title: Bioengineering factor Xa to treat bleeding.
abstract: There is a clinical need to develop safe and rapid therapeutic strategies to control bleeding arising from a host of emergent situations. Over the past several years our laboratory has developed novel zymogen-like FXa variants and tested their safety and efficacy using hemophilia as a model system. The variants have a spectrum of properties resulting from an amino acid change at the N-terminus of the heavy chain that alters a critical conformational change. These properties, which include resistance to plasma protease inhibitors, low activity in the absence of FVa, and rescue of low activity upon incorporation in prothrombinase, yield remarkably effective pro-hemostatic agents. The FVa-dependent restoration of activity is a key aspect to their efficacy and also contributes to localizing the variants to the site of vascular injury. While pre-clinical data support their use in the setting of hemophilia, they have the potential to act as rapid pro-hemostatic agents for the treatment of a range of bleeding conditions. This review will discuss the biochemical properties of these FXa zymogen-like variants and their in vivo characterization.
authors.affiliation: The Children's Hospital of Philadelphia, The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, and Division of Hematology, Department of Pediatrics, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104. Electronic address: rcamire@mail.med.upenn.edu.
authors.forename: Rodney M
authors.initials: RM
authors.lastname: Camire
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D015951:Factor Xa / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy*; D002836:Hemophilia B / Q000097:blood / Q000188:drug therapy*; D006470:Hemorrhage / Q000097:blood / Q000188:drug therapy*; D006490:Hemostatics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D015202:Protein Engineering
chemical_list: D004792:Enzyme Precursors; D006490:Hemostatics; D015951:Factor Xa
keywords: bleeding; factor Xa; hemophilia; hemostatic agent; procoagulant; zymogen