

10.1111/j.1538-7933.2003.00617.x

10.1111/j.1538-7933.2004.00618.x

10.1016/j.thromres.2004.11.003

10.1182/blood.V70.2.490.490

10.1002/jlb.48.2.156

10.1093/ajcp/98.5.531

10.1097/00001721-200209000-00008

10.1016/0049-3848(96)00028-X

10.1111/j.1538-7836.2005.01396.x

2005, J Thromb Haemost, 3, OR381.

Ghosh S Ezban M Persson E Pendurthi U Hedner U Rao LV. Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface. J Thromb Haemost . In press.

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Thông tin xuất bản

Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 27 Số 3

683-689

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