- Email: [email protected]
Coagulopathy Management in Liver Transplantation
Coagulopathy Management in Liver Transplantation A. Sabate, A. Dalmau, M. Koo, I. Aparicio, M. Costa, and L. Contreras ABSTRACT Risk of bleeding and transfusion in liver transplantation is determined by age, severity of liver disease, as well as hemoglobin and plasma fibrinogen values. During the hepatectomy and the anhepatic phase, the coagulopathy is related to a decrease in clotting factors caused by surgical bleeding, facilitated by the increased portal hypertension and esophageal-gastric venous distension. Corrections of hematologic disturbances by administration of large volumes of crystalloid, colloid, or blood products may worsen the coagulopathy. Also, impaired clearance of fibrinolytic enzymes released from damaged cells can lead to primary fibrinolysis. At time of graft reperfusion further deterioration may occur as characterized by global reduction among all coagulation factors, decreased plasminogen activator inhibitor factors, and simultaneous generation of tissue plasminogen activator. In situations with inherent risk of bleeding, hypofibrinogenemia must be corrected. Concern about unwanted events is a major limitation of preventive therapy. There is some evidence for the efficacy of antifibrinolytic drugs to reduce red blood cell requirements. A guide for antifibrinolytic therapy are clot firmness in trhomboelastometry or alternatively, diffuse bleeding associated to a fibrinogen value less than 1 g/L. Because thrombin generation is limited in severe thrombocytopenia, platelet administration is recommended when active bleeding coexists with a platelet count below 50,000/mm3. When the administration of hemoderivates and antifibrinolytic drugs does not correct severe bleeding, consumption coagulopathy and secondary fibrinolysis should be suspected. Treatment of affected patients should be based upon correcting the underlying cause, mostly related to tissue hypoxia due to critical hypoperfusion. FTER INJURY, arteries constrict to reduce blood flow to the injured area, facilitating the adhesion of platelets to the site, where they can join the extravascular matrix to form a platelet clot. Tissue factor, a glycoprotein attached to the subendothelium, once exposed serves as a high affinity receptor for factor VII. The complex activates factors IX and X, and thereafter factor V, which combines to produce small amounts of thrombin. The latter complexes, with factor IXa activate the factor X on the surface of platelets, which interacts with factor Va to produce a “burst” of thrombin, which is required to convert fibrinogen into sufficient fibrin to establish a fully stabilized clot that is resistant to premature fibrinolysis, wherein factor XIII is required. Transfusion of blood products is common in liver transplantation (OLT). It significantly influences patient outcomes and the viability of the transplanted organ. Severe bleeding in OLT results from a combination of blood loss of surgical origin and diffuse bleeding that requires a systemic
A
approach for treatment. Advanced cirrhosis produces a complex balance between procoagulant and antihemostatic actions1–3 that is characterized by a decreased levels of hemostatic proteins, low synthesis of anticoagulants (ATIII, protein C), thrombocytopenia, increased of von Willebrand factor and factor VIII, increased nitric oxide and prostacyclin as well as a subtle equilibrium between tissue plasminegen activator (t-PA) and PAI-1. There are limited correlations between conventional hemostasis and coagulation tests with bleeding during OLT. The risks of bleeding and transfusion in OLT seem to be determined by patient age, severity of liver disease accordFrom the Department of Anesthesia and Reanimation, Hospital Universitari de Bellvitge, IDIBELL, Health Universitat de Barcelona Campus, Barcelona, Spain. Address reprint requests to Antoni Sabate, Feixa Llarga s/n L’Hospitalet de Llobregat. ‘Barcelona 08907, Spain. E-mail: [email protected]
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.05.004
Transplantation Proceedings, 44, 1523–1525 (2012)
1523
1524
SABATE, DALMAU, KOO ET AL
ing to the value of Model for End-stage Liver Disease, preoperative hemoglobin and plasma fibrinogen values.4,5 “Point of care monitoring” based on thromboelastogram or thromboelastrometry (TEG) can be used for decision making, because the risk of bleeding or of thrombosis coexist during surgery and when empirical treatments are applied. In the cirrhotic patient the TEG pattern is characterized by decreases in maximum clot firmness (MCF), clotting time, and clot formation time that show good correlations with fibrinogen and platelets.6 BLEEDING DURING OLT
During the hepatectomy and anhepatic phases, the coagulopathy results from decreased clotting factors caused by surgical bleeding, facilitated by the increased portal hypertension and the esophageal-gastric venous distension caused by compressive maneuvers and by vascular clamping. Corrections of hematologic disturbances by administration of large volumes of crystalloid, colloid, or blood products worsen the coagulopathy. In addition, the thickness of platelets and clotting factors can be affected by acidosis, hypocalcemia, and hypothermia, as well as by fibrinolytic enzymes released from damaged cells that increases fibrinolysis of already formed blood clots. These observations reinforce the importance of fluid restriction to minimize hemodilution of hemostatic and coagulation substrates and to avoid increased portal venous pressure. Studying the roles of phlebotomy and administration of phenylephrine Massicotte and coworkers,7 showed a reduction in transluminal portal vessel flow with minimal blood product usage without renal impairment. However, no other study has reproduced these findings. Preservation of the vena cava (piggyback technique) helps to reduce bleeding during OLT, probably because it improves physiological parameters of body temperature, cardiac output, tissue perfusion, gas exchange, acid-base status, and fluidelectrolyte balance.8 –10 At the time of graft reperfusion, depending on the graft quality, further deterioration may occur characterized by global reduction of all coagulation factors, decreased anti-
thrombotic factors (antithrombin III, protein C), decreased plasminogen activator inhibitory and other natural antifibrinolytic (alpha-2-antiplasmin) factors and simultaneous generation of tPA.11 Simplifying, the profile during OLT is characterized by thrombocytopenia and hypofibrinogenemia with a good correlation with MCF at 10 minutes in the TEG.12,13 Also, formation of d-dimer complexes occurs in particular at the end of transplantation or in the immediate postoperative period. PROPHYLAXIS AND PREVENTIVE CURRENT TREATMENT OF BLEEDING AMONG PATIENTS WITH HEPATIC IMPAIRMENT AND OLT
Reduction of blood product requirements had been generalized achieved in OLT (Table 1); however, the procedure may still be associated with massive bleeding.14 –20 There is no evidence of clinical improvement by prophylactic correction of clotting factors; however, decreased plasma fibrinogen levels influence blood product requirements.21 It is accepted that in situations of bleeding risk fibrinogen must be corrected to plasma levels below 1.5 g/L using fresh frozen plasma (600 –1200 mL) or fibrinogen concentrates (1 g of fibrinogen to increase by 0.28 g/L of plasma fibrinogen). Concern about unwanted events is a major limitation of prophylactic therapy to normalize plasma fibrinogen levels, even if there has not been communicated any thrombosis or elevations of d-dimers related to hypofibrinogenemia correction.22 There is some evidence that antifibrinolytic drugs show efficacy to reduce red blood cell requirements.23–25 Criteria to identify patients who could benefit from prophylactic treatment has not been presented,26 because this effect not only depends on the preoperative patient condition but also on donor liver quality as well as surgical conditions during the hepatectomy and anhepatic stages. Guidelines for antifibrinolytic therapy are the clot firmness in TEG or, alternatively, when diffuse bleeding is detected, a fibrinogen value less than 1 g/L. Antifibrinolytic drugs must not be used in patients with a medical history of thrombotic events, acute liver failure, or biliary cirrhosis. Data on thromboem-
Table 1. Transfusion in Adult Liver Transplantation Study, Year, Patients
RBCs
% No RBCs
MELD
Preoperative Hemoglobin
Surgical Technique
Benson, 2002–9, n ⫽ 525 Rice,15 2004–7, n ⫽ 194 Massicotte,16 2002–9, n ⫽ 400 Listman,17 2004–6, n ⫽ 194 Audet,18 2000–5, n ⫽ 423 Bispo,19 2005–8, n ⫽ 77 Roulet,20 2004–8, n ⫽ 148 HUB 1998–2008 Tnx n ⫽ 427 Aprotinine n ⫽ 69 ConAntFibr n ⫽ 45
8 (3–15)* 3 (0–35) 0.5 ⫾ 1.3 1.8 (0–26) 3 (1–48) 5.7 ⫾ 3.5 4 (2–8)
14 25 80 35 ? ? ?
25 (21–29) 17 (6–40) 22 ⫾ 10 ? ? 18.5 ⫾ 6.8 15 ⫾ 6 18 ⫾ 7
? 12 (6.8–7.5) 10.8 ⫾ 2.4 ? ? 10.4 ⫾ 7.7 12.4 (10.6–13.7)
? Piggyback Total vascular clamp Piggyback Piggyback Piggyback Piggyback
3 (1–27)* 3 (1–17)* 5 (1–25)*
45 35 18
14
11.48 ⫾ 2.2 11.28 ⫾ 2.2 10.67 ⫾ 1.9
Piggyback Piggyback Piggyback
Tnx, patient with prophylactic tranexamic acid; ConAntFibr, patients in who antifibrinolytic prophylaxis were contraindicated; RBCs, red blood cell units; MELD, Model for End-stage Liver Disease; HuB, . Hemoglobin expressed in grams per liter. Data expressed as: mean ⫾ standard deviation; median and range. *Median and range of transfused patients.
COAGULOPATHY MANAGEMENT
bolic complications in OLT are inconclusive.27,28 Tripodi and coworkers29 observed thrombin generation to be limited in severe thrombocytopenia, so that it seems reasonable to administer platelets when active bleeding coexists with a platelet count be low 50,000/mm3. Even if there are no controlled trials desmopressin may improve hemostasis in this situation. A note of caution should be mentioned when administration of high volumes of hemoderivates and antifibrinolytics do not correct severe bleeding; a consumption coagulopathy with secondary fibrinolysis should be suspected. Treatment of these patients must be based on correcting the underlying cause, mostly related to tissue hypoxia due to critical hypoperfusion.27
REFERENCES 1. Tripodi A, Mannucci PM: The coagulopathy of chronic liver disease. N Engl J Med 365:147, 2011 2. Lismann T, Caldwell SH, Burroughd AK, et al: Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 53:362, 2010 3. Roberts LN, Patel RK, Roope A: Haemostasis and thrombosis in liver disease. Br J Haematology 148:507, 2009 4. Mangus RS, Kinsella SB, Nobari MM, et al: Predictors of blood product use in orthotopic liver transplantation using the piggyback hepatectomy technique. Transplant Proc 39:3207, 2007 5. Xia VW, Du B, Braunfeld M, et al: Preoperative and intraoperative and vasopressor caracheristics requirements in patients with low vs. high MELD scores. Liver Transpl 12:614, 2006 6. Tripodi A, Primignani M, Chantrangkul V, et al: The coagulopathy of cirrhosis trhomboelastometry assessed by conventional and its correlation with coagulation parameters. Thromb Res 124:132, 2009 7. Massicotte L, Perrault MA, Denault AY, et al: Effects of phlebotomy and infusion on phenyleprrine portal venous pressure and systemic hemodynamics during liver transplantation. Transplantation 27:89:920, 2010 8. Jovine E, Mazziotti A, Grazi GL, et al: Piggy-back versus conventional technique in liver transplantation: report of a randomized trial. Transpl Int 10:109, 1997 9. Miyamoto S, Polak WG, Geuken E, et al: Liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback tècniques in adults. Clin Transplant 18:686, 2004 10. Kang Y, Audu P: Coagulation and liver transplantation. Anesthesiol Clin 44:17, 2006 11. Wang Y, Liu Y, Han R, et al: Hemostatic variation during perioperative period of orthotopic liver. Thromb Res 122:161, 2008 12. Roullet S, Pillet J, Freyburg G, et al: Rotation detects thromboelastometry thrombocytopenia and orthotopic liver transplantation during hypofibrinogenaemia. Br J Anaesth 104:422, 2010
1525 13. Herbstreit F, Winter EM, Peters J, et al: Monitoring of haemostasis in liver transplantation: comparison of laboratory based and point of care tests. Anaesthesia 65:44, 2010 14. Benson A, Burton JR, Austin GL, et al: Differential effects of plasma and red blood cell transfusions on acute lung injury and infection risk following liver transplantation. Liver Transplant 17:149, 2011 15. Rice MJ, Wenlung A, Firpy RJ, et al: Transfusion has no effect on recurrence in hepatitic C after liver transplantation. Acta Anaesthesiol Scand 54:1224, 2010 16. Massicotte L, Desault AY, Beaulieu D, et al: Aprotinin versus tranexamic acid during liver transplantatio: impact on blood rpoduct requirements and survival. Transplantation 9:1273, 2011 17. Ijstman DJ, van der Helst E, de Boer MT, et al: The clinical relevance of the anhepatic phase during liver transplantation. Liver Transpl 15:1050, 2009 18. Audet M, Pizoli T, Panaro T, et al: Four hundred and twenty-three consecutive adults piggyback liver transplantation with the three suprahepatic veins: was the portal systemic shunt required? J Gastroenterol Hepatol 25:591, 2010 19. Bispo M, Marcelino P, Marques HP, et al: Domino versus dedceased donor liver transplantation association with early gtraft function and perioperative bleeding. Liver Transpl 17:270, 2011 20. Roulet S, BIais M, Millas F, et al: Risk factors for bleeding and transfusion during orthotopic liver transplantation. Annals Françaises d’Anesthesie et de Reanimation 30:349, 2011 21. Costa M, Sabate A, Dalmau A, et al: Predictive factors of blood product requirements in liver transplantation. Eur J Anaesth 28:S48, 2011 22. Farriols Danes A, Gallur Cuenca L, Rodriguez Bueno S, et al: Efficacy and tolerability of human fibrinogen concentrate administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding. Vox Sang 94:221, 2008 23. Boylan JF, Klinck JR, Sandler AN, et al: Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 85:1043, 1996 24. Dalmau A, Sabate A, Acosta F, et al: Tranexamic acid reduces red cell transfusion better than epsilon-aminocaproic acid or placebo in liver transplantation. Anesth Analg 91:29, 2000 25. Dalmau A, Sabate A, Koo M, et al: The prophylactic use of tranexamic acid and aprotinin in orthotopic liver transplantation: a comparative study. Liver Transpl 10:279, 2004 26. McCluskey SA, Karkouti K, Wijeysundera DN, et al: Derivation of a risk index for the prediction of massive blood transfusion in liver transplantation. Liver Transpl 12:1584, 2006 27. Gologorsky E, De Wolf AM, Scott V, et al: Intracardiac thrombus formation and pulmonary thromboembolism immediately after graft reperfusion in 7 patients undergoing liver transplantation. Liver Transpl 7:783, 2007 28. Molenaar IQ, Warnaar N, Groen H, et al: Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review. Am J Transplant 7:185, 2007 29. Tripodi A, Primignanai M, Chantarangkul V, et al: Thrombin generation in patients with cirrhosis: the the role of platelets. Hepatology 44:440, 2006
A
approach for treatment. Advanced cirrhosis produces a complex balance between procoagulant and antihemostatic actions1–3 that is characterized by a decreased levels of hemostatic proteins, low synthesis of anticoagulants (ATIII, protein C), thrombocytopenia, increased of von Willebrand factor and factor VIII, increased nitric oxide and prostacyclin as well as a subtle equilibrium between tissue plasminegen activator (t-PA) and PAI-1. There are limited correlations between conventional hemostasis and coagulation tests with bleeding during OLT. The risks of bleeding and transfusion in OLT seem to be determined by patient age, severity of liver disease accordFrom the Department of Anesthesia and Reanimation, Hospital Universitari de Bellvitge, IDIBELL, Health Universitat de Barcelona Campus, Barcelona, Spain. Address reprint requests to Antoni Sabate, Feixa Llarga s/n L’Hospitalet de Llobregat. ‘Barcelona 08907, Spain. E-mail: [email protected]
© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.05.004
Transplantation Proceedings, 44, 1523–1525 (2012)
1523
1524
SABATE, DALMAU, KOO ET AL
ing to the value of Model for End-stage Liver Disease, preoperative hemoglobin and plasma fibrinogen values.4,5 “Point of care monitoring” based on thromboelastogram or thromboelastrometry (TEG) can be used for decision making, because the risk of bleeding or of thrombosis coexist during surgery and when empirical treatments are applied. In the cirrhotic patient the TEG pattern is characterized by decreases in maximum clot firmness (MCF), clotting time, and clot formation time that show good correlations with fibrinogen and platelets.6 BLEEDING DURING OLT
During the hepatectomy and anhepatic phases, the coagulopathy results from decreased clotting factors caused by surgical bleeding, facilitated by the increased portal hypertension and the esophageal-gastric venous distension caused by compressive maneuvers and by vascular clamping. Corrections of hematologic disturbances by administration of large volumes of crystalloid, colloid, or blood products worsen the coagulopathy. In addition, the thickness of platelets and clotting factors can be affected by acidosis, hypocalcemia, and hypothermia, as well as by fibrinolytic enzymes released from damaged cells that increases fibrinolysis of already formed blood clots. These observations reinforce the importance of fluid restriction to minimize hemodilution of hemostatic and coagulation substrates and to avoid increased portal venous pressure. Studying the roles of phlebotomy and administration of phenylephrine Massicotte and coworkers,7 showed a reduction in transluminal portal vessel flow with minimal blood product usage without renal impairment. However, no other study has reproduced these findings. Preservation of the vena cava (piggyback technique) helps to reduce bleeding during OLT, probably because it improves physiological parameters of body temperature, cardiac output, tissue perfusion, gas exchange, acid-base status, and fluidelectrolyte balance.8 –10 At the time of graft reperfusion, depending on the graft quality, further deterioration may occur characterized by global reduction of all coagulation factors, decreased anti-
thrombotic factors (antithrombin III, protein C), decreased plasminogen activator inhibitory and other natural antifibrinolytic (alpha-2-antiplasmin) factors and simultaneous generation of tPA.11 Simplifying, the profile during OLT is characterized by thrombocytopenia and hypofibrinogenemia with a good correlation with MCF at 10 minutes in the TEG.12,13 Also, formation of d-dimer complexes occurs in particular at the end of transplantation or in the immediate postoperative period. PROPHYLAXIS AND PREVENTIVE CURRENT TREATMENT OF BLEEDING AMONG PATIENTS WITH HEPATIC IMPAIRMENT AND OLT
Reduction of blood product requirements had been generalized achieved in OLT (Table 1); however, the procedure may still be associated with massive bleeding.14 –20 There is no evidence of clinical improvement by prophylactic correction of clotting factors; however, decreased plasma fibrinogen levels influence blood product requirements.21 It is accepted that in situations of bleeding risk fibrinogen must be corrected to plasma levels below 1.5 g/L using fresh frozen plasma (600 –1200 mL) or fibrinogen concentrates (1 g of fibrinogen to increase by 0.28 g/L of plasma fibrinogen). Concern about unwanted events is a major limitation of prophylactic therapy to normalize plasma fibrinogen levels, even if there has not been communicated any thrombosis or elevations of d-dimers related to hypofibrinogenemia correction.22 There is some evidence that antifibrinolytic drugs show efficacy to reduce red blood cell requirements.23–25 Criteria to identify patients who could benefit from prophylactic treatment has not been presented,26 because this effect not only depends on the preoperative patient condition but also on donor liver quality as well as surgical conditions during the hepatectomy and anhepatic stages. Guidelines for antifibrinolytic therapy are the clot firmness in TEG or, alternatively, when diffuse bleeding is detected, a fibrinogen value less than 1 g/L. Antifibrinolytic drugs must not be used in patients with a medical history of thrombotic events, acute liver failure, or biliary cirrhosis. Data on thromboem-
Table 1. Transfusion in Adult Liver Transplantation Study, Year, Patients
RBCs
% No RBCs
MELD
Preoperative Hemoglobin
Surgical Technique
Benson, 2002–9, n ⫽ 525 Rice,15 2004–7, n ⫽ 194 Massicotte,16 2002–9, n ⫽ 400 Listman,17 2004–6, n ⫽ 194 Audet,18 2000–5, n ⫽ 423 Bispo,19 2005–8, n ⫽ 77 Roulet,20 2004–8, n ⫽ 148 HUB 1998–2008 Tnx n ⫽ 427 Aprotinine n ⫽ 69 ConAntFibr n ⫽ 45
8 (3–15)* 3 (0–35) 0.5 ⫾ 1.3 1.8 (0–26) 3 (1–48) 5.7 ⫾ 3.5 4 (2–8)
14 25 80 35 ? ? ?
25 (21–29) 17 (6–40) 22 ⫾ 10 ? ? 18.5 ⫾ 6.8 15 ⫾ 6 18 ⫾ 7
? 12 (6.8–7.5) 10.8 ⫾ 2.4 ? ? 10.4 ⫾ 7.7 12.4 (10.6–13.7)
? Piggyback Total vascular clamp Piggyback Piggyback Piggyback Piggyback
3 (1–27)* 3 (1–17)* 5 (1–25)*
45 35 18
14
11.48 ⫾ 2.2 11.28 ⫾ 2.2 10.67 ⫾ 1.9
Piggyback Piggyback Piggyback
Tnx, patient with prophylactic tranexamic acid; ConAntFibr, patients in who antifibrinolytic prophylaxis were contraindicated; RBCs, red blood cell units; MELD, Model for End-stage Liver Disease; HuB, . Hemoglobin expressed in grams per liter. Data expressed as: mean ⫾ standard deviation; median and range. *Median and range of transfused patients.
COAGULOPATHY MANAGEMENT
bolic complications in OLT are inconclusive.27,28 Tripodi and coworkers29 observed thrombin generation to be limited in severe thrombocytopenia, so that it seems reasonable to administer platelets when active bleeding coexists with a platelet count be low 50,000/mm3. Even if there are no controlled trials desmopressin may improve hemostasis in this situation. A note of caution should be mentioned when administration of high volumes of hemoderivates and antifibrinolytics do not correct severe bleeding; a consumption coagulopathy with secondary fibrinolysis should be suspected. Treatment of these patients must be based on correcting the underlying cause, mostly related to tissue hypoxia due to critical hypoperfusion.27
REFERENCES 1. Tripodi A, Mannucci PM: The coagulopathy of chronic liver disease. N Engl J Med 365:147, 2011 2. Lismann T, Caldwell SH, Burroughd AK, et al: Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 53:362, 2010 3. Roberts LN, Patel RK, Roope A: Haemostasis and thrombosis in liver disease. Br J Haematology 148:507, 2009 4. Mangus RS, Kinsella SB, Nobari MM, et al: Predictors of blood product use in orthotopic liver transplantation using the piggyback hepatectomy technique. Transplant Proc 39:3207, 2007 5. Xia VW, Du B, Braunfeld M, et al: Preoperative and intraoperative and vasopressor caracheristics requirements in patients with low vs. high MELD scores. Liver Transpl 12:614, 2006 6. Tripodi A, Primignani M, Chantrangkul V, et al: The coagulopathy of cirrhosis trhomboelastometry assessed by conventional and its correlation with coagulation parameters. Thromb Res 124:132, 2009 7. Massicotte L, Perrault MA, Denault AY, et al: Effects of phlebotomy and infusion on phenyleprrine portal venous pressure and systemic hemodynamics during liver transplantation. Transplantation 27:89:920, 2010 8. Jovine E, Mazziotti A, Grazi GL, et al: Piggy-back versus conventional technique in liver transplantation: report of a randomized trial. Transpl Int 10:109, 1997 9. Miyamoto S, Polak WG, Geuken E, et al: Liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback tècniques in adults. Clin Transplant 18:686, 2004 10. Kang Y, Audu P: Coagulation and liver transplantation. Anesthesiol Clin 44:17, 2006 11. Wang Y, Liu Y, Han R, et al: Hemostatic variation during perioperative period of orthotopic liver. Thromb Res 122:161, 2008 12. Roullet S, Pillet J, Freyburg G, et al: Rotation detects thromboelastometry thrombocytopenia and orthotopic liver transplantation during hypofibrinogenaemia. Br J Anaesth 104:422, 2010
1525 13. Herbstreit F, Winter EM, Peters J, et al: Monitoring of haemostasis in liver transplantation: comparison of laboratory based and point of care tests. Anaesthesia 65:44, 2010 14. Benson A, Burton JR, Austin GL, et al: Differential effects of plasma and red blood cell transfusions on acute lung injury and infection risk following liver transplantation. Liver Transplant 17:149, 2011 15. Rice MJ, Wenlung A, Firpy RJ, et al: Transfusion has no effect on recurrence in hepatitic C after liver transplantation. Acta Anaesthesiol Scand 54:1224, 2010 16. Massicotte L, Desault AY, Beaulieu D, et al: Aprotinin versus tranexamic acid during liver transplantatio: impact on blood rpoduct requirements and survival. Transplantation 9:1273, 2011 17. Ijstman DJ, van der Helst E, de Boer MT, et al: The clinical relevance of the anhepatic phase during liver transplantation. Liver Transpl 15:1050, 2009 18. Audet M, Pizoli T, Panaro T, et al: Four hundred and twenty-three consecutive adults piggyback liver transplantation with the three suprahepatic veins: was the portal systemic shunt required? J Gastroenterol Hepatol 25:591, 2010 19. Bispo M, Marcelino P, Marques HP, et al: Domino versus dedceased donor liver transplantation association with early gtraft function and perioperative bleeding. Liver Transpl 17:270, 2011 20. Roulet S, BIais M, Millas F, et al: Risk factors for bleeding and transfusion during orthotopic liver transplantation. Annals Françaises d’Anesthesie et de Reanimation 30:349, 2011 21. Costa M, Sabate A, Dalmau A, et al: Predictive factors of blood product requirements in liver transplantation. Eur J Anaesth 28:S48, 2011 22. Farriols Danes A, Gallur Cuenca L, Rodriguez Bueno S, et al: Efficacy and tolerability of human fibrinogen concentrate administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding. Vox Sang 94:221, 2008 23. Boylan JF, Klinck JR, Sandler AN, et al: Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 85:1043, 1996 24. Dalmau A, Sabate A, Acosta F, et al: Tranexamic acid reduces red cell transfusion better than epsilon-aminocaproic acid or placebo in liver transplantation. Anesth Analg 91:29, 2000 25. Dalmau A, Sabate A, Koo M, et al: The prophylactic use of tranexamic acid and aprotinin in orthotopic liver transplantation: a comparative study. Liver Transpl 10:279, 2004 26. McCluskey SA, Karkouti K, Wijeysundera DN, et al: Derivation of a risk index for the prediction of massive blood transfusion in liver transplantation. Liver Transpl 12:1584, 2006 27. Gologorsky E, De Wolf AM, Scott V, et al: Intracardiac thrombus formation and pulmonary thromboembolism immediately after graft reperfusion in 7 patients undergoing liver transplantation. Liver Transpl 7:783, 2007 28. Molenaar IQ, Warnaar N, Groen H, et al: Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review. Am J Transplant 7:185, 2007 29. Tripodi A, Primignanai M, Chantarangkul V, et al: Thrombin generation in patients with cirrhosis: the the role of platelets. Hepatology 44:440, 2006