Current Transplantation Reports

, Volume 5, Issue 3, pp 251–263 | Cite as

Current Hematological Concepts and Viscoelastic-Based Transfusion Practices During Liver Transplantation

  • Arun UthayashankarEmail author
  • Michael Kaufman
Anesthesia and Critical Care in Transplantation (D Axelrod and M Kaufman, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Anesthesia and Critical Care in Transplantation



When the cascade model of coagulation was postulated in 1964, it convincingly explained the conventional tests of coagulation and their therapeutic applications for existing anticoagulants. But the conventional tests only tend to measure the procoagulant factors and not the anticoagulant factors present in the blood, as a result, the coagulation concept was updated to cell-based model in 2001. Despite these facts, the conventional tests are still used perioperatively in liver transplantation for blood product management, at the risk of causing over-transfusion and deleterious prothrombotic effects. This article reviews the current understanding of coagulation and suggests an improved method to manage intraoperative blood product replacement.

Recent Findings

We set out to develop a diagnostic and dosing protocol based on viscoelastic tests, which more accurately reflect the dynamic interplay between pro and anticoagulants in the end-stage liver disease patient. This approach reduces the overtransfusion and resulting harm from excessive coagulation without increasing the risk of intraoperative bleeding.


While we were successful in formulating a dosing regimen based on available literature and our own institutional practices for treating deficiencies of clotting factors and fibrinogen, more research is needed to arrive at a dosing regimen for platelets based on functional deficiency.


Liver transplant Current concepts Hematology Viscoelastic tests ROTEM-based protocol 



A Disintegrin And Metalloproteinase with a ThromboSpondin Type 1 motif


adenosine diphosphate


aprotinin-added ROTEM


activated partial thromboplastin time




clot formation time


clotting time


end-stage liver disease


extrinsic pathway component of ROTEM




heparinase-added ROTEM


intrinsic pathway component of ROTEM




liver transplant


maximum clot formation


maximum lysis


platelet-activating factor


plasminogen activator inhibitor


protease-activated receptors


plasmin inhibitor


prothrombin time


arginine-glycine-D aspartate


rotational thromboelastometry


thrombin activatable fibrinolysis inhibitor




tissue factor


tissue factor pathway inhibitor




tissue plasminogen activator


urine plasminogen activator




von Willebrand factor


Compliance with Ethical Standards

Conflict of Interest

Arun Uthayashankar and Michael Kaufman declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Sucker C, Zotz RB. The cell-based coagulation model. In: Marcucci C, Schoettker P, editors. Perioperative hemostasis. Berlin: Springer; 2015.Google Scholar
  2. 2.
    Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol. 2006;26:41–8, originally published December 22, 2005. Scholar
  3. 3.
    Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958–65.CrossRefPubMedGoogle Scholar
  4. 4.
    Hoffman M, Monroe DM, Roberts HR. Cellular interactions in hemostasis. Haemostasis. 1996;26(SUPPL. 1):12–6.PubMedGoogle Scholar
  5. 5.
    Osterud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci. 1977;74(12):5260–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Wildgoose P, Kisiel W. Activation of human factor VII by factors IXa and Xa on human bladder carcinoma cells. Blood. 1989;73:1888–95.PubMedGoogle Scholar
  7. 7.
    Gailani D, Broze G. Factor XI in a revised model of blood coagulation. Science (New York, N.Y.). 1991;253:909–12. Scholar
  8. 8.
    Gailani D, Broze GJ Jr. Factor XI activation by thrombin and factor XIa. Semin Thromb Hemost. 1993;19(4):396–404. Scholar
  9. 9.
    Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol. 1999;19:170–7. Scholar
  10. 10.
    Monkovic DD, Tracy PB. Activation of human factor V by factor Xa and thrombin. Biochemistry. 1990;29(5):1118–28.CrossRefPubMedGoogle Scholar
  11. 11.
    Hung DT, Vu TK, Wheaton VI, Ishii K, Coughlin SR. Cloned platelet thrombin receptor is necessary for thrombin-induced platelet activation. J Clin Invest. 1992;89(4):1350–3.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Monković D, Tracy P. Functional characterization of human platelet-released Factor V and its activation by Factor Xa and thrombin. J Biol Chem. 1990;265:17132–40.PubMedGoogle Scholar
  13. 13.
    Hultin MB. Modulation of thrombin-mediated activation of factor VIII:C by calcium ions, phospholipid and platelets. Blood. 1985;66(1):53–8.PubMedGoogle Scholar
  14. 14.
    Crawley JTB, Zanardelli S, Chion CKNK, Lane DA. The central role of thrombin in hemostasis. J Thromb Haemost. 2007;5(Suppl. 1):95–101.CrossRefPubMedGoogle Scholar
  15. 15.
    Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost. 2003;1(7):1504–14.Google Scholar
  16. 16.
    Lane DA, Philippou H, Huntington JA. Directing thrombin. Blood. 2005;106(8):2605–12.Google Scholar
  17. 17.
    Philippou H, Rance J, Myles T, Hall SW, Ariens RA, Grant PJ, et al. Roles of low specificity and cofactor interaction sites on thrombin during factor XIII activation. Competition for cofactor sites on thrombin determines its fate. J Biol Chem. 2003;278(34):32020–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Li CQ, Vindigni A, Sadler JE, Wardell MR. Platelet glycoprotein Ib alpha binds to thrombin anion-binding exosite II inducing allosteric changes in the activity of thrombin. J Biol Chem. 2001;276(9):6161–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Streusand VJ, Björk I, Gettins PGW, Petitou M, Olson ST. Mechanism of acceleration of antithrombin-proteinase reactions by low affinity heparin. J Biol Chem. 1995;270:9043–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Sadler JE. Thrombomodulin structure and function. Thromb Haemost. 1997;78(1):392–5.CrossRefPubMedGoogle Scholar
  21. 21.
    McDowall J. Fibrinogen; interpro/protein of the month, Nov 2006, page 1.
  22. 22.
    Ariëns RA, Lai T, Weisel JW, Greenberg CS, Grant PJ. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood. 2002;100(3):743–54.CrossRefPubMedGoogle Scholar
  23. 23.
    Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol. 2005;129(3):307–21. Scholar
  24. 24.
    Esmon C. Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost. 2006;32(Suppl 1):49–60.CrossRefPubMedGoogle Scholar
  25. 25.
    Olson ST, Björk I. Regulation of thrombin activity by antithrombin and heparin. Sem Thromb Hemost. 1994;20(4):373–409. Scholar
  26. 26.
    van Hinsbergh VWM. Endothelium—role in regulation of coagulation and inflammation. Semin Immunopathol. 2012;34(1):93–106.CrossRefPubMedGoogle Scholar
  27. 27.
    Kujovich JL. Coagulopathy in liver disease: a balancing act. Hematology Am Soc Hematol Educ Program. 2015;2015:243–9.PubMedGoogle Scholar
  28. 28.
    Krzanicki D, Sugavanam A, Mallett S. Intraoperative hypercoagulability during liver transplantation as demonstrated by thromboelastography. Liver Transpl. 2013;19(8):852–61. Scholar
  29. 29.
    Alamo JM, León A, Mellado P, Bernal C, Marín LM, Cepeda C, et al. Is "intra-operating room" thromboelastometry useful in liver transplantation? A case-control study in 303 patients. Transplant Proc. 2013;45(10):3637–9. Scholar
  30. 30.
    De Pietri L, Ragusa F, Deleuterio A, Begliomini B, Serra V. Reduced transfusion during OLT by POC coagulation management and TEG functional fibrinogen: a retrospective observational study. Transplant Direct. 2016;2(1):e49. Scholar
  31. 31.
    Ak K, Isbir CS, Tetik S, Atalan N, Tekeli A, Aljodi M, et al. Thromboelastography-based transfusion algorithm reduces blood product use after elective CABG: a prospective randomized study. J Card Surg. 2009;24(4):404–10. Scholar
  32. 32.
    Wang SC, Shieh JF, Chang KY, Chu YC, Liu CS, Loong CC, et al. Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. Transplant Proc. 2010 Sep;42(7):2590–3. Scholar
  33. 33.
    • Heim C, Schoettker P. Viscoelastic tests of hemostasis. In: Marcucci C, Schoettker P, editors. Perioperative hemostasis. Berlin: Springer; 2015.Google Scholar
  34. 34.
    Andy NG, Curry JM, Pierce T. Conventional and near-patient tests of coagulation. Contin Educ Anaesth Crit Care Pain. 2007;7(2):45–50. Scholar
  35. 35.
    Smith NK, Kim S, Hill B, Goldberg A, DeMaria S, Zerillo J. Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in liver transplantation: a case report and focused review. Semin Cardiothorac Vasc Anesth. 2017;22:180–90. CrossRefPubMedGoogle Scholar
  36. 36.
    • Tapia NM, Chang A, Norman M, Welsh F, Scott B, Wall MJ Jr, et al. TEG-guided resuscitation is superior to standardized MTP resuscitation in massively transfused penetrating trauma patients. J Trauma Acute Care Surg. 2013;74(2):378–85. discussion 385–6CrossRefPubMedGoogle Scholar
  37. 37.
    Westbrook A, Olsen J, Bailey M, Bates J, Scully M, Salamonsen R. Protocol based on thromboelastograph (TEG) out-performs physician preference using laboratory coagulation tests to guide blood replacement during and after cardiac surgery: a pilot study. Heart Lung Circ. 2009;18:277–88.CrossRefPubMedGoogle Scholar
  38. 38.
    Jeppsson A. Earlier detection of coagulopathy with thromboelastometry during pediatric cardiac surgery: a prospective observational study. Paediatr Anaesth. 2013;23(3):222–7. Scholar
  39. 39.
    Lerner AB, Sundar E, Mahmood F, Sarge T, Hanto DW, Panzica PJ. Four cases of cardiopulmonary thromboembolism during liver transplantation without the use of antifibrinolytic drugs. Anesth Analg. 2005;101(6):1608–12.CrossRefPubMedGoogle Scholar
  40. 40.
    Sankarankutty A, Nascimento B, da Luz LT, Rizoli S. TEG® and ROTEM® in trauma: similar test but different results? World J Emerg Surg. 2012;7(Suppl 1):S3. Published: 22 August 2012CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Lang T, Bauters A, Braun S, Pötzsch B, von Pape K-W, Kolde H-J, et al. Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis. 2005;16:301–10. Scholar
  42. 42.
    Larsen OH, Fenger-Eriksen C, Christiansen K, Ingerslev J, Sørensen B. Diagnostic performance and therapeutic consequence of thromboelastometry activated by kaolin versus a panel of specific reagents. Anesthesiology. 2011;115(2):294–302. Scholar
  43. 43.
    Görlinger K, Dirkmann D, Solomon C, Hanke AA. Fast interpretation of thromboelastometry in non-cardiac surgery: reliability in patients with hypo-, normo-, and hypercoagulability. BJA. 2013;110(2):222–30. Scholar
  44. 44.
    ROTEM Website [Tem International GmbH].Google Scholar
  45. 45.
    Rugeri L, Levrat A, David JS, Delecroix E, Floccard B, Gros A, et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost. 2007;5:289–95.CrossRefPubMedGoogle Scholar
  46. 46.
    Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol. 2014;89(2):228–32. Scholar
  47. 47.
    • Song J-G, Jeong S-M, Jun I-G, Lee H-M, Hwang G-S. Five-minute parameter of thromboelastometry is sufficient to detect thrombocytopenia and hypofibrinogenaemia in patients undergoing liver transplantation. BJA. 2014;112(2):290–7. Scholar
  48. 48.
    Görlinger K, Fries D, Dirkmann D, Weber CF, Alexander A, Hanke, et al. Reduction of fresh frozen plasma requirements by perioperative point-of-care coagulation management with early calculated goal-directed therapy. Transfus Med Hemother. 2012;39:104–13. Scholar
  49. 49.
    Sørensen B, Ingerslev J. Thromboelastography and recombinant factor VIIa—hemophilia and beyond. Semin Hematol. 2004;41(1 Suppl 1):140–4.CrossRefPubMedGoogle Scholar
  50. 50.
    Levrat A, Gros A, Rugeri L, Inaba K, Floccard B, Negrier C, et al. Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. BJA. 2008;100(6):792–7. Scholar
  51. 51.
    Hunt BJ, Segal H. Hyperfibrinolysis. J Clin Pathol. 1996;49(12):958.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Pereboom ITA, Lisman T, Porte RJ. Platelets in liver transplantation: friend or foe? Liver Transpl. 2008;14:923–31.CrossRefPubMedGoogle Scholar
  53. 53.
    Smalberg JH, Leebeek FW. Superimposed coagulopathic conditions in cirrhosis: infection and endogenous heparinoids, renal failure, and endothelial dysfunction. Clin Liver Dis. 2009;13(1):33–42. Scholar
  54. 54.
    de Boer MT, Christensen MC, Asmussen M, van der Hilst CS, Hendriks HG, Slooff MJ, et al. The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation. Anesth Analg. 2008;106(1):32–44.CrossRefPubMedGoogle Scholar
  55. 55.
    Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology. 2005;41(3):553–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Tripodi A, Primignani M, Chantarangkul V, Clerici M, Dell'Era A, Fabris F, et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology. 2006 Aug;44(2):440–5.CrossRefPubMedGoogle Scholar
  57. 57.
    Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44(1):53–61.CrossRefPubMedGoogle Scholar
  58. 58.
    Hugenholtz GG, Porte RJ, Lisman T. The platelet and platelet function testing in liver disease. Clin Liver Dis. 2009;13(1):11–20. Scholar
  59. 59.
    Escolar G, Cases A, Viñas M, Pino M, Calls J, Cirera I, et al. Evaluation of acquired platelet dysfunctions in uremic and cirrhotic patients using the platelet function analyzer (PFA-100): influence of hematocrit elevation; Haematologica. 1999;(7):614–9.Google Scholar
  60. 60.
    Rand ML, Leung R, Packham MA. Platelet function assays. Transfus Apher Sci. 2003;28(3):307–17.CrossRefPubMedGoogle Scholar
  61. 61.
    Kundu SK, Heilmann EJ, Sio R, Garcia C, Davidson RM, Ostgaard RA. Description of an in vitro platelet function analyzer—PFA-100. Semin Thromb Hemost. 1995;21(Suppl 2):106–12.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Lahey Hospital and Medical CenterBurlingtonUSA
  2. 2.Tufts University School of MedicineBostonUSA
  3. 3.LongmeadowUSA

Personalised recommendations