Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model

Markus Honickel; Benjamin Maron; Joanne van Ryn; Till Braunschweig; Hugo ten Cate; Henri M. H. Spronk; Rolf Rossaint; Oliver Grottke

doi:10.1160/th15-03-0266

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(02): 271-284
DOI: 10.1160/th15-03-0266

Coagulation and Fibrinolysis

Schattauer GmbH

Therapy with activated prothrombin complex concentrate is effective in reducing dabigatran-associated blood loss in a porcine polytrauma model

Authors

Markus Honickel

¹Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
Benjamin Maron

¹Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
Joanne van Ryn

²CardioMetabolic Diseases Research, Boehringer Ingelheim GmbH & Co. KG, Biberach, Germany
Till Braunschweig

³Department of Pathology RWTH Aachen University Hospital, Aachen, Germany
Hugo ten Cate

⁴Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
Henri M. H. Spronk

⁴Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
Rolf Rossaint

¹Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
Oliver Grottke

¹Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany

Abstract

Summary

Clinical use of non-vitamin K antagonist oral anticoagulants is increasingly well established. However, specific agents for reversal of these drugs are not currently available. It was to objective of this study to investigate the impact of activated prothrombin complex concentrate (aPCC) on the anticoagulant effects of dabigatran in a randomised, controlled, porcine trauma model. Twenty-one pigs received oral and intravenous dabigatran, resulting in supratherapeutic plasma concentrations. Twelve minutes after injury (standardised bilateral femur fractures and blunt liver injury), animals (n=7/group) received 25 or 50 U/kg aPCC (aPCC25 and aPCC50) or placebo (control) and were followed for 5 hours. The primary endpoint was total volume of blood loss (BL). Haemodynamic and coagulation variables (prothrombin time [PT], activated partial thromboplastin time, diluted thrombin time, thrombin–antithrombin complexes, thromboelastometry, thrombin generation and D-dimers) were measured. Twelve minutes post-injury, BL was similar between groups. Compared with control (total BL: 3807 ± 570 ml) and aPCC25 (3690 ± 454 ml; p=0.77 vs control), a significant reduction in total BL (1639 ± 276 ml; p< 0.0001) and improved survival (p< 0.05) was observed with aPCC50. Dabigatran’s anticoagulant effects were effectively treated in the aPCC50 group, as measured by several parameters including EXTEM clotting time (CT) and PT. In contrast, with aPCC25, laboratory values were initially corrected but subsequently deteriorated due to ongoing blood loss. Thromboembolic or bleeding effects were not detected. In conclusion, blood loss following trauma in dabigatran-anticoagulated pigs was successfully reduced by 50 U/kg aPCC. Optimal methodology for measuring amelioration of dabigatran anticoagulation by aPCC is yet to be determined.

Keywords

Anticoagulants - aPCC - dabigatran - FEIBA - polytrauma - reversal - idarucizumab

Full Text

References

References
1 Miller CS, Grandi SM, Shimony A. et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012; 110: 453-460.
2 Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc 2013; 88: 495-511.
3 Pradaxa 110 mg hard capsules - Summary of Product Characteristics. Available at: http://www.medicines.org.uk/emc/medicine/20760#INDICATIONS Accessed September 18, 2014.
4 Levy JH, Faraoni D, Spring JL. et al. Managing new oral anticoagulants in the perioperative and intensive care unit setting. Anesthesiology 2013; 118: 1466-1474.
5 Maegele M, Lefering R, Yucel N. et al. Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury 2007; 38: 298-304.
6 Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care 2007; 13: 680-685.
7 Holbrook A, Schulman S, Witt DM. et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e152S-184S.
8 Spahn DR, Bouillon B, Cerny V. et al. Management of bleeding and coagulo-pathy following major trauma: an updated European guideline. Crit Care 2013; 17: R76.
9 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.
10 Khadzhynov D, Wagner F, Formella S. et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013; 109: 596-605.
11 Stangier J, Rathgen K, Stahle H. et al. Influence of renal impairment on the phar-macokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49: 259-268.
12 ClinicalTrials.gov. Reversal of Dabigatran Anticoagulant Effect With Idarucizu-mab. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02104947?term=nct02104947&rank=1 Accessed November 21, 2014.
13 Pollack Jr. CV, Reilly PA, Eikelboom J. et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015 Epub ahead of print.
14 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterisation. Blood 2013; 121: 3554-3562.
15 Greinacher A, Thiele T, Selleng K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015; 113: 931-942.
16 Lu G, DeGuzman FR, Hollenbach SJ. et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-451.
17 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.
18 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.
19 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.
20 Guide for the Care and Use of Laboratory Animals. 7th ed.. Institute of Laboratory Animal Resources, Commission of Life Sciences, National Research Council Washington DC: National Academy Press; 1996
21 Baxter Healthcare Ltd.. FEIBA 500 U powder and solvent for solution for infusion. Available at: https://www.medicines.org.uk/emc/medicine/30169 Accessed June 21, 2015.
22 Baker TA, Romero J, Bach HHt. 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 van Ryn J, Kink-Eiband M, Kuritsch I. et al. Meloxicam does not affect the anti-platelet effect of aspirin in healthy male and female volunteers. J Clin Pharmacol 2004; 44: 777-784.
26 Grottke O, Braunschweig T, Zimmermann L. et al. Recombinant factor VIIa reduces bleeding after blunt liver injury in coagulopathic, hypofibrinogenaemic pigs. Br J Anaesth 2010; 105: 789-797.
27 Zhou W, Schwarting S, Illanes S. et al. Hemostatic therapy in experimental intra-cerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke 2011; 42: 3594-3599.
28 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.
29 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.
30 Hess JR, Brohi K, Dutton RP. et al. The coagulopathy of trauma: a review of mechanisms. J Trauma 2008; 65: 748-754.
31 Brohi K, Cohen MJ, Ganter MT. et al. Acute coagulopathy of trauma: hypoperfu-sion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008; 64: 1211-1217.
32 Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion 2009; 49: 2652-2660.
33 Grottke O, Braunschweig T, Spronk HM. et al. Increasing concentrations of pro-thrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood 2011; 118: 1943-1951.
34 Dusel CH, Grundmann C, Eich S. et al. Identification of prothrombin as a major thrombogenic agent in prothrombin complex concentrates. Blood Coagul Fibri-nolysis 2004; 15: 405-411.
35 Schulman S, Ritchie B, Goy JK. et al. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol 2014; 164: 308-310.
36 Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med 2013; 41: e42-46.
37 Hoffman M, Dargaud Y. Mechanisms and monitoring of bypassing agent therapy. J Thromb Haemost 2012; 10: 1478-1485.
38 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.
39 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.
40 Herrmann R, Thom J, Wood A. et al. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and riva-roxaban. Thromb Haemost 2014; 111: 989-995.
41 Honickel M, Treutler S, van Ryn J. et al. Reversal of dabigatran anticoagulation ex vivo: Porcine study comparing prothrombin complex concentrates and ida-rucizumab. Thromb Haemost 2015; 113: 728-740.
42 Curvers J, van de Kerkhof D, Stroobants AK. et al. Measuring direct thrombin inhibitors with routine and dedicated coagulation assays: which assay is helpful?. Am J Clin Pathol 2012; 138: 551-558.
43 Davenport RA, Brohi K. Coagulopathy in trauma patients: importance of thrombocyte function?. Curr Opin Anaesthesiol 2009; 22: 261-266.
44 Schochl H, Voelckel W, Schlimp CJ. Management of traumatic haemorrhage the European perspective. Anaesthesia 2015; 70 (Suppl. 01) 102-107 e35-37.