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

Markus Honickel
1  Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
,
Benjamin Maron
1  Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
,
Joanne van Ryn
2  CardioMetabolic Diseases Research, Boehringer Ingelheim GmbH & Co. KG, Biberach, Germany
,
Till Braunschweig
3  Department of Pathology RWTH Aachen University Hospital, Aachen, Germany
,
Hugo ten Cate
4  Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
,
Henri M. H. Spronk
4  Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
,
Rolf Rossaint
1  Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
,
Oliver Grottke
1  Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
› Author Affiliations
Financial support: Meridian HealthComms provided editorial assistance, funded by Boehringer Ingelheim, Germany. This study was supported by Boehringer Ingelheim, Germany and the START program of the Faculty of Medicine, RWTH Aachen.
Further Information

Publication History

Received: 29 March 2015

Accepted after major revision: 20 July 2015

Publication Date:
29 November 2017 (online)

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.