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Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and idarucizumab
29 August 2014
Accepted after major revision: 19 January 2014
24 November 2017 (online)
Urgent surgery or life-threatening bleeding requires prompt reversal of the anticoagulant effects of dabigatran. This study assessed the ability of three- and four-factor prothrombin complex concentrate (PCC) and idarucizumab (specific antidote for dabigatran) to reverse the anticoagulant effects of dabigatran in a porcine model of trauma. Twelve animals were given dabigatran etexilate (DE) orally and dabigatran intravenously, before infliction of trauma. Six animals received tranexamic acid plus fibrinogen concentrate 12 minutes post-injury. Six PCCs (each 30 and 60 U/kg) and idarucizumab (30 and 60 mg/kg) were added to blood samples ex vivo. Coagulation was assessed by several coagulation assays. All coagulation parameters were altered after dabigatran infusion (plasma level: 442 ± 138 ng/ml). Both threeand four-factor PCCs mostly or completely reversed the effects of dabigatran on thromboelastometry variables and PT but not on aPTT. Idarucizumab neutralised plasma concentrations of dabigatran, and reversed the effects of the drug on coagulation variables. Thrombin generation showed dose-dependent over-correction following the addition of PCC, implying that elevated levels of thrombin are required to overcome dabigatran-induced coagulopathy. In contrast, treatment with idarucizumab returned thrombin generation to baseline levels. Following trauma, therapy with tranexamic acid plus fibrinogen improved correction of coagulation parameters by PCC, and thromboelastometry parameters by idarucizumab. All investigated PCCs improved dabigatran- and trauma-induced coagulopathy to a similar degree. In conclusion, this study shows that three- and four-factor PCCs are similarly effective for dabigatran reversal. Idarucizumab also reversed the effects of dabigatran and, unlike PCCs, was not associated with over-correction of thrombin generation.
Note: This study was performed at the RWTH Aachen University Hospital, Pauwelsstrasse 30, D-52074 Aachen, Germany.
- 1 Pradaxa summary of product characteristics. Available from http://www.medicines.org.uk/emc/medicine/20760#INDICATIONS Accessed August 2014
- 2 van Ryn J, Goss A, Hauel N. et al. The discovery of dabigatran etexilate. Front Pharmacol 2013; 04: 12.
- 3 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
- 4 Spahn DR, Bouillon B, Cerny V. et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 2013; 17: R76.
- 5 Liesenfeld KH, Staab A, Hartter S. et al. Pharmacometric characterization of dabigatran hemodialysis. Clin Pharmacokinet 2013; 52: 453-462.
- 6 Heidbuchel H, Verhamme P, Alings M. et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15: 625-651.
- 7 Dickneite G, Pragst I. Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model. Br J Anaesth 2009; 102: 345-354.
- 8 Grottke O, Braunschweig T, Spronk HM. et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood 2011; 118: 1943-1951.
- 9 Honickel M, Rieg A, Rossaint R. et al. Prothrombin complex concentrate reduces blood loss and enhances thrombin generation in a pig model with blunt liver injury under severe hypothermia. Thromb Haemost 2011; 106: 724-733.
- 10 Grottke O, Rossaint R, Henskens Y. et al. Thrombin generation capacity of prothrombin complex concentrate in an in vitro dilutional model. PLoS One 2013; 08: e64100.
- 11 Sarode R, Milling Jr. TJ, Refaai MA. et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128: 1234-1243.
- 12 Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?. Thromb Haemost 2014; 111: 189-198.
- 13 Siegal DM, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis 2013; 35: 391-398.
- 14 Grottke O, van Ryn J, Spronk HM. et al. Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model. Crit Care 2014; 18: R27.
- 15 Herzog E, Kaspereit FJ, Krege W. et al. Thrombotic safety of prothrombin complex concentrate (Beriplex P/N) for dabigatran reversal in a rabbit model. Thromb Res 2014; 134: 729-736.
- 16 Pragst I, Zeitler SH, Doerr B. et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost 2012; 10: 1841-1848.
- 17 CRASH-2 collaborators. Roberts I, Shakur H. et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377: 1096-1101.
- 18 Davenport R, Brohi K. Fibrinogen depletion in trauma: early, easy to estimate and central to trauma-induced coagulopathy. Crit Care 2013; 17: 190.
- 19 Rourke C, Curry N, Khan S. et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost 2012; 10: 1342-1351.
- 20 Schlimp CJ, Voelckel W, Inaba K. et al. Impact of fibrinogen concentrate alone or with prothrombin complex concentrate (+/-fresh frozen plasma) on plasma fibrinogen level and fibrin-based clot strength (FIBTEM) in major trauma: a retrospective study. Scand J Trauma Resusc Emerg Med 2013; 21: 74.
- 21 Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council. Guide for the Care and Use of Laboratory Animals. 7th edition. Washington DC: National Academy Press; 1996
- 22 Baker TA, Romero J, Bach 4th HH. et al. Systemic release of cytokines and heat shock proteins in porcine models of polytrauma and hemorrhage. Crit Care Med 2012; 40: 876-885.
- 23 Grottke O, Braunschweig T, Philippen B. et al. A new model for blunt liver injuries in the swine. Eur Surg Res 2010; 44: 65-73.
- 24 Spronk HM, Dielis AW, De Smedt E. et al. Assessment of thrombin generation II: Validation of the Calibrated Automated Thrombogram in platelet-poor plasma in a clinical laboratory. Thromb Haemost 2008; 100: 362-364.
- 25 Honickel M, Van Ryn J, Spronk HM. et al. Prothrombin complex concentrate restores haemostasis in a dabigatran anticoagulated polytrauma pig model. Crit Care 2014; 18 (Suppl. 01) P115.
- 26 van Ryn J, Schurer J, Kink-Eiband M. et al. Reversal of dabigatran-induced bleeding by coagulation factor concentrates in a rat-tail bleeding model and lack of effect on assays of coagulation. Anesthesiology 2014; 120: 1429-1440.
- 27 Lambourne MD, Eltringham-Smith LJ, Gataiance S. et al. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J Thromb Haemost 2012; 10: 1830-1840.
- 28 Zhou W, Schwarting S, Illanes S. et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42: 3594-3599.
- 29 Herrmann R, Thom J, Wood A. et al. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 2014; 111: 989-995.
- 30 Marlu R, Hodaj E, Paris A. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108: 217-224.
- 31 Harinstein LM, Morgan JW, Russo N. Treatment of dabigatran-associated bleeding: case report and review of the literature. J Pharm Pract 2013; 26: 264-269.
- 32 Eerenberg ES, Kamphuisen PW, Sijpkens MK. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573-1579.
- 33 Schochl H, Voelckel W, Maegele M. et al. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit Care 2014; 18: R147.
- 34 Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014; 89: 228-232.
- 35 Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Engl J Med 2011; 365: 2039-2040.
- 36 Glund S, Stangier J, Schmohl M. et al. A Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Healthy Male Volunteers. Circulation 2013; 128: A17765.
- 37 Grottke O. Coagulation management. Curr Opin Crit Care 2012; 18: 641-646.
- 38 Kind SL, Spahn-Nett GH, Emmert MY. et al. Is dilutional coagulopathy induced by different colloids reversible by replacement of fibrinogen and factor XIII concentrates?. Anesth Analg 2013; 117: 1063-1071.
- 39 Zentai C, Braunschweig T, Schnabel J. et al. Fibrinogen Concentrate Does Not Suppress Endogenous Fibrinogen Synthesis in a 24-hour Porcine Trauma Model. Anesthesiology 2014; 121: 753-764.
- 40 Wagner CL, Mascelli MA, Neblock DS. et al. Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 1996; 88: 907-914.
- 41 Fries D, Innerhofer P, Reif C. et al. The effect of fibrinogen substitution on reversal of dilutional coagulopathy: an in vitro model. Anesth Analg 2006; 102: 347-351.
- 42 Grottke O, Braunschweig T, Henzler D. et al. Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury. Crit Care 2010; 14: R62.
- 43 Connors NJ, Gill J, Nakanishi A. et al. Porcine blood and surrogate markers do not prove benefit of aDabi-Fab. Crit Care 2014; 18: 435.
- 44 Tanaka KA, Bolliger D. On the reversal of new oral anti-coagulants: can we simply extrapolate data from the animal models to humans?. Br J Anaesth 2013; 110: 329-332.