A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa
Genmin Lu,Francis DeGuzman,Stanley J. Hollenbach,Mark Karbarz,Keith Abe,Gail Lee,Peng Luan,Athiwat Hutchaleelaha,Mayuko Inagaki,Pamela B. Conley,David Phillips,Uma Sinha +11 more
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TLDR
In this article, a modified form of coagulation factor Xa (fXa) was used as an antidote for fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors.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.read more
Citations
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The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition
Rolf Rossaint,Bertil Bouillon,Vladimir Cerny,Timothy J Coats,Jacques Duranteau,Enrique Fernández-Mondéjar,Daniela Filipescu,Beverley J. Hunt,Radko Komadina,Giuseppe Nardi,Edmund Neugebauer,Yves Ozier,Louis Riddez,Arthur Schultz,Jean Louis Vincent,Donat R. Spahn +15 more
TL;DR: The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation, and may also serve as a basis for local implementation.
Journal ArticleDOI
Management of severe perioperative bleeding Guidelines from the European Society of Anaesthesiology
Sibylle A. Kozek-Langenecker,Arash Afshari,Pierre Albaladejo,Cesar Aldecoa Alvarez Santullano,Edoardo De Robertis,Daniela Filipescu,Dietmar Fries,Thorsten Haas,Georgina Imberger,Matthias Jacob,Marcus D. Lancé,Juan V. Llau,Susan Mallett,Jens Meier,Niels Rahe-Meyer,Charles Marc Samama,Andrew Smith,Cristina Solomon,Philippe Van der Linden,Anne Wikkelsø,Patrick Wouters,Piet Wyffels +21 more
TL;DR: These guidelines are intended to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible.
Journal ArticleDOI
Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity
Abstr Act,Deborah M. Siegal,John T. Curnutte,Stuart J. Connolly,Genmin Lu,Pamela B. Conley,Brian L. Wiens,Vandana Mathur,Janice Castillo,Michele D. Bronson,Janet M. Leeds,Florie A. Mar,Alex Gold,Mark Crowther +13 more
TL;DR: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.
Journal ArticleDOI
Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report
Gregory Y.H. Lip,Amitava Banerjee,Giuseppe Boriani,Chern En Chiang,Ramiz Fargo,Ben Freedman,Deirdre A. Lane,Christian T. Ruff,Mintu P. Turakhia,David J. Werring,Sheena Patel,Lisa K. Moores +11 more
TL;DR: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF with ≥1 non‐sex CHA2DS2‐VASc stroke risk factor(s), and stroke prevention (ie, oral antICOagulation therapy) is the next step.
Journal ArticleDOI
Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors
Stuart J. Connolly,Truman J. Milling,John W. Eikelboom,C. Michael Gibson,John T. Curnutte,Alex Gold,Michele D. Bronson,Genmin Lu,Pamela B. Conley,Peter Verhamme,Jeannot Schmidt,Saskia Middeldorp,Alexander T. Cohen,Jan Beyer-Westendorf,Pierre Albaladejo,Jose Lopez-Sendon,Shelly Goodman,Janet M. Leeds,Brian L. Wiens,Deborah M. Siegal,Elena Zotova,Brandi Meeks,Juliet Nakamya,W. Ting Lim,Mark Crowther +24 more
TL;DR: An initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%.
References
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Apixaban versus Warfarin in Patients with Atrial Fibrillation
Christopher B. Granger,John H. Alexander,Renato D. Lopes,Elaine M. Hylek,Michael G. Hanna,Hussein R. Al-Khalidi,Jack Ansell,Dan Atar,Alvaro Avezum,M. Cecilia Bahit,Rafael Diaz,J. Donald Easton,Justin A. Ezekowitz,Greg C. Flaker,David A. Garcia,Margarida Geraldes,Bernard J. Gersh,Sergey P. Golitsyn,Shinya Goto,Antonio G. Hermosillo,Stefan H. Hohnloser,John D. Horowitz,Puneet Mohan,Petr Jansky,Basil S. Lewis,Jose Lopez-Sendon,Prem Pais,Alexander Parkhomenko,Jun Zhu,Lars Wallentin +29 more
TL;DR: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.
Journal ArticleDOI
Apixaban in Patients with Atrial Fibrillation
Stuart J. Connolly,John W. Eikelboom,Campbell D. Joyner,Hans-Christoph Diener,Robert G. Hart,Sergey P. Golitsyn,Greg C. Flaker,Alvaro Avezum,Stefan H. Hohnloser,Rafael Diaz,Mario Talajic,Jun Zhu,Prem Pais,Andrzej Budaj,Alexander Parkhomenko,Petr Jansky,Patrick J. Commerford,Ru San Tan,Kui-Hian Sim,Basil S. Lewis,Walter Van Mieghem,Jae Hyung Kim,Fernando Lanas-Zanetti,Antonio Gonzalez-Hermosillo,Antonio L. Dans,Muhammad Munawar,John H. Lawrence,Gayle Lewis,Rizwan Afzal,Salim Yusuf +29 more
TL;DR: In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing therisk of major bleeding or intracranial hemorrhage.
Journal ArticleDOI
Rivaroxaban in Patients with a Recent Acute Coronary Syndrome
Jessica L. Mega,Eugene Braunwald,Stephen D. Wiviott,Jean-Pierre Bassand,Deepak L. Bhatt,Christoph Bode,Paul Burton,Marc Cohen,Nancy Cook-Bruns,Shinya Goto,Sabina A. Murphy,Alexei N. Plotnikov,David J. Schneider,Xiang Sun,C. Michael Gibson +14 more
TL;DR: In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke in a double-blind, placebo-controlled trial.
Journal ArticleDOI
Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.
Elise S. Eerenberg,Pieter Willem Kamphuisen,Meertien K. Sijpkens,Joost C. M. Meijers,Harry R. Büller,Marcel Levi +5 more
TL;DR: In this article, the authors evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of Rivaroxaban and dabigatran.
Journal ArticleDOI
Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.
Michael R. Lassen,Walter Ageno,Lars C. Borris,Jay R. Lieberman,Nadia Rosencher,Tiemo J. Bandel,Frank Misselwitz,Alexander G.G. Turpie +7 more
TL;DR: Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding.
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