Reversal of rivaroxaban anticoagulant effect by prothrombin complex concentrates: which dose is sufficient to restore no
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Reversal of rivaroxaban anticoagulant effect by prothrombin complex concentrates: which dose is sufficient to restore normal thrombin generation? Lorine Giffard-Quillon1, Helene Desmurs-Clavel1,2, Claire Grange1,3, Yohann Jourdy4 and Yesim Dargaud1,4,5* Abstract Rivaroxaban has the most available data to support the use of prothrombin complex concentrates (PCC) as a reversal agent. However, PCC might increase the incidence of thrombotic events by shifting the haemostatic balance towards hypercoagulability. We assessed the in vitro efficacy and safety of three 4-factor PCCs for reversing rivaroxaban anticoagulant effect. Our in vitro finding indicates that 4-factor PCCs at the dose of 25 U.kg− 1 may be sufficient to reverse rivaroxaban anticoagulant effect. Rivaroxaban is a direct oral activated factor X inhibitor. One of the main advantages of direct acting oral anticoagulants (DOAC) is the lower incidence of major bleeding complications, with 50% lower chances of intracranial haemorrhages compared with warfarin. However, DOAC may increase gastrointestinal bleeding and have been associated with heavy menstrual bleeding [1, 2]. Therefore, neutralization of the anticoagulant effect is a key step in the management of DOAC-related major bleeding complications. Andexanet-α is a catalytically inactive recombinant factor Xa protein that binds to both factor Xa inhibitors and native factor Xa (1:1 ratio), thus acting as competitive inhibitor. However, andexanet-α has been only conditionally approved by the European Medicines Agency because of the observed high incidence of thromboembolic events [3]. International guidelines recommend the administration of prothrombin complex concentrates (PCCs) in case of life* Correspondence: [email protected] 1 GEMMAT Groupe d’Etude Multidisciplinaire en Maladies Thrombotiques, Lyon, France 4 Laboratoire d’Hematologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France Full list of author information is available at the end of the article
threatening bleeding caused by DOACs, in the absence of specific reversal agents [3, 4]. The initial dose of 50 U.kg1 is effective for achieving haemostasis and restoring thrombin generation. However, different groups have recently reported that PCCs at 25 U.kg− 1 provides effective anticoagulant reversal in patients with major bleeding complications associated with factor Xa inhibitors [5, 6]. Moreover, some experts suggested that activated PCC (APCC, FEIBA©, Takeda, Japan) could be an effective strategy to improve haemostasis in DOAC-related major bleeding events [7, 8]. Although clinical guidelines recommend PCCs for the treatment of DOAC-associated bleeding events [9], some authors suggested that PCCs may not be effective in this situation [10]. In the present study, we assessed the in vitro efficacy and safety of three 4-factor PCCs that contain the human coagulation factors II, VII, IX and X and are commercially available in France for reversing rivaroxaban anticoagulant effect. After informe
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