Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests Ton Lisman 1,2, * ,  , Kamran Bakhtiari 3,  , Ilona T.A. Pereboom 1,2 , Herman G.D. Hendriks 4 , Joost C.M. Meijers 3,  , Robert J. Porte 2,  1 Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 2 Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 3 Department of Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; 4 Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Background & Aims: Patients with liver disease often show sub- stantial changes in their hemostatic system, which may aggra- vate further during liver transplantation. Recently, thrombin generation in patients with stable disease was shown to be indis- tinguishable from controls provided thrombomodulin, the natu- ral activator of the anticoagulant protein C system, was added to the plasma. These results indicated that the hemostatic bal- ance is preserved in patients with liver disease, despite conven- tional coagulation tests suggest otherwise. Methods: Here we examined thrombin generation profiles in serial plasma samples taken from ten consecutive patients under- going liver transplantation. Results: At all time points, the endogenous thrombin potential (ETP) was slightly lower compared to healthy volunteers, despite substantially prolonged PT and APTT values. However, when thrombin generation was tested in the presence of thrombomod- ulin, the ETP was equal to or even higher than that in healthy subjects. In fact, thrombin generation was hardly affected by thrombomodulin, while thrombin generation in healthy subjects decreased profoundly upon the addition of thrombomodulin. In patients undergoing liver transplantation, efficient thrombin gen- eration in the presence of thrombomodulin may be explained by decreased levels of protein C, S, and antithrombin, and by ele- vated levels of FVIII. Conclusions: Thrombin generation in patients undergoing liver transplantation is equal or even superior to thrombin generation in healthy volunteers when tested in the presence of exogenous thrombomodulin. These results support the recently advocated restrictive use of plasma during liver transplantation and war- rants further study of the prophylactic use of anticoagulants to reduce thromboembolic complications after transplantation. Ó 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Introduction Cirrhosis of the liver may result in substantial changes in the hemostatic system including thrombocytopenia and reduced platelet function, and decreased levels of pro-coagulant and anti- fibrinolytic proteins [1]. Although these alterations result in a reduced prohemostatic capacity, they are all, at least to a certain extent, balanced by compensatory factors. The reduced platelet count and function are balanced by highly increased levels of the platelet adhesive protein von Willebrand factor [2]. Reduced levels of pro-coagulant proteins are balanced by reduced levels of natural anticoagulant proteins [3], and the reduced levels of anti- fibrinolytic proteins are balanced by reduced levels of profibrino- lytic proteins [4]. Traditionally, the hemostatic changes in patients with liver disease are thought to result in a hemostatic-dependent bleed- ing tendency [5]. However, recent clinical and laboratory data have challenged this theory which has led to the concept of ‘rebalanced hemostasis’ in patients with liver disease [6–8]. The hemostatic capacity of patients with liver disease appears to be preserved, but the balance is more easily disturbed as compared to healthy individuals. Indeed, patients with liver disease can present with hemostasis-related bleeding episodes, but may also be at risk for developing thromboembolic compli- cations [9,10]. These thrombotic complications even occur in patients with liver disease while they are being treated with anticoagulant drugs [9]. Journal of Hepatology 2010 vol. 52 j 355–361 Keywords: Coagulation; Liver transplantation; Thrombin; Thrombomodulin; Prothrombin time. Received 20 July 2009; received in revised form 25 August 2009; accepted 21 October 2009; available online 24 December 2009 * Corresponding author. Address: Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, BA44, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 361 9028; fax: +31 50 363 2796. E-mail address: j.a.lisman@chir.umcg.nl (T. Lisman).   These authors contributed equally. Abbreviations: APTT, activated partial thromboplastin time; PT, prothrombin time; CAT, calibrated automated thrombinography; ETP, endogenous thrombin poten- tial; HCC, hepatocellular carcinoma; TM, thrombomodulin. Research Article