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A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia.
Arterioscler Thromb Vasc Biol 2007; 27(3):683-9AT

Abstract

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.

Authors+Show Affiliations

Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17204663

Citation

Allen, Geoffrey A., et al. "A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an in Vitro Model of Hemophilia." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 3, 2007, pp. 683-9.
Allen GA, Persson E, Campbell RA, et al. A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia. Arterioscler Thromb Vasc Biol. 2007;27(3):683-9.
Allen, G. A., Persson, E., Campbell, R. A., Ezban, M., Hedner, U., & Wolberg, A. S. (2007). A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(3), pp. 683-9.
Allen GA, et al. A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an in Vitro Model of Hemophilia. Arterioscler Thromb Vasc Biol. 2007;27(3):683-9. PubMed PMID: 17204663.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A variant of recombinant factor VIIa with enhanced procoagulant and antifibrinolytic activities in an in vitro model of hemophilia. AU - Allen,Geoffrey A, AU - Persson,Egon, AU - Campbell,Robert A, AU - Ezban,Mirella, AU - Hedner,Ulla, AU - Wolberg,Alisa S, Y1 - 2007/01/04/ PY - 2007/1/6/pubmed PY - 2007/3/8/medline PY - 2007/1/6/entrez SP - 683 EP - 9 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 27 IS - 3 N2 - 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/17204663/A_variant_of_recombinant_factor_VIIa_with_enhanced_procoagulant_and_antifibrinolytic_activities_in_an_in_vitro_model_of_hemophilia_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.ATV.0000257204.82396.2b?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -