Semin Thromb Hemost 2020; 46(06): 743-750
DOI: 10.1055/s-0040-1715452
Review Article

Anticoagulant Management and Synthesis of Hemostatic Proteins during Machine Preservation of Livers for Transplantation

Shanice A. Karangwa
1   Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Ton Lisman
1   Department of Surgery, Surgical Research Laboratory, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Robert J. Porte
2   Section of HPB Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
› Author Affiliations

Abstract

Liver transplantation remains the only curative treatment for patients with end-stage liver disease. Despite a steadily increasing demand for suitable donor livers, the current pool of donor organs fails to meet this demand. To resolve this discrepancy, livers traditionally considered to be of suboptimal quality and function are increasingly utilized. These marginal livers, however, are less tolerant to the current standard cold preservation of donor organs. Therefore, alternative preservation methods have been sought and are progressively applied into clinical practice. Ex situ machine perfusion is a promising alternative preservation modality particularly for suboptimal donor livers as it provides the ability to resuscitate, recondition, and test the viability of an organ prior to transplantation. This review addresses the modalities of machine perfusion currently being applied, and particularly focuses on the hemostatic management employed during machine perfusion. We discuss the anticoagulant agents used, the variation in dosage, and administration, as well as the implications of perfusion for extended periods of time in terms of coagulation activation associated with production of coagulation factors during perfusion. Furthermore, in regard to viability testing of an organ prior to transplantation, we discuss the possibilities and limitations of utilizing the synthesis of liver-derived coagulation factors as potential viability markers.



Publication History

Article published online:
05 August 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.

 
  • References

  • 1 Starzl TE, Demetris AJ, Van Thiel D. Liver transplantation (1). N Engl J Med 1989; 321 (15) 1014-1022
  • 2 Neuberger J. Liver transplantation. J Hepatol 2000; 32 (Suppl. 01) 198-207
  • 3 de Boer MT, Molenaar IQ, Hendriks HG, Slooff MJ, Porte RJ. Minimizing blood loss in liver transplantation: progress through research and evolution of techniques. Dig Surg 2005; 22 (04) 265-275
  • 4 Henry Z, Northup PG. The rebalanced hemostasis system in end-stage liver disease and its impact on liver transplantation. Int Anesthesiol Clin 2017; 55 (02) 107-120
  • 5 Donohue CI, Mallett SV. Reducing transfusion requirements in liver transplantation. World J Transplant 2015; 5 (04) 165-182
  • 6 Massicotte L, Denault AY, Beaulieu D. , et al. Transfusion rate for 500 consecutive liver transplantations: experience of one liver transplantation center. Transplantation 2012; 93 (12) 1276-1281
  • 7 Ceresa CDL, Nasralla D, Coussios CC, Friend PJ. The case for normothermic machine perfusion in liver transplantation. Liver Transpl 2018; 24 (02) 269-275
  • 8 Saidi RF. Utilization of expanded criteria donors in liver transplantation. Int J Organ Transplant Med 2013; 4 (02) 46-59
  • 9 Ravikumar R, Leuvenink H, Friend PJ. Normothermic liver preservation: a new paradigm?. Transpl Int 2015; 28 (06) 690-699
  • 10 Schlegel A, Muller X, Dutkowski P. Hypothermic liver perfusion. Curr Opin Organ Transplant 2017; 22 (06) 563-570
  • 11 Croome KP, Lee DD, Keaveny AP, Taner CB. Noneligible donors as a strategy to decrease the organ shortage. Am J Transplant 2017; 17 (06) 1649-1655
  • 12 Karangwa SA, Dutkowski P, Fontes P. , et al. Machine perfusion of donor livers for transplantation: a proposal for standardized nomenclature and reporting guidelines. Am J Transplant 2016; 16 (10) 2932-2942
  • 13 Guarrera JV, Henry SD, Samstein B. , et al. Hypothermic machine preservation facilitates successful transplantation of “orphan” extended criteria donor livers. Am J Transplant 2015; 15 (01) 161-169
  • 14 Dutkowski P, Schlegel A, de Oliveira M, Müllhaupt B, Neff F, Clavien PA. HOPE for human liver grafts obtained from donors after cardiac death. J Hepatol 2014; 60 (04) 765-772
  • 15 Schlegel A, Muller X, Kalisvaart M. , et al. Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation. J Hepatol 2019; 70 (01) 50-57
  • 16 van Rijn R, Karimian N, Matton APM. , et al. Dual hypothermic oxygenated machine perfusion in liver transplants donated after circulatory death. Br J Surg 2017; 104 (07) 907-917
  • 17 Fondevila C, Busuttil RW, Kupiec-Weglinski JW. Hepatic ischemia/reperfusion injury—a fresh look. Exp Mol Pathol 2003; 74 (02) 86-93
  • 18 Schlegel A, Kron P, Dutkowski P. Hypothermic machine perfusion in liver transplantation. Curr Opin Organ Transplant 2016; 21 (03) 308-314
  • 19 Schlegel A, Kron P, Graf R, Clavien PA, Dutkowski P. Hypothermic oxygenated machine perfusion (HOPE) down-regulates the immune response in a rat model of liver transplantation. Ann Surg 2014; 260 (05) 931-937
  • 20 Schlegel A, Graf R, Clavien PA, Dutkowski P. Hypothermic oxygenated machine perfusion (HOPE) prevents biliary injury after transplantation of DCD liver grafts. Liver Transpl 2013; 19 (06) S86
  • 21 Hartmann M, Szalai C, Saner FH. Hemostasis in liver transplantation: pathophysiology, monitoring, and treatment. World J Gastroenterol 2016; 22 (04) 1541-1550
  • 22 Calmus Y, Cynober L, Dousset B. , et al. Evidence for the detrimental role of proteolysis during liver preservation in humans. Gastroenterology 1995; 108 (05) 1510-1516
  • 23 Rauen U, Polzar B, Stephan H, Mannherz HG, de Groot H. Cold-induced apoptosis in cultured hepatocytes and liver endothelial cells: mediation by reactive oxygen species. FASEB J 1999; 13 (01) 155-168
  • 24 van Leeuwen OB, de Vries Y, Fujiyoshi M. , et al. Transplantation of high-risk donor livers after ex situ resuscitation and assessment using combined hypo- and normothermic machine perfusion: a prospective clinical trial. Ann Surg 2019; 270 (05) 906-914
  • 25 Mergental H, Perera MT, Laing RW. , et al. Transplantation of declined liver allografts following normothermic ex-situ evaluation. Am J Transplant 2016; 16 (11) 3235-3245
  • 26 Nasralla D, Coussios CC, Mergental H. , et al; Consortium for Organ Preservation in Europe. A randomized trial of normothermic preservation in liver transplantation. Nature 2018; 557 (7703): 50-56
  • 27 He X, Guo Z, Zhao Q. , et al. The first case of ischemia-free organ transplantation in humans: a proof of concept. Am J Transplant 2018; 18 (03) 737-744
  • 28 Watson CJ, Kosmoliaptsis V, Randle LV. , et al. Preimplant normothermic liver perfusion of a suboptimal liver donated after circulatory death. Am J Transplant 2016; 16 (01) 353-357
  • 29 Bral M, Gala-Lopez B, Bigam D. , et al. Preliminary single-center Canadian experience of human normothermic ex vivo liver perfusion: results of a clinical trial. Am J Transplant 2017; 17 (04) 1071-1080
  • 30 Perera T, Mergental H, Stephenson B. , et al. First human liver transplantation using a marginal allograft resuscitated by normothermic machine perfusion. Liver Transpl 2016; 22 (01) 120-124
  • 31 Fontes P, Lopez R, van der Plaats A. , et al. Liver preservation with machine perfusion and a newly developed cell-free oxygen carrier solution under subnormothermic conditions. Am J Transplant 2015; 15 (02) 381-394
  • 32 Selzner M, Goldaracena N, Echeverri J. , et al. Normothermic ex vivo liver perfusion using steen solution as perfusate for human liver transplantation: First North American results. Liver Transpl 2016; 22 (11) 1501-1508
  • 33 Seal JB, Bohorquez H, Reichman T. , et al. Thrombolytic protocol minimizes ischemic-type biliary complications in liver transplantation from donation after circulatory death donors. Liver Transpl 2015; 21 (03) 321-328
  • 34 Dries S, Karimian N, Sutton ME. , et al. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am J Transplant 2013; 13 (05) 1327-1335
  • 35 Banan B, Watson R, Xu M, Lin Y, Chapman W. Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers. Liver Transpl 2016; 22 (07) 979-993
  • 36 Vogel T, Brockmann JG, Quaglia A. , et al. The 24-hour normothermic machine perfusion of discarded human liver grafts. Liver Transpl 2017; 23 (02) 207-220
  • 37 Karangwa SA, Burlage LC, Adelmeijer J. , et al. Activation of fibrinolysis, but not coagulation, during end-ischemic ex situ normothermic machine perfusion of human donor livers. Transplantation 2017; 101 (02) e42-e48
  • 38 Laing RW, Bhogal RH, Wallace L. , et al. The use of an acellular oxygen carrier in a human liver model of normothermic machine perfusion. Transplantation 2017; 101 (11) 2746-2756
  • 39 Karangwa SA, Adelmeijer J, Matton APM, de Meijer VE, Lisman T, Porte RJ. Production of physiologically relevant quantities of hemostatic proteins during ex situ normothermic machine perfusion of human livers. Liver Transpl 2018; 24 (09) 1298-1302
  • 40 Watson CJ, Randle LV, Kosmoliaptsis V, Gibbs P, Allison M, Butler AJ. 26-hour storage of a declined liver before successful transplantation using ex vivo normothermic perfusion. Ann Surg 2017; 265 (01) e1-e2
  • 41 Lisman T, Platto M, Meijers JC, Haagsma EB, Colledan M, Porte RJ. The hemostatic status of pediatric recipients of adult liver grafts suggests that plasma levels of hemostatic proteins are not regulated by the liver. Blood 2011; 117 (06) 2070-2072
  • 42 Farmacotherapeutisch kompas: Geneesmiddelen: Vergelijken apixaban-dabigatran-rivaroxaban. Available at: https://Www.farmacotherapeutischkompas.nl/vergelijken/preparaatteksten?vergelijkTeksten=apixaban,dabigatran,rivaroxaban,edoxaban . Accessed May 2019; December 2019
  • 43 Selleng S, Selleng K. Heparin-induced thrombocytopenia in cardiac surgery and critically ill patients. Thromb Haemost 2016; 116 (05) 843-851
  • 44 Benchekroun S, Eychenne B, Mericq O. , et al. Heparin half-life and sensitivity in normal subjects and in patients affected by deep vein thrombosis. Eur J Clin Invest 1986; 16 (06) 536-539
  • 45 Laing RW, Mergental H, Yap C. , et al. Viability testing and transplantation of marginal livers (VITTAL) using normothermic machine perfusion: study protocol for an open-label, non-randomised, prospective, single-arm trial. BMJ Open 2017; 7 (11) e017733
  • 46 Imber CJ, St Peter SD, Lopez de Cenarruzabeitia I. , et al. Advantages of normothermic perfusion over cold storage in liver preservation. Transplantation 2002; 73 (05) 701-709
  • 47 St Peter SD, Imber CJ, Lopez I, Hughes D, Friend PJ. Extended preservation of non-heart-beating donor livers with normothermic machine perfusion. Br J Surg 2002; 89 (05) 609-616
  • 48 Reddy SP, Bhattacharjya S, Maniakin N. , et al. Preservation of porcine non-heart-beating donor livers by sequential cold storage and warm perfusion. Transplantation 2004; 77 (09) 1328-1332
  • 49 Banan B, Chung H, Xiao Z. , et al. Normothermic extracorporeal liver perfusion for donation after cardiac death (DCD) livers. Surgery 2015; 158 (06) 1642-1650