title: A rapid pro-hemostatic approach to overcome direct oral anticoagulants.
abstract: Direct inhibitors of coagulation factor Xa (FXa) or thrombin are promising oral anticoagulants that are becoming widely adopted. The ability to reverse their anticoagulant effects is important when serious bleeding occurs or urgent medical procedures are needed. Here, using experimental mouse models of hemostasis, we show that a variant coagulation factor, FXa(I16L), rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXa(I16L) to reverse the anticoagulant effects of FXa inhibitor depends, at least in part, on the ability of the active site inhibitor to hinder antithrombin-dependent FXa inactivation, paradoxically allowing uninhibited FXa to persist in plasma. Because of its inherent catalytic activity, FXa(I16L) is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXa(I16L) also reduces the anticoagulant-associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXa(I16L) may be able to fill an important unmet clinical need for a rapid, pro-hemostatic agent to reverse the effects of several new anticoagulants.
authors.affiliation: Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.|Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Division of Hematology, Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Nabil K
authors.initials: NK
authors.lastname: Thalji
authors.affiliation: Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.|Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Division of Hematology, Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Lacramioara
authors.initials: L
authors.lastname: Ivanciu
authors.affiliation: Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.|Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Davidson
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.|Division of Hematology, Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswamy
authors.affiliation: Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania, USA.|Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.|Division of Hematology, Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Rodney M
authors.initials: RM
authors.lastname: Camire
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D015951:Factor Xa / Q000737:chemistry / Q000494:pharmacology*; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D000069552:Rivaroxaban / Q000494:pharmacology*; D013916:Thrombelastography
chemical_list: D000931:Antidotes; D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban; D015951:Factor Xa