Eva Herzog1, Franz Kaspereit2, Wilfried Krege3, Jochen Mueller-Cohrs4, Baerbel Doerr5, Peter Niebl6, Gerhard Dickneite7. 1. Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: eva.herzog@cslbehring.com. 2. Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: franz.kaspereit@cslbehring.com. 3. Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: wilfried.krege@cslbehring.com. 4. Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: jochen.mueller-cohrs@cslbehring.com. 5. Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: baerbel.doerr@cslbehring.com. 6. Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: peter.niebl@cslbehring.com. 7. Preclinical Research & Development, CSL Behring GmbH, PO Box 1230, 35002 Marburg, Germany. Electronic address: gerhard.dickneite@cslbehring.com.
Abstract
INTRODUCTION: Rivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of its clinical use is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery). MATERIALS AND METHODS: This study assessed the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex(®)/Kcentra(®)) for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model, and evaluated the correlations between in vitro coagulation parameters and haemostasis in vivo. RESULTS: Administration of single intravenous doses of rivaroxaban (150-450 μg/kg) resulted in increased and prolonged bleeding following standardised kidney incision. Pre-incision treatment with 4F-PCC (25-100 IU/kg) resulted in a dose-dependent reversal of rivaroxaban (150 and 300 μg/kg)-associated increases in time to haemostasis and blood loss; no reversal was seen at the highest rivaroxaban dose (450 μg/kg). Of the in vitro biomarkers tested, thrombin generation and whole-blood clotting time correlated well with in vivo measures of 4F-PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using the phospholipid-only reagent being the most predictive of effective haemostasis in vivo. CONCLUSIONS: In summary, in a rabbit model of acute bleeding, treatment with 4F-PCC reduced bleeding to control levels following rivaroxaban 150 μg/kg and 300 μg/kg administration.
INTRODUCTION:Rivaroxaban is an oral, selective direct factor Xa inhibitor approved for several indications in patients at risk of thrombotic events. One limitation of its clinical use is the lack of data pertaining to its reversal in situations where urgent response is critical (e.g. acute bleeding events or emergency surgery). MATERIALS AND METHODS: This study assessed the effectiveness of a four-factor prothrombin complex concentrate (4F-PCC; Beriplex(®)/Kcentra(®)) for the reversal of rivaroxaban-associated bleeding in an in vivo rabbit model, and evaluated the correlations between in vitro coagulation parameters and haemostasis in vivo. RESULTS: Administration of single intravenous doses of rivaroxaban (150-450 μg/kg) resulted in increased and prolonged bleeding following standardised kidney incision. Pre-incision treatment with 4F-PCC (25-100 IU/kg) resulted in a dose-dependent reversal of rivaroxaban (150 and 300 μg/kg)-associated increases in time to haemostasis and blood loss; no reversal was seen at the highest rivaroxaban dose (450 μg/kg). Of the in vitro biomarkers tested, thrombin generation and whole-blood clotting time correlated well with in vivo measures of 4F-PCC-mediated effects. Thrombin generation was highly reagent-dependent, with the assay initiated using the phospholipid-only reagent being the most predictive of effective haemostasis in vivo. CONCLUSIONS: In summary, in a rabbit model of acute bleeding, treatment with 4F-PCC reduced bleeding to control levels following rivaroxaban 150 μg/kg and 300 μg/kg administration.
Authors: Rolf Rossaint; Bertil Bouillon; Vladimir Cerny; Timothy J Coats; Jacques Duranteau; Enrique Fernández-Mondéjar; Daniela Filipescu; Beverley J Hunt; Radko Komadina; Giuseppe Nardi; Edmund A M Neugebauer; Yves Ozier; Louis Riddez; Arthur Schultz; Jean-Louis Vincent; Donat R Spahn Journal: Crit Care Date: 2016-04-12 Impact factor: 9.097
Authors: Herm Jan M Brinkman; Frauke Swieringa; Marleen Zuurveld; Alicia Veninga; Sanne L N Brouns; Johan W M Heemskerk; Joost C M Meijers Journal: Res Pract Thromb Haemost Date: 2022-04-25
Authors: E Herzog; F Kaspereit; W Krege; J Mueller-Cohrs; B Doerr; P Niebl; G Dickneite Journal: J Thromb Haemost Date: 2015-11-24 Impact factor: 5.824