Download PDF
Thromb Haemost 2020; 120(09): 1240-1247
DOI: 10.1055/s-0040-1713752
Coagulation and Fibrinolysis

In Vitro Evaluation of Pro- and Anticoagulant Drugs in Children with End-Stage Liver Disease Undergoing Liver Transplantation

Maureen J. M. Werner
1   Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2   Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Jelle Adelmeijer
2   Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Vincent E. de Meijer
1   Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Ruben H. J. de Kleine
1   Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
René Scheenstra
3   Department of Pediatric Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Sander T. H. Bontemps
4   Department of Pediatric Intensive Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Koen M. E. M. Reyntjens
5   Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Jan B. F. Hulscher
6   Section of Pediatric Surgery, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Robert J. Porte
1   Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2   Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Ton Lisman
1   Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2   Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
› Author Affiliations Funding Research funding was obtained by the University Medical Center Groningen Transplantation Research Foundation, Groningen, the Netherlands.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Background Pro- and anticoagulant drugs are commonly used in pediatric liver transplantation to prevent and treat thrombotic and bleeding complications. However, the combination of baseline hemostatic changes in children with liver disease and additional changes induced by transplantation makes this very challenging. This study aimed to analyze the efficacy of clinically available pro- and anticoagulant drugs in plasma from children undergoing liver transplantation.

Methods In vitro effects of pro- and anticoagulant drugs on thrombin generation capacity were tested in plasma samples of 20 children (≤ 16 years) with end-stage liver disease undergoing liver transplantation, and compared with 30 age-matched healthy controls.

Results Addition of pooled normal plasma had no effect in patients or controls, while 4-factor prothrombin complex concentrate increased thrombin generation in both patients and controls, with enhanced activity in patients. At start of transplantation, dabigatran and unfractionated heparin had a higher anticoagulant potency in patients, whereas 30 days after transplantation low molecular weight heparin was slightly less effective in patients. Effects of rivaroxaban were comparable between patients and controls.

Conclusion This study revealed important differences in efficacy of commonly used pro- and anticoagulant drugs in children with end-stage liver disease undergoing liver transplantation. Therefore, dose adjustments of these drugs may be required. The results of this study may be helpful in the development of urgently needed protocols for strategies to prevent and treat bleeding and thrombotic complications in pediatric liver transplantation.

Keywords

coagulation - hemostasis - liver transplantation - pro- and anticoagulant drugs - thrombosis

Supplementary Material



Publication History

Received: 26 March 2020

Accepted: 18 May 2020

Article published online:
06 July 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Borst AJ, Sudan DL, Wang LA, Neuss MJ, Rothman JA, Ortel TL. Bleeding and thrombotic complications of pediatric liver transplant. Pediatr Blood Cancer 2018; 65 (05) e26955
    CrossrefPubMedGoogle Scholar
  • 2 Ziaziaris WA, Darani A, Holland AJA. , et al. Reducing the incidence of hepatic artery thrombosis in pediatric liver transplantation: effect of microvascular techniques and a customized anticoagulation protocol. Pediatr Transplant 2017; 21 (04) DOI: 10.1111/petr.12917.
    CrossrefPubMedGoogle Scholar
  • 3 Kamran Hejazi Kenari S, Mirzakhani H, Eslami M, Saidi RF. Current state of the art in management of vascular complications after pediatric liver transplantation. Pediatr Transplant 2015; 19 (01) 18-26
    CrossrefPubMedGoogle Scholar
  • 4 Werner MJM, de Meijer VE, Adelmeijer J. , et al. Evidence for a rebalanced hemostatic system in pediatric liver transplantation: a prospective cohort study. Am J Transplant 2020; 20 (05) 1384-1392
    CrossrefPubMedGoogle Scholar
  • 5 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
    CrossrefPubMedGoogle Scholar
  • 6 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (06) 878-885
    CrossrefPubMedGoogle Scholar
  • 7 Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment. Dig Surg 2007; 24 (04) 250-258
    CrossrefPubMedGoogle Scholar
  • 8 Arshad F, Lisman T, Porte RJ. Hypercoagulability as a contributor to thrombotic complications in the liver transplant recipient. Liver Int 2013; 33 (06) 820-827
    CrossrefPubMedGoogle Scholar
  • 9 Lisman T, Caldwell SH, Burroughs AK. , et al; Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 2010; 53 (02) 362-371
    CrossrefPubMedGoogle Scholar
  • 10 Werner MJM, de Kleine RHJ, de Boer MT. , et al. Routine postoperative antithrombotic therapy in pediatric liver transplantation: impact on bleeding and thrombotic complications. Thromb Haemost 2020; 120 (04) 627-637
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Srivastava P, Agarwal A, Jha A. , et al. Utility of prothrombin complex concentrate as first-line treatment modality of coagulopathy in patients undergoing liver transplantation: a propensity score-matched study. Clin Transplant 2018; 32 (12) e13435
    CrossrefPubMedGoogle Scholar
  • 12 Nacoti M, Corbella D, Fazzi F, Rapido F, Bonanomi E. Coagulopathy and transfusion therapy in pediatric liver transplantation. World J Gastroenterol 2016; 22 (06) 2005-2023
    CrossrefPubMedGoogle Scholar
  • 13 Kirchner C, Dirkmann D, Treckmann JW. , et al. Coagulation management with factor concentrates in liver transplantation: a single-center experience. Transfusion 2014; 54 (10 Pt 2): 2760-2768
    CrossrefPubMedGoogle Scholar
  • 14 Lisman T, Kleiss S, Patel VC. , et al. In vitro efficacy of pro- and anticoagulant strategies in compensated and acutely ill patients with cirrhosis. Liver Int 2018; 38 (11) 1988-1996
    CrossrefPubMedGoogle Scholar
  • 15 Tripodi A, Chantarangkul V, Primignani M. , et al. Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma. Intern Emerg Med 2012; 7 (02) 139-144
    CrossrefPubMedGoogle Scholar
  • 16 Voulgarelis S, Vitola B, Lerret SM, Hong JC, Scott JP. Perioperative anticoagulation practices for pediatric liver transplantation. Pediatr Transplant 2018; 22 (04) e13193
    CrossrefPubMedGoogle Scholar
  • 17 Calinescu AM, Karam O, Wilde JCH, Ansari M, McLin VA, Wildhaber BE. International survey on anticoagulation and antiplatelet strategies after pediatric liver transplantation. Pediatr Transplant 2019; 23 (01) e13317
    CrossrefPubMedGoogle Scholar
  • 18 Ignjatovic V, Furmedge J, Newall F. , et al. Age-related differences in heparin response. Thromb Res 2006; 118 (06) 741-745
    CrossrefPubMedGoogle Scholar
  • 19 Monagle P, Ignjatovic V, Savoia H. Hemostasis in neonates and children: pitfalls and dilemmas. Blood Rev 2010; 24 (02) 63-68
    CrossrefPubMedGoogle Scholar
  • 20 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80 (08) 1998-2005
    CrossrefPubMedGoogle Scholar
  • 21 Northup P, Reutemann B. Management of coagulation and anticoagulation in liver transplantation candidates. Liver Transpl 2018; 24 (08) 1119-1132
    CrossrefPubMedGoogle Scholar
  • 22 Potze W, Arshad F, Adelmeijer J. , et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS One 2014; 9 (02) e88390
    CrossrefPubMedGoogle Scholar
  • 23 Potze W, Adelmeijer J, Lisman T. Decreased in vitro anticoagulant potency of rivaroxaban and apixaban in plasma from patients with cirrhosis. Hepatology 2015; 61 (04) 1435-1436
    CrossrefPubMedGoogle Scholar
  • 24 Hemker HC, Giesen P, Al Dieri R. , et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (01) 4-15
    CrossrefPubMedGoogle Scholar
  • 25 Lisman T, Porte RJ. Value of preoperative hemostasis testing in patients with liver disease for perioperative hemostatic management. Anesthesiology 2017; 126 (02) 338-344
    CrossrefPubMedGoogle Scholar
  • 26 Weeder PD, Porte RJ, Lisman T. Hemostasis in liver disease: implications of new concepts for perioperative management. Transfus Med Rev 2014; 28 (03) 107-113
    CrossrefPubMedGoogle Scholar
  • 27 Lisman T, Caldwell SH, Porte RJ, Leebeek FW. Consequences of abnormal hemostasis tests for clinical practice. J Thromb Haemost 2006; 4 (09) 2062-2063
    CrossrefPubMedGoogle Scholar
  • 28 Priyanka P, Kupec JT, Krafft M, Shah NA, Reynolds GJ. Newer oral anticoagulants in the treatment of acute portal vein thrombosis in patients with and without cirrhosis. Int J Hepatol 2018; 2018: 8432781
    CrossrefPubMedGoogle Scholar
  • 29 Lisman T, Kamphuisen PW, Northup PG, Porte RJ. Established and new-generation antithrombotic drugs in patients with cirrhosis - possibilities and caveats. J Hepatol 2013; 59 (02) 358-366
    CrossrefPubMedGoogle Scholar
  • 30 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 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
    CrossrefPubMedGoogle Scholar
  • 32 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
    CrossrefPubMedGoogle Scholar
  • 33 Ignjatovic V, Summerhayes R, Yip YY, Monagle P. The in vitro anticoagulant effects of danaparoid, fondaparinux, and lepirudin in children compared to adults. Thromb Res 2008; 122 (05) 709-714
    CrossrefPubMedGoogle Scholar
  • 34 Potze W, Arshad F, Adelmeijer J. , et al. Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis. Br J Haematol 2013; 163 (05) 666-673
    CrossrefPubMedGoogle Scholar
  • 35 Ninivaggi M, Apitz-Castro R, Dargaud Y, de Laat B, Hemker HC, Lindhout T. Whole-blood thrombin generation monitored with a calibrated automated thrombogram-based assay. Clin Chem 2012; 58 (08) 1252-1259
    CrossrefPubMedGoogle Scholar
  • 36 Senzolo M, Rodriguez-Castro KI, Rossetto V. , et al. Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis. J Thromb Haemost 2012; 10 (09) 1823-1829
    CrossrefPubMedGoogle Scholar