We thank Saner and colleagues1 for their critical appraisal of our recently published analysis on haemostasis assessment in patients with cirrhosis and the relevance of the rotational thromboelastometry (ROTEM) tests.2 We wish to provide a point-by-point response to their comments.
Firstly, Saner and colleagues report on the variations of serum fibrinogen. However, by definition, fibrinogen cannot be measured in the serum. In addition, antithrombin has not been denominated as ‘antithrombin III’ for more than 10 years in the International Society of Thrombosis and Haemostasis standards.
Saner and colleagues contend that endogenous thrombin potential has long been assessed in patients with cirrhosis and that we did not provide any new data with respect to the concept of rebalanced haemostasis in patients with cirrhosis.3,4 However, our study was not limited to the assessment of endogenous thrombin potential.2 We first noted that conflicting aspects of the haemostatic process of patients with cirrhosis had been previously reported in separate studies, conducted over a long time interval.3,4 Therefore, we thought that a comprehensive study of three aspects of haemostasis, conducted simultaneously, was deemed necessary in patients with cirrhosis, with special regard to the relevance of ROTEM analysis.2 Indeed, the relevance of ROTEM tests remain unclear in clinical practice, in this group of patients.6 Furthermore, the article that is cited by Saner and colleagues to support the lack of improvement of fibrinogen levels with fresh frozen plasma should be viewed with caution because of a possible conflict of interest of the authors: at the time of publication the first author was the medical director of the ROTEM company.7
Saner and colleagues argue that the study of platelet-poor plasma rules out our results. However, contradictory information is available.5 Endogenous thrombin potential has long been measured in platelet-poor and platelet-rich plasma from patients with normal, hypo and hypercoagulable states.5 In these studies, platelet-poor and platelet-rich plasmas were demonstrated to be suitable testing material.5 Moreover, with the exception of one study,4 endogenous thrombin potential measured in platelet-poor plasma has provided contributive information on thrombin capacity in patients with cirrhosis and in normal controls, including the study by Lisman et al.3 and quoted by Saner and colleagues.5
Saner and colleagues write in their letter that it is impossible to contend that hypercoagulable values of ROTEM-MCF may encourage fresh frozen plasma transfusion. Throughout our article,2 we have argued that, as a consequence of the linear correlation between ROTEM-MCF and factor V, ROTEM analysis must be regarded as an index of liver dysfunction in patients with cirrhosis and is likely to indicate hypocoagulability, not hypercoagulability. Indeed, this alleged hypocoagulability could indicate a need for transfusion of fresh frozen plasma.2 In contrast, in our study, measurement of endogenous thrombin potential showed normocoagulability or even hypercoagulability in patients with cirrhosis, thus precluding the idea of fresh frozen plasma transfusion, as interpreted by Saner and colleagues.2
Based on a review article, which quotes retrospective studies conducted in cardiac surgery, Saner and colleagues challenge our methods and results, and, importantly, the overall relevance of the assessment of endogenous thrombin potential.7 Cardiac surgery was out of the scope of our investigation.2 We exclusively investigated patients with cirrhosis.2 In this group of patients, our findings confirmed that ROTEM-MCF was a reliable index of liver dysfunction, which therefore could indicate hypocoagulability whereas assessment of endogenous thrombin potential shows normo or even hypercoagulability.2–4 Concerning the overall relevance of ROTEM tests, a vast list of references shows that overall coagulation is no longer restricted to the concept of separate extrinsic and intrinsic coagulation pathways on which ROTEM analysis is based.8 ROTEM analysis accounts only for the conversion of fibrinogen to fibrin in the very early phase of thrombin formation, when more than 95% of total thrombin has not yet been generated.8 At the present time, thrombin, not fibrinogen, is regarded as the key enzyme of the coagulation process.8 Consequently, assessment of endogenous thrombin potential is regarded as reflecting best the in-vivo balance of pro and anticoagulant proteins in plasma, and the dynamics of thrombin generated in vivo.8 In clinical investigations, assessment of endogenous thrombin potential detected all congenital or acquired alterations of coagulation.8 This large panel of situations is out of the scope of ROTEM analysis.8
Saner and colleagues support our conclusions that pretreatment of the abnormal coagulation values in patients with liver dysfunction undergoing liver transplantation is not warranted and that in patients with cirrhosis undergoing liver transplantation, transfusion must mainly be triggered by the clinical assessment of bleeding.2
Finally, Saner and colleagues emphasise that ROTEM analysis is the best tool for haemostatic assessment. This is contrary to recent studies that were conducted in patients with liver disease.2–4,6 Point-of-care testing based on the ROTEM system has not yet been validated by the International Society of Thrombosis and Haemostasis, in contrast to the thrombin generation test, which is an internationally recognised research tool.8
Acknowledgements relating to this article
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Conflicts of interest: none.
1. Saner FH, Bezinover D, Sakai T. Assessment of haemostasis in patients with liver cirrhosis. Eur J Anaesthesiol
2. Lentschener C, Flaujac C, Ibrahim F, et al. Haemostasis assessment in patients with cirrhosis: relevance of the ROTEM® tests? A prospective, cross-sectional study. Eur J Anaesthesiol
3. Lisman T, Bakhtiari K, Pereboom IT, et al. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol
4. Tripodi A, Primignani M, Chantarangkul V, et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology
5. Chantarangkul V, Clerici M, Bressi C, et al. Thrombin generation assessed as endogenous thrombin potential in patients with hyper- or hypo-coagulability. Haematologica
6. Roullet S, Freyburger G, Cruc M, et al. Management of bleeding and transfusion during liver transplantation before and after the introduction of a rotational thromboelastometry-based algorithm. Liver Transpl
7. Gorlinger K, Shore-Lesserson L, Dirkmann D, et al. Management of hemorrhage in cardiothoracic surgery. J Cardiothorac Vasc Anesth
8. Dielis AWJH, Castoldi E, Spronk HMH, et al. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost