title: A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa.
abstract: Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.
authors: Department of Biology, Portola Pharmaceuticals Inc., South San Francisco, California, USA.
authors: Genmin
authors: G
authors: Lu
authors: Francis R
authors: FR
authors: DeGuzman
authors: Stanley J
authors: SJ
authors: Hollenbach
authors: Mark J
authors: MJ
authors: Karbarz
authors: Keith
authors: K
authors: Abe
authors: Gail
authors: G
authors: Lee
authors: Peng
authors: P
authors: Luan
authors: Athiwat
authors: A
authors: Hutchaleelaha
authors: Mayuko
authors: M
authors: Inagaki
authors: Pamela B
authors: PB
authors: Conley
authors: David R
authors: DR
authors: Phillips
authors: Uma
authors: U
authors: Sinha
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000037:antagonists & inhibitors*; D000931:Antidotes / Q000494:pharmacology*; D001549:Benzamides / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000037:antagonists & inhibitors; D015951:Factor Xa / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D000077425:Fondaparinux; D006470:Hemorrhage / Q000188:drug therapy; D006487:Hemostasis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000037:antagonists & inhibitors; D011134:Polysaccharides / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000037:antagonists & inhibitors; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D000069552:Rivaroxaban; D013876:Thiophenes / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D000931:Antidotes; D001549:Benzamides; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D009025:Morpholines; C580915:PRT064445; D011134:Polysaccharides; D011720:Pyrazoles; D011725:Pyridines; D011728:Pyridones; D011994:Recombinant Proteins; D013876:Thiophenes; C522181:apixaban; C543086:betrixaban; D000069552:Rivaroxaban; D015951:Factor Xa; D000077425:Fondaparinux