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      Reversal of direct oral anticoagulants in hemophilia treatment : ASH meeting 2015

      review-article
      , MD ,
      Memo
      Springer Vienna
      Thrombophilia screening, Pregnancy, Anticoagulation, Antidote, Hemophilia A, Inhibitor

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          Summary

          During the 57 th annual meeting of the American Society of Hematology 2015 in Orlando, Florida, various aspects in the field of hemostaseology were presented. The Choosing Wisely® campaign pointed out the importance of the critical use of diagnostic tools to rule out pulmonary embolism and questioned the relevance of thrombophilia testing in women undergoing routine infertility evaluation. Furthermore, the approval of idarucizumab, a specific antidote for the reversal of the anticoagulant effects of the direct thrombin inhibitor dabigatran, was highlighted. Finally, hemophilia specialists awaited the results of the SIPPET Trial, which were presented for the first time during the plenary session. Replacement therapy of previously untreated hemophilia A patients with plasma-derived factor VIII containing von Willebrand factor resulted in a lower incidence of inhibitors compared with patients treated with recombinant factor VIII.

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          Most cited references16

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          Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation.

          It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding.
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            Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.

            Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P<0.001) that was immediately and completely reversed by PCC (12.8±1.0; P<0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P=0.002) and normalized with PCC (114±26%; P<0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration- URL: http://www.trialregister.nl. Unique identifier: NTR2272.
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              A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa.

              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.
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                Author and article information

                Contributors
                +43-512-50482272 , +43-512-50424006 , clemens.feistritzer@i-med.ac.at
                Journal
                Memo
                Memo
                Memo
                Springer Vienna (Vienna )
                1865-5041
                1865-5076
                12 September 2016
                12 September 2016
                2016
                : 9
                : 3
                : 131-135
                Affiliations
                Internal Medicine V – Hematology and Oncology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria
                Author information
                http://orcid.org/0000-0001-5182-7217
                Article
                284
                10.1007/s12254-016-0284-2
                5045483
                c101c9e9-3a9d-4912-8101-4ebed84fd048
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 7 June 2016
                : 17 August 2016
                Categories
                Short Review
                Custom metadata
                © Springer-Verlag Wien 2016

                thrombophilia screening,pregnancy,anticoagulation,antidote,hemophilia a,inhibitor

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