CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(09): 1573-1583
DOI: 10.1055/s-0042-1744542
Stroke, Systemic or Venous Thromboembolism

Anticoagulant Effects of Dabigatran on Coagulation Laboratory Parameters in Pediatric Patients: Combined Data from Five Pediatric Clinical Trials

Lesley G. Mitchell
1   Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Daniel Röshammar
2   Pharmetheus AB, Uppsala, Sweden
Fenglei Huang
3   Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States
Manuela Albisetti
4   Hematology Department, University Children's Hospital, Zürich, Switzerland
Leonardo R. Brandão
5   Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
6   Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
Lisa Bomgaars
7   Department of Pediatrics, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, United States
Elizabeth Chalmers
8   The Glasgow Children's Haemophilia Unit, Royal Hospital for Children, Glasgow, Scotland, United Kingdom
Jacqueline Halton
9   Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada
Matteo Luciani
10   Pediatric Hematology/Oncology Department, Pediatric Hospital Bambino Gesù, Rome, Italy
David Joseph
3   Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, United States
Igor Tartakovsky
11   Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany
Savion Gropper
12   Therapeutic Area Inflammation Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany
Martina Brueckmann
11   Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany
13   Faculty of Medicine Mannheim of the University of Heidelberg, Mannheim, Germany
› Author Affiliations
Funding The study was supported by Boehringer Ingelheim International GmbH. Medical writing assistance, editorial, and technical support in the preparation of the manuscript was provided by Carolyn Bowler of Parexel and supported financially by Boehringer Ingelheim International GmbH.


Background Dabigatran etexilate, a direct oral thrombin inhibitor, is approved to treat venous thromboembolism (VTE) in both adults and children.

Objectives This population analysis characterized relationships between dabigatran total plasma concentrations and coagulation laboratory parameters (activated partial thromboplastin time [aPTT]; diluted thrombin time [dTT]; ecarin clotting time [ECT]).

Methods Data from three phase 2a and one single-arm and one randomized, comparative phase 2b/3 pediatric studies (measurements: aPTT 2,925 [N = 358]; dTT 2,348 [N = 324]; ECT 2,929 [N = 357]) were compared with adult data (5,740 aPTT, 3,472 dTT, 3,817 ECT measurements; N = 1,978). Population models were fitted using nonlinear mixed-effects modeling. Covariates (e.g., sex, age) were assessed on baseline and drug-effect parameters, using a stepwise covariate model-building procedure.

Results Overall, relationships between dabigatran, aPTT, dTT, and ECT were similar in children and adults. For children aged <6 months, a higher proportion of baseline samples were outside or close to the upper aPTT and ECT adult ranges. No age-related differences were detected for dTT. With increasing dabigatran concentration, aPTT rose nonlinearly (half the maximum effect at 368 ng/mL dabigatran) while dTT and ECT increased linearly (0.37 and 0.73% change per ng/mL dabigatran, respectively). Mean baseline aPTT (45 vs. 36 seconds) and ECT (40 vs. 36 seconds) were slightly increased for those aged <6 months versus older children.

Conclusion The similar relationships of laboratory parameters observed across pediatric age groups suggests that developmental changes in the hemostatic system may have little effect on response to dabigatran.

Author Contributions

L.G.M., D.R., F.H., and D.J., contributed to the concept, design, and analysis of the data. All authors contributed to critical writing or revising of intellectual content and final approval of the version to be published.

Trial Registrations identifiers: NCT00844415, NCT01083732, NCT02223260, NCT01895777, NCT02197416, NCT01688830, NCT01955720, NCT00291330, and NCT00657150.

Data Sharing Statement

To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Researchers should use the link to request access to study data and visit for further information.

Supplementary Material

Publication History

Received: 23 July 2021

Accepted: 10 February 2022

Article published online:
31 July 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Andrew M, David M, Adams M. et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994; 83 (05) 1251-1257
  • 2 Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124 (04) 1001-1008
  • 3 Monagle P, Chan AKC, Goldenberg NA. et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e737S-e801S
  • 4 Chan AK, Monagle P. Updates in thrombosis in pediatrics: where are we after 20 years?. Hematology (Am Soc Hematol Educ Program) 2012; 2012: 439-443
  • 5 Streif W, Andrew M, Marzinotto V. et al. Analysis of warfarin therapy in pediatric patients: a prospective cohort study of 319 patients. Blood 1999; 94 (09) 3007-3014
  • 6 Massicotte P, Leaker M, Marzinotto V. et al. Enhanced thrombin regulation during warfarin therapy in children compared to adults. Thromb Haemost 1998; 80 (04) 570-574
  • 7 Chan AK, Berry LR, Monagle PT, Andrew M. Decreased concentrations of heparinoids are required to inhibit thrombin generation in plasma from newborns and children compared to plasma from adults due to reduced thrombin potential. Thromb Haemost 2002; 87 (04) 606-613
  • 8 Kuhle S, Eulmesekian P, Kavanagh B. et al. Lack of correlation between heparin dose and standard clinical monitoring tests in treatment with unfractionated heparin in critically ill children. Haematologica 2007; 92 (04) 554-557
  • 9 Mitchell LG, Vegh P. Conventional chromogenic heparin assays are influenced by patient's endogenous plasma antithrombin levels. Klin Padiatr 2010; 222 (03) 164-167
  • 10 Brandão LR, Albisetti M, Halton J. et al; DIVERSITY Study Investigators. Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children. Blood 2020; 135 (07) 491-504
  • 11 Halton J, Brandão LR, Luciani M. et al; DIVERSITY Trial Investigators. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol 2021; 8 (01) e22-e33
  • 12 Schulman S, Kakkar AK, Goldhaber SZ. et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
  • 13 Schulman S, Kearon C, Kakkar AK. et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
  • 14 Schulman S, Kearon C, Kakkar AK. et al; RE-MEDY Trial Investigators, RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
  • 15 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47 (05) 285-295
  • 16 Maas H, Gropper S, Huang F. et al. Anticoagulant effects of dabigatran in paediatric patients compared with adults: combined data from three paediatric clinical trials. Thromb Haemost 2018; 118 (09) 1625-1636
  • 17 Halton JM, Lehr T, Cronin L. et al. Safety, tolerability and clinical pharmacology of dabigatran etexilate in adolescents. An open-label phase IIa study. Thromb Haemost 2016; 116 (03) 461-471
  • 18 Halton JML, Albisetti M, Biss B. et al. Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability. J Thromb Haemost 2017; 15 (11) 2147-2157
  • 19 Halton JML, Picard AC, Harper R. et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of dabigatran etexilate oral liquid formulation in infants with venous thromboembolism. Thromb Haemost 2017; 117 (11) 2168-2175
  • 20 Glund S, Stangier J, Schmohl M. et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015; 386 (9994): 680-690
  • 21 Glund S, Stangier J, van Ryn J. et al. Effect of age and renal function on idarucizumab pharmacokinetics and idarucizumab-mediated reversal of dabigatran anticoagulant activity in a randomized, double-blind, crossover phase Ib study. Clin Pharmacokinet 2017; 56 (01) 41-54
  • 22 Eriksson BI, Dahl OE, Huo MH. et al; RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105 (04) 721-729
  • 23 Andrew M, Paes B, Milner R. et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70 (01) 165-172
  • 24 Nowak-Göttl U, Dietrich K, Schaffranek D. et al. In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. Blood 2010; 116 (26) 6101-6105
  • 25 Kuhle S, Massicotte P, Dinyari M. et al. Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events. Thromb Haemost 2005; 94 (06) 1164-1171
  • 26 Weinstein JR, Anderson S. The aging kidney: physiological changes. Adv Chronic Kidney Dis 2010; 17 (04) 302-307
  • 27 Röshammar D, Huang F, Albisetti M. et al. Pharmacokinetic modeling and simulation support for age- and weight-adjusted dosing of dabigatran etexilate in children with venous thromboembolism. J Thromb Haemost 2021; 19 (05) 1259-1270
  • 28 Dietrich K, Stang L, van Ryn J, Mitchell LG. Assessing the anticoagulant effect of dabigatran in children: an in vitro study. Thromb Res 2015; 135 (04) 630-635
  • 29 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151