Thromb Haemost 2010; 103(06): 1116-1127
DOI: 10.1160/TH09-11-0758
Clinical Focus
Schattauer GmbH

Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity

Joanne van Ryn
1   Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Joachim Stangier
2   Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Sebastian Haertter
2   Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Karl-Heinz Liesenfeld
2   Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Wolfgang Wienen
3   Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Martin Feuring
4   Department of Medical Affairs, Boehringer Ingelheim GmbH, Ingelheim, Germany
Andreas Clemens
4   Department of Medical Affairs, Boehringer Ingelheim GmbH, Ingelheim, Germany
› Author Affiliations
Further Information

Publication History

Received: 05 November 2009

Accepted after major revision: 15 January 2010

Publication Date:
22 November 2017 (online)


Dabigatran etexilate is an oral, reversible direct thrombin inhibitor that is approved in the EU and several other countries for the prevention of venous thromboembolism after elective hip and knee replacement, and is in advanced clinical development for other thromboembolic disorders. Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for routine coagulation monitoring. In certain clinical situations such as serious bleeding into critical organs (e.g. intracerebral bleeding), potential overdose and emergency surgery, clinicians will need to make an assessment of the anticoagulant status of a patient receiving dabigatran before deciding on future management strategies. If available, thrombin clotting time (TT), ecarin clotting time (ECT) and TT determined by Hemoclot thrombin inhibitor assay are sensitive tests to evaluate the anticoagulant effects of dabigatran. Prothrombin time (INR) is less sensitive than other assays and cannot be recommended. The activated partial thromboplastin time (aPTT) can provide a useful qualitative assessment of anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels. There are limited data for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity. In case of potential overdose, the feasibility of early administration of activated charcoal and subsequent charcoal filtration are undergoing preclinical evaluation. Dabigatran can also be dialysed in patients with renal impairment. In instances of life-threatening bleeding, where conventional measures have failed or are unavailable, other non-specific prohaemo -static agents such as recombinant activated factor VII and prothrombin complex concentrates can be considered.

Disclosure statement: All authors are employees of Boehringer Ingelheim.

Figure 1 has been corrected in this version of the article.

  • References

  • 1 Hauel NH, Nar H, Priepke H. et al. Structure-based design of novel potent non-peptide thrombin inhibitors. J Med Chem 2002; 45: 1757-1766.
  • 2 Wienen W, Stassen JM, Priepke H. et al. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 2007; 98: 155-162.
  • 3 van Ryn J, Hauel N, Waldmann L. et al. Dabigatran inhibits both clot-bound and fluid phase thrombin in vitro: Effects compared to heparin and hirudin (abstract). Blood 2007; 110: 3998.
  • 4 Connolly SJ, Ezekowitz MD, Yusuf S. et al the RE-LY Steering Committee and Investigators.. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
  • 5 Schulman S, Kearon C, Kakkar AK. et al the RE-COVER Study Group.. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
  • 6 Oldgren J, Budaj A, Granger CB. et al. Randomised dabigatran etexilate dose finding study in patients with acute coronary syndromes post index event with additional risk factors for cardiovascular complications also receiving aspirin and clopidogrel (RE-DEEM)(Abstract 165). Presented at American Heart Association Scientific Sessions 2009; Nov. 14–18, 2009; Orlando, FL,USA. AHA 2009.
  • 7 Blech S, Ebner T, Ludwig-Schwellinger E. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
  • 8 Liesenfeld KH, Schäfer HG, Trocóniz IF. et al. Effects of the direct thrombin inhibitor dabigatran on ex vivo coagulation time in orthopaedic surgery patients: a population model analysis. Br J Clin Pharmacol 2006; 62: 527-537.
  • 9 Stangier J, Nehmiz G, Reilly P. et al. Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran in a dose finding trial in atrial fibrillation (abstract). J Thromb Haemost 2005; 03 (Suppl. 01) OR271.
  • 10 Ezekowitz MD, Reilly PA, Nehmiz G. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100: 1419-1426.
  • 11 Stangier J, Rathgen K, Stähle H. et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate. Clin Pharmacokinet 2010; 49: 259-268.
  • 12 European Medicines Agency.. Pradaxa. Summary of Product Characteristics. Available from: [Accessed 2009, Aug 21].
  • 13 Stangier J, Eriksson BI, Dahl OE. et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45: 555-563.
  • 14 Stangier J, Rathgen K, Stähle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
  • 15 Stangier J, Stähle H, Rathgen K. et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47-59.
  • 16 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
  • 17 Stangier J. The use of the safety biomarker aPTT in a phase II clinical study with a novel direct thrombin inhibitor in patients with atrial fibrillation. Presentation at Biomarkers Europe meeting, 5th November 2007, Vienna, Austria.
  • 18 Carlsson SC, Mattsson C, Eriksson UG. et al. A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays. Thromb Res 2005; 115: 9-18.
  • 19 Ulehlova J, Slavik L, Krcova V. et al. Laboratory monitoring of dabigatran during orthopedic surgery (abstract PP-WE-142). J Thromb Haemost 2009; 07 (Suppl. 02) 674.
  • 20 Johansson S, Wåhlander K, Larson G. et al. Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men. Blood Coagul Fibrinolysis 2003; 14: 677-684.
  • 21 Stangier J, Wetzel K, Wienen W. et al. Measurement of the pharmacodynamic effect of dabigatran etexilate: thrombin clotting time (abstract PP-TH-134). J Thromb Haemost 2009; 07 (Suppl. 02) 978.
  • 22 Peyrafitte M, Vissac A, Amiral J. Direct thrombin inhibitors’ activity measurement in plasma (abstract no. PP6.6–8). 53rd Annual Meeting of the Society on Thrombosis and Haemostasis Research, February 4–7 2009, Vienna, Austria.
  • 23 Mitchell LG, Dietrich K, Stang L. et al. Comparison of Hemoclot to standard coagulation assays for monitoring the direct thrombin inhibitor (dabigatran) in pediatric patients: an in vitro study (abstract PP-WE-448). J Thromb Haemost 2009; 07 (Suppl. 02) 777.
  • 24 Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 2003; 33: 173-183.
  • 25 Rao SV, O’Grady K, Pieper KS. et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005; 96: 1200-1206.
  • 26 Eikelboom JW, Mehta SR, Anand SS. et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774-782.
  • 27 Manoukian SV, Feit F, Mehran R. et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol 2007; 49: 1362-1368.
  • 28 Hirsh J, Bauer KA, Donati MB. et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06) 141S-159S.
  • 29 Porsche R, Brenner ZR. Allergy to protamine sulfate. Heart Lung 1999; 28: 418-428.
  • 30 Lubetsky A, Yonath H, Olchovsky D. et al. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 2003; 163: 2469-2473.
  • 31 Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev 2007; 21: 37-48.
  • 32 van Ryn J, Sieger P, Kink-Eiband M. et al. Adsorption of dabigatran etexilate in water or dabigatran in pooled human plasma by activated charcoal in vitro [Abstract no. 1065]. In: 51st ASH Annual Meeting and Exposition [website]. New Orleans (LA): American Society of Hematology; 2009. Available at: (accessed 2009 Dec 1).
  • 33 Wolowacz SE, Roskell NS, Plumb JM. et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost 2009; 101: 77-85.
  • 34 Eriksson BI, Kurth AA, Friedman RJ. et al. Risk of bleeding with dabigatran etexilate in patients undergoing major orthopaedic surgery is not increased by concomitant use of non-steroidal anti-inflammatory drugs or acetylsalicylic acid (abstract PP-MO-167). J Thromb Haemost 2009; 07 (Suppl. 02) 374.
  • 35 Holmes Jr DR, Kereiakes DJ, Kleiman NS. et al. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009; 54: 95-109.
  • 36 Fernlöf G, Sjöström BM, Lindell KM. et al. Management of major bleedings during anticoagulant treatment with the oral direct thrombin inhibitor ximelagatran or warfarin. Blood Coagul Fibrinolysis 2009; 20: 667-674.
  • 37 Crowther MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost 2009; 07 (Suppl. 01) 107-110.
  • 38 Monroe DM, Hoffman M, Oliver JA. et al. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997; 99: 542-547.
  • 39 Sartori MT, Imbergamo S, Zanon E. et al. Effect of recombinant activated Factor VII in critical bleeding: Clinical experience of a single center. Clin Appl Thromb Hemost 2009; 15: 628-635.
  • 40 Gruber A, Carlsson S, Kotze HF. et al. Hemostatic effect of activated factor VII without promotion of thrombus growth in melagatran-anticoagulated primates. Thromb Res 2007; 119: 121-127.
  • 41 Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009; 48: 1-22.
  • 42 van Ryn J, Ruehl D, Priepke H. et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant Factor VIIa or activated prothrombin complex concentrate (abstract 0370). Haematologica 2008; 93 (Suppl. 01) 148.
  • 43 Wolzt M, Levi M, Sarich TC. et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 2004; 91: 1090-1096.
  • 44 Sorensen B, Ingerslev J. A direct thrombin inhibitor studied by dynamic whole blood clot formation. Haemostatic response to ex-vivo addition of recombinant factor VIIa or activated prothrombin complex concentrate. Thromb Haemost 2006; 96: 446-453.
  • 45 Stratmann G, de Silva AM, Tseng EE. et al. Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. Anesth Analg 2004; 98: 1635-1639.
  • 46 Oh JJ, Akers WS, Lewis D. et al. Recombinant factor VIIa for refractory bleeding after cardiac surgery secondary to anticoagulation with the direct thrombin inhibitor lepirudin. Pharmacotherapy 2006; 26: 569-577.
  • 47 Leissinger CA, Blatt PM, Hoots WK. et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008; 83: 137-143.
  • 48 Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008; 111: 4871-4879.
  • 49 Elg M, Carlsson S, Gustafsson D. Effect of activated prothrombin complex concentrate or recombinant factor VIIa on the bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res 2001; 101: 145-157.
  • 50 Eriksson UG, Samuelsson O, Attman PO. et al. Melagatran is efficiently eliminated by hemodialysis in uremic patients (abstract PO073). Pathophysiol Haemost Thromb 2004; 33 (Suppl. 02) 96.
  • 51 Benz K, Nauck MA, Bohler J. et al. Hemofiltration of recombinant hirudin by different hemodialyzer membranes: implications for clinical use. Clin J Am Soc Nephrol 2007; 02: 470-476.
  • 52 Elg M, Carlsson S, Gustafsson D. Effects of agents, used to treat bleeding disorders, on bleeding time prolonged by a very high dose of a direct thrombin inhibitor in anesthesized rats and rabbits. Thromb Res 2001; 101: 159-170.
  • 53 Haverkamp D, Hutten BA, Büller HR. et al. The use of specific antidotes as a response to bleeding complications during anticoagulant therapy for venous thromboembolism. J Thromb Haemost 2003; 01: 69-73.
  • 54 Wallentin LC, Ezekowitz M, Simmers TA. et al. the PETRO Investigators.. Safety and efficacy of a new oral direct thrombin inhibitor dabigatran in atrial fibrillation – a dose finding trial with comparison to warfarin (abstract P2949). Eur Heart J 2005; 26 (Suppl. 01) 482-483.