A Variant of Recombinant Factor Viia with Enhanced Procoagulant and Antifibrinolytic Activities in an in Vitro Model of Hemophilia.
From: Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA.
Arteriosclerosis, thrombosis, and vascular biology
- Publish Date: Mar 2007
- ISSN: 1524-4636
- Volume: 27
- Issue: 3
- Pages: 683-9
- Medium: Internet
- Language: English
- Citation (JAMA): Allen Geoffrey A, Persson Egon, Campbell Robert A, 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. Mar 2007;27:683-9
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.
Mesh Headings (Keywords): Antifibrinolytic Agents, Blood Platelets, Cells, Cultured, Factor VIIa, Factor X, Hemophilia A, Humans, Leukocytes, Mononuclear, Platelet Activation, Recombinant Proteins, Sensitivity and Specificity, Thrombin
Check for Full Text / PubMed Unique Identifier (PMID): 17204663
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