Abstract | INTRODUCTION: Acute bleeding leads to significant morbidity and mortality. Recombinant wildtype Factor VIIa (WT FVIIa) had been reported to have some therapeutic effects in some clinical trials, however, its use was associated with thromboembolic events. We sought to develop a novel FVIIa molecule (CT-001) with enhanced activity and lowered thrombogenicity risk. METHODS AND METHODS: RESULTS: In mice, CT-001 had a half-life of 5 min and a clearance of 467 mL/h/kg at 3 mg/kg, significantly faster than WT FVIIa (t1/2 = 1.8 h, Cl = 39 mL/h/kg). Interestingly, CT-001 was efficacious in reducing blood loss even with its rapid clearance. In a severe hemorrhage mouse model with tail amputated 5 cm from the tip, 1 mg/kg CT-001 provided efficacy comparable to 3 mg/kg WT FVIIa. The fast clearance of CT-001 resulted in significantly reduced thrombogenicity in comparison to WT FVIIa in a FeCl3-induced carotid artery thrombosis mouse model, and further confirmed in a soluble tissue factor-induced thrombosis model. CONCLUSIONS: The data on CT-001 demonstrate that a short duration of highly active FVIIa procoagulant activity has the potential to be an optimal paradigm for the treatment of acute bleeds.
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Authors | Derek S Sim, Cornell R Mallari, John M Teare, Maxine Bauzon, Terry W Hermiston |
Journal | Thrombosis research
(Thromb Res)
Vol. 215
Pg. 58-66
(07 2022)
ISSN: 1879-2472 [Electronic] United States |
PMID | 35640516
(Publication Type: Journal Article)
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Copyright | Copyright © 2022 Elsevier Ltd. All rights reserved. |
Chemical References |
- Hemostatics
- Thromboplastin
- Factor VIIa
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Topics |
- Animals
- Disease Models, Animal
- Factor VIIa
(pharmacology, therapeutic use)
- Hemorrhage
(drug therapy)
- Hemostatics
- Humans
- Mice
- Thromboplastin
- Tomography, X-Ray Computed
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