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Rendering factor Xa zymogen-like as a therapeutic strategy to treat bleeding

Thalji, Nabil K.; Camire, Rodney M.

doi: 10.1097/MOH.0000000000000369
HEMOSTASIS AND THROMBOSIS: Edited by Alvin H. Schmaier
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Purpose of review New therapies are needed to control bleeding in a range of clinical conditions. This review will discuss the biochemical properties of zymogen-like factor Xa, its preclinical assessment in different model systems, and future development prospects.

Recent findings Underlying many procoagulant therapeutic approaches is the rapid generation of thrombin to promote robust clot formation. Clinically tested prohemostatic agents (e.g., factor VIIa) can provide effective hemostasis to mitigate bleeding in hemophilia and other clinical situations. Over the past decade, we explored the possibility of using zymogen-like factor Xa variants to rapidly improve clot formation for the treatment of bleeding conditions. Compared to the wild-type enzyme, these variants adopt an altered, low activity, conformation which enables them to resist plasma protease inhibitors. However, zymogen-like factor Xa variants are conformationally dynamic and ligands such as its cofactor, factor Va, stabilize the molecule rescuing procoagulant activity. At the site of vascular injury, the variants in the presence of factor Va serve as effective prohemostatic agents. Preclinical data support their use to stop bleeding in a variety of clinical settings. Phase 1 studies suggest that zymogen-like factor Xa is safe and well tolerated, and a phase 1b is ongoing to assess safety in patients with intracerebral hemorrhage.

Summary Zymogen-like factor Xa is a unique prohemostatic agent for the treatment of a range of bleeding conditions.

Division of Hematology, Department of Pediatrics, The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence to Rodney M. Camire, PhD, Division of Hematology, The Children's Hospital of Philadelphia, 5018 Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, PA 19104, USA. Tel: +1 215 590-9968; fax: +1 215 590 3660; e-mail: rcamire@mail.med.upenn.edu

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