Blood loss during liver transplantation has long been recognized as an important cause of morbidity and, especially in the early days, also mortality. It is well known that blood transfusions are associated with an increased risk of postoperative complications, such as infections, pulmonary complications, protracted recovery, and a higher rate of reoperations. Many studies have been performed during the past decades to elucidate the mechanisms of increased blood loss in liver transplantation. In the late 1980s, primary hyperfibrinolysis was identified as an important mechanism of bleeding during liver transplantation. This has provided the scientific basis for the use of antifibrinolytic drugs in liver transplant recipients. Several randomized, controlled studies have shown the efficacy of these compounds in reducing blood loss and transfusion requirements during liver transplantation. In addition, increasing experience and improvements in surgical technique, anesthesiological care and better graft preservation methods have contributed to a steady decrease in blood transfusion requirements in most liver transplant programs. Several centers are now reporting liver transplantation without any need for blood transfusion in up to 30% of their patients. Despite these improvements, most patients undergoing liver transplantation still require blood transfusions that have a negative impact on outcome, emphasizing the need for further attempts to control blood loss by surgeons and anesthesiologists. This paper provides an overview of the clinical and research developments, which have contributed to a reduction in blood loss and transfusion requirements, resulting in an important reduction in morbidity and mortality after liver transplantation during the last two decades.

1.
Adam R, McMaster P, O’Grady JG, Castaing D, Klempnauer JL, Jamieson N, Neuhaus P, Lerut J, Salizzoni M, Pollard S, Muhlbacher F, Rogiers X, Garcia Valdecasas JC, Berenguer J, Jaeck D, Moreno Gonzalez E: Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry. Liver Transpl 2003;9:231–1243.
2.
Starzl TE, Marchioro TL, Von Kaulla KN, Herman G: Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963:659–676.
3.
Belzer FO, Southard JH: Principles of solid-organ preservation by cold storage. Transplantation 1988;45:673–676.
4.
Bismuth H, Castaing D, Ericzon BG, Otte JB, Rolles K, Ringe B, Slooff M: Hepatic transplantation in Europe. First Report of the European Liver Transplant Registry. Lancet 1987;ii:674–676.
5.
Lewis JH, Bontempo FA, Cornell F, Kiss JE, Larson P, Ragni MV, Rice EO, Spero JA, Starzl TE: Blood use in liver transplantation. Transfusion 1987;27:222–225.
6.
Porte RJ, Knot EA, Bontempo FA: Hemostasis in liver transplantation. Gastroenterology 1989;97:488–501.
7.
Porte RJ: Coagulation and fibrinolysis in orthotopic liver transplantation: current views and insights. Semin Thromb Hemost 1993;19:191–196.
8.
Porte RJ, Leebeek FW: Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002;62:2193–2211.
9.
Ramos E, Dalmau A, Sabate A, Lama C, Llado L, Figueras J, Jaurrieta E: Intraoperative red blood cell transfusion in liver transplantation: influence on patient outcome, prediction of requirements, and measures to reduce them. Liver Transpl 2003;9:1320–1327.
10.
Cacciarelli TV, Keeffe EB, Moore DH, Burns W, Chuljian P, Busque S, Concepcion W, So SK, Esquivel CO: Primary liver transplantation without transfusion of red blood cells. Surgery 1996;120:698–704.
11.
Porte RJ, Hendriks HG, Slooff MJ: Blood conservation in liver transplantation: the role of aprotinin. J Cardiothorac Vasc Anesth 2004;18:S31–S37.
12.
Brand A: Immunological aspects of blood transfusions. Transpl Immunol 2002;10:183–190.
13.
Mor E, Jennings L, Gonwa TA, Holman MJ, Gibbs J, Solomon H: The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 1993;176:219–227.
14.
Bechstein WO, Neuhaus P: A surgeon’s perspective on the management of coagulation disorders before liver transplantation. Liver Transpl Surg 1997;3:653–655.
15.
Sieders E, Peeters PM, TenVergert EM, de Jong KP, Porte RJ, Zwaveling JH, Bijleveld CM, Slooff MJ: Prognostic factors for long-term actual patient survival after orthotopic liver transplantation in children. Transplantation 2000;70:1448–1453.
16.
Peeters PM, ten Vergert EM, Bijleveld CM, Pisarski P, Verwer R, Slooff MJ: The influence of intraoperative blood loss on graft survival and morbidity after orthotopic liver transplantation in children. Pediatr Surg Int 1995;10:120–125.
17.
Hendriks HG, van der Meer J, de Wolf JTM, Peeters PMJG, de Jong KP, Lip H, Post WJ, Slooff MJH: Intraoperative blood transfusion requirement is the main determinant of early surgical reintervention after orthotopic liver transplantation. Transpl Int 2005;17:673–679.
18.
Hendriks HG, van der Meer J, Klompmaker IJ, Choudhury N, Hagenaars JA, Porte RJ, de Kam PJ, Slooff MJ, de Wolf JT: Blood loss in orthotopic liver transplantation: a retrospective analysis of transfusion requirements and the effects of autotransfusion of cell saver blood in 164 consecutive patients. Blood Coagul Fibrinolysis 2000;11:S87–S93.
19.
Kang YG, Martin DJ, Marquez J, Lewis JH, Bontempo FA, Shaw BW Jr, Starzl TE, Winter PM: Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 1985;64:888–896.
20.
Brozovic M: Acquired disorders of coagulation; in Bloom AL, Thomas DP (eds): Haemostasis and Thrombosis. Edinburgh, Churchill Livingstone, 1987, pp 542–553.
21.
Lewis JH, Bontempo FA, Awad SA, Kang YG, Kiss JE, Ragni MV, Spero JA, Starzl TE: Liver transplantation: intraoperative changes in coagulation factors in 100 first transplants. Hepatology 1989;9:710–714.
22.
Porte RJ, Bontempo FA, Knot EA, Lewis JH, Kang YG, Starzl TE: Systemic effects of tissue plasminogen activator-associated fibrinolysis and its relation to thrombin generation in orthotopic liver transplantation. Transplantation 1989;47:978–984.
23.
Dzik WH, Arkin CF, Jenkins RL, Stump DC: Fibrinolysis during liver transplantation in humans: role of tissue-type plasminogen activator. Blood 1988;71:1090–1095.
24.
Bakker CM, Metselaar HJ, Gomes MJ, Porte RJ, Groenland TN, Schalm SW, Terpstra OT, Stibbe J: Intravascular coagulation in liver transplantation – Is it present or not? A comparison between orthotopic and heterotopic liver transplantation. Thromb Haemost 1993;69:25–28.
25.
Hutchison DE, Genton E, Porter KA, Daloze PM, Huguet C, Brettschneider L, Groth CG, Starzl TE: Platelet changes following clinical and experimental hepatic homotransplantation. Arch Surg 1968;97:27–33.
26.
Porte RJ, Blauw E, Knot EA, de Maat MP, de Ruiter C, Minke BC, Terpstra OT: Role of the donor liver in the origin of platelet disorders and hyperfibrinolysis in liver transplantation. J Hepatol 1994;21:592–600.
27.
Schalm SW, Terpstra JL, Achterberg JR, Noordhoek Hegt V, Haverkate F, Popescu DT, Krom RA, Veltkamp JJ: Orthotopic liver transplantation: an experimental study on mechanisms of hemorrhagic diathesis and thrombosis. Surgery 1975;78:499–507.
28.
Himmelreich G, Muser M, Neuhaus P, Bechstein WO, Slama KJ, Jochum M, Riess H: Different aprotinin applications influencing hemostatic changes in orthotopic liver transplantation. Transplantation 1992;53:132–136.
29.
Sindram D, Porte RJ, Hoffman MR, Bentley RC, Clavien PA: Platelets induce sinusoidal endothelial cell apoptosis upon reperfusion of the cold ischemic rat liver. Gastroenterology 2000;118:183–191.
30.
Sindram D, Porte RJ, Hoffman MR, Bentley RC, Clavien PA: Synergism between platelets and leukocytes in inducing endothelial cell apoptosis in the cold ischemic rat liver: a Kupffer cell-mediated injury. Faseb J 2001;15:1230–1232.
31.
Kettner SC, Gonano C, Seebach F, Sitzwohl C, Acimovic S, Stark J, Schellongowski A, Blaicher A, Felfernig M, Zimpfer M: Endogenous heparin-like substances significantly impair coagulation in patients undergoing orthotopic liver transplantation. Anesth Analg 1998;86:691–695.
32.
Harding SA, Mallett SV, Peachey TD, Cox DJ: Use of heparinase modified thrombelastography in liver transplantation. Br J Anaesth 1997;78:175–179.
33.
Shaw BW Jr, Martin DJ, Marquez JM, Kang YG, Bugbee AC Jr, Iwatsuki S, Griffith BP, Hardesty RL, Bahnson HT, Starzl TE: Venous bypass in clinical liver transplantation. Ann Surg 1984;200:524–34.
34.
Tzakis A, Todo S, Starzl TE: Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 1989;210:649–652.
35.
Jovine E, Mazziotti A, Grazi GL, Ercolani G, Masetti M, Morganti M, Pierangeli F, Begliomini B, Mazzetti PG, Rossi R, Paladini R, Cavallari A: Piggy-back versus conventional technique in liver transplantation: report of a randomized trial. Transpl Int 1997;10:109–112.
36.
Miyamoto S, Polak WG, Geuken E, Peeters PM, Jong KP, Porte RJ, Berg AP, Hendriks HG, Slooff MJ: Liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback techniques in adults. Clin Transplant 2004;18:686–693.
37.
Hendriks HG: Transfusion requirements in orthotopic liver transplantation; Thesis, Groningen. ISBN 90-367-2015-X.
38.
Reed RL 2nd, Bracey AW Jr, Hudson JD, Miller TA, Fischer RP: Hypothermia and blood coagulation: dissociation between enzyme activity and clotting factor levels. Circ Shock 1990;32:141–152.
39.
Ferrara A, MacArthur JD, Wright HK, Modlin IM, McMillen MA: Hypothermia and acidosis worsen coagulopathy in the patient requiring massive transfusion. Am J Surg 1990;160:515–518.
40.
Ritter D, Retke SR, Lunn RJ, Bowie EJ, Ilstrup D: Preoperative coagulation screen does not predict intraoperative blood product requirements in orthotopic liver transplantation. Transpl Proc 1989;21:3533–3534.
41.
Reyle-Hahn M, Rossaint R: Coagulation techniques are not important in directing blood product transfusion during liver transplantation. Liver Transpl Surg 1997;3:659–663.
42.
Jones RM, Moulton CE, Hardy KJ: Central venous pressure and its effect on blood loss during liver resection. Br J Surg 1998;85:1058–1060.
43.
Royston D: High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Vasc Anesth 1992;6:76–100.
44.
Neuhaus P, Bechstein WO, Lefebre B, Blumhardt G, Slama K: Effect of aprotinin on intraoperative bleeding and fibrinolysis in liver transplantation. Lancet 1989;ii:924–925.
45.
Marcel RJ, Stegall WC, Suit CT, Arnold JC, Vera RL, Ramsay MA, O’Donnell MB, Swygert TH, Hein HA, Whitten CW: Continuous small-dose aprotinin controls fibrinolysis during orthotopic liver transplantation. Anesth Analg 1996;82:1122–1125.
46.
Patrassi GM, Viero M, Sartori MT, De Silvestro G, Rossaro L, Burra P, Nolli ML, Piccinni P, Bassi N: Aprotinin efficacy on intraoperative bleeding and transfusion requirements in orthotopic liver transplantation. Transfusion 1994;34:507–511.
47.
Groh J, Welte M, Azad SC, Anthuber M, Haller M, Kratzer MA: Does aprotinin really reduce blood loss in orthotopic liver transplantation? Semin Thromb Hemost 1993;19:306–308.
48.
Mallett SV, Cox D, Burroughs AK, Rolles K: The intra-operative use of trasylol (aprotinin) in liver transplantation. Transpl Int 1991;4:227–230.
49.
Garcia-Huete L, Domenech P, Sabate A, Martinez-Brotons F, Jaurrieta E, Figueras J: The prophylactic effect of aprotinin on intraoperative bleeding in liver transplantation: a randomized clinical study. Hepatology 1997;26:1143–1148.
50.
Porte RJ, Molenaar IQ: Aprotinin in liver transplantation. Hepatology 1998;27:1169–1171.
51.
Porte RJ, Molenaar IQ, Begliomini B, Groenland TH, Januszkiewicz A, Lindgren L, Palareti G, Hermans J, Terpstra OT: Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentre randomised double-blind study. Lancet 2000;355:1303–1309.
52.
Findlay JY, Rettke SR, Ereth MH, Plevak DJ, Krom RA, Kufner RP: Aprotinin reduces red blood cell transfusion in orthotopic liver transplantation: a prospective, randomized, double-blind study. Liver Transpl 2001;7:802–807.
53.
Dalmau A, Sabate A, Koo M, Bartolome C, Rafecas A, Figueras J, Jaurrieta E: The prophylactic use of tranexamic acid and aprotinin in orthotopic liver transplantation: a comparative study. Liver Transpl 2004;10:279–284.
54.
Porte RJ, Slooff MJ: Aprotinin: safe and effective in all patients undergoing orthotopic liver transplantation? Liver Transpl 2001;7:808–810.
55.
Molenaar IQ, Veldman M, Begliomini B, Groenland HN, Januszkiewicz A, Lindgren L, Metselaar HJ, Terpstra OT, Porte RJ: Improved early graft survival in patients receiving aprotinin during orthotopic liver transplantation. Transplant Proc 2001;33:1345–1346.
56.
Molenaar IQ, Begliomini B, Martinelli G, Putter H, Terpstra OT, Porte RJ: Reduced need for vasopressors in patients receiving aprotinin during orthotopic liver transplantation. Anesthesiology 2001;94:433–438.
57.
Molenaar IQ, Begliomini B, Grazi GL, Ringers J, Terpstra OT, Porte RJ: The effect of aprotinin on renal function in orthotopic liver transplantation. Transplantation 2001;71:247–252.
58.
Kuyvenhoven JP, Molenaar IQ, Verspaget HW, Veldman MG, Palareti G, Legnani C, Moolenburgh SE, Terpstra OT, Lamers CB, van Hoek B, Porte RJ: Plasma MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 during human orthotopic liver transplantation. The effect of aprotinin and the relation to ischemia/reperfusion injury. Thromb Haemost 2004;91:506–513.
59.
Molenaar IQ, Porte RJ: Aprotinin and thromboembolism in liver transplantation: is there really a causal effect? Anesth Analg 2002;94:1367–1368.
60.
Molenaar IQ, Legnani C, Groenland TH, Palareti G, Begliomini B, Terpstra OT, Porte RJ: Aprotinin in orthotopic liver transplantation: evidence for a prohemostatic, but not a prothrombotic, effect. Liver Transpl 2001;7:896–903.
61.
Boylan JF, Klinck JR, Sandler AN, Arellano R, Greig PD, Nierenberg H, Roger SL, Glynn MF: Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 1996;85:1043–1048.
62.
Kaspar M, Ramsay MA, Nguyen AT, Cogswell M, Hurst G, Ramsay KJ: Continuous small-dose tranexamic acid reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation. Anesth Analg 1997;85:281–285.
63.
Dalmau A, Sabate A, Acosta F, Garcia-Huete L, Koo M, Sansano T, Rafecas A, Figueras J, Jaurrieta E, Parrilla P: Tranexamic acid reduces red cell transfusion better than ε-aminocaproic acid or placebo in liver transplantation. Anesth Analg 2000;91:29–34.
64.
Hendriks HG, Meijer K, de Wolf JT, Klompmaker IJ, Porte RJ, de Kam PJ, Hagenaars AJ, Melsen T, Slooff MJ, van der Meer J: Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study. Transplantation 2001;71:402–405.
65.
Hendriks HG, Meijer K, de Wolf JT, Porte RJ, Klompmaker IJ, Lip H, Slooff MJ, van der Meer J: Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation. Blood Coagul Fibrinolysis 2002;13:309–313.
66.
Planinsic RM, van der Meer J, Testa G, Grande L, Candela A, Porte RJ, Ghobrial RM, Isoniemi H, Schelde PB, Erhardtsen E, Klintmalm G, Emre S: Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11:895–900.
67.
Lodge JP, Jonas S, Jones RM, Olausson M, Mir JP, Soefelt S, Garcia-Valdecasas JC, McAlister V, Mirza D: Efficacy and safety of repeated periopeartive doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11:973–979.
68.
Porte RJ, Caldwell SH: The role of recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11:872–874.
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