Mallet et al.1 raise several critical issues concerning our recently published study on the assessment of haemostasis in patients with cirrhosis and the relevance of the ROTEM (Tem Innovations GmbH, Munich, Germany) tests.2
Our information was actually not new. As pointed out in our article, specific aspects of the complex haemostatic process have been studied in patients with cirrhosis before.2–5 We had designed our comprehensive, cross-sectional prospective study on haemostasis as a global issue.2
Mallet et al. ask why we looked only at maximum clot firmness. If we had designed the investigation of ROTEM-based triggers for transfusion of fresh frozen plasma, fibrinogen or platelets, the additional measurements of ROTEM-clotting time and clot formation time would have been more conclusive.6 α-Angle measurement would not have added any additional information to the maximum clot firmness, as demonstrated before.2,5,6 However, our investigation aimed at studying a ROTEM-based index of clot firmness for comparison with data provided by the thrombin generation test and standard haemostatic tests.2 In this respect, in our study, as in the medical literature, normality of ROTEM-maximum clot firmness consistently indicated normal clot firmness and normocoagulability.2,4–7 As maximum clot firmness values are strongly correlated with factor V values, low ROTEM-maximum clot firmness values could indicate decreased clot firmness and hypocoagulability, resulting in inadequate transfusion of fresh frozen plasma when Factor V is decreased.2,4–7 However, it has been shown that thrombin generation test values indicated normocoagulability or hyper-coagulability in contrast with ROTEM-maximum clot firmness values and standard haemostatic data.2,4–7
There is no evidence in the medical literature, including the articles quoted by Mallett et al.,8,9 that ROTEM-maximum clot firmness has reduced transfusion of fresh frozen plasma in patients with cirrhosis. No relevant correlation has been reported between haemostatic disturbances and intraoperative bleeding in cirrhotic patients undergoing abdominal paracentesis, insertion of an intracranial pressure monitor, liver biopsy, dental extraction, venous line insertion and liver transplantation.10 Also, the results of the two references quoted by Mallett et al. may be interpreted differently.8,9 De Pietri et al.,8 for instance, reported that a thromboelastography-guided pre-procedural haemostatic transfusion strategy led to a significantly lower use of procedural blood products compared with a pre-procedural strategy based on measurements of international normalized ratio (INR) and platelet count. However, in this study, triggers for transfusion were not scientifically based but were arbitrarily guided by local practices. Also in both groups, similar intra-procedural and post-procedural bleeding were recorded.8 Finally, the authors concluded that thromboelastography thresholds should be re-evaluated.8 Debernardi Venon et al.9 compared the administration of haemostatic components based on ROTEM data or platelet aggregometry. In this study, triggers for pre-procedural, per-procedural and post-procedural transfusions were also arbitrarily defined.9 Unfortunately, the study was retrospective only, and haemorrhagic events did not differ between treatment groups, and although the incidence of portal thrombosis was 22% in both groups, thromboelastography analysis did not show any hyper-coagulability.9
Mallet et al. claim that viscoelastic tests are within normal ranges despite a prolonged prothrombin time (PT)/INR ratio and low platelet counts in many patients with chronic liver disease. However, indicators of clot firmness have been reported to only sometimes be increased when cirrhosis is caused by an inflammatory disease.3 Also, when the PT/INR ratio was indeed prolonged, viscoelastic indicators of clot firmness were consistently reduced in all studies conducted in patients with cirrhosis, as in our study.2,5,11 It is somewhat contradictory that Mallett et al. confirm later in their letter that many cirrhotic patients undergo invasive procedures without the need for blood products.10
We believe that our patients were representative of the vast spectrum of liver diseases. To limit the risk of confounding factors, we designed a restricted subgroup of cirrhotic patients of all three child classes with no cancer, infection or inflammatory disease.2
Mallet and colleagues also question whether thrombin generation test analyses are standardised. We believe that further debate concerning this issue is no longer warranted.6 When patients are investigated under standard conditions, consistency is shown in the results of the thrombin generation test.6
It may also be questioned as to whether in patients with cirrhosis, the relevance of the thrombin generation test is offset by the investigation of platelet-poor plasma. Interestingly, all thrombin generation test assessments in patients with cirrhosis have been conducted with platelet-poor plasma, with the exception of the study by Lisman et al.2,4,5,11 In Lisman's study,4 a high level of von Willebrand factor compensated for defects in platelet number and function, in patients with cirrhosis, thus confirming our findings.
Referring to an investigation in patients undergoing splenectomy,12 Mallett et al. defend the viewpoint that ROTEM tests is more contributive than thrombin generation tests. In our study, we exclusively included patients with cirrhosis.2 The thrombin generation test is an internationally recognised research tool which, contrary to the ROTEM system, has been validated by the International Society on Thrombosis and Haemostasis.13 Importantly, overall coagulation is not anymore restricted to the concept of separate extrinsic and intrinsic coagulation pathways on which are based ROTEM analyses.13 Also, ROTEM analysis accounts only for the conversion of fibrinogen to fibrin at the very early phase of thrombin formation, when more than 95% of total thrombin has not yet been generated.13 Additionally, the thrombin generation test in the presence of thrombomodulin monitors all generated thrombin which is regarded as the controlling enzyme of coagulation.13 Finally, in clinical investigations, the thrombin generation test detects all congenital or acquired alterations of coagulation.13 These situations are beyond the scope of the ROTEM analyses.13
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1. Mallett S, Simioni P, Görlinger K, et al. Thrombin generation tests and viscoelastic testing in cirrhosis: comparing apples and oranges? Eur J Anaesthesiol
2. Lentschener C, Flaujac C, Ibrahim F, et al. Assessment of haemostasis in patients with cirrhosis: relevance of the ROTEM tests? A prospective, cross-sectional study. Eur J Anaesthesiol
3. Ben-Ari Z, Panagou M, Patch D, et al. Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thromboelastography. J Hepatol
4. Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology
5. Kleinegris MC, Bos MH, Roest M, et al. Cirrhosis patients have a coagulopathy that is associated with decreased clot formation capacity. J Thromb Haemost
6. Hemker HC, Giesen P, Al Dieri R, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb
7. Dargaud Y, Luddington R, Gray E, et al. Effect of standardization and normalization on imprecision of calibrated automated thrombography: an international multicenter study. Br J Haematol
8. De Pietri L, Bianchini M, Montalti R, et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy. A randomized controlled trial. Hepatology
9. Debernardi Venon W, Ponzo P, Sacco M, et al. Usefulness of thromboelastometry in predicting the risk of bleeding in cirrhotics who undergo invasive procedures. Eur J Gastroenterol Hepatol
10. Perdigao JP, de Almeida PC, Rocha TD, et al. Postoperative bleeding after dental extraction in liver pretransplant patients. J Oral Maxillofac Surg
11. Tripodi A, Primignani M, Chantarangkul V, et al. The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters. Thromb Res
12. Tripodi A, Cappellini MD, Chantarangkul V, et al. Hypercoagulability in splenectomized thalassemic patients detected by whole-blood thromboelastometry, but not by thrombin generation in platelet-poor plasma. Haematologica
13. Dielis AW, Castoldi E, Spronk HM. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost