Thrombin generation tests and viscoelastic testing in cirrhosis (2016)

Editor, We read with interest the observational study by Lentschener et al.1 and particularly their conclusion that ‘ROTEM may not be appropriate for haemostasis assessment in patients with cirrhosis and could lead to the unnecessary transfusion of fresh frozen plasma’. The authors found that ROTEM (thromboelastography) performed in whole blood indicated hypocoagulability in some patients, which correlated with the degree of liver dysfunction, MELD (Model for End-stage Liver Disease) score and thrombocytopenia, whereas in contrast thrombin generation tests performed in platelet-poor plasma indicated normal or even increased coagulability, with increased thrombin generation correlating with worsening liver function. This is not new information, and is well documented.2,3 However, it is the maximum clot firmness, which is a function of platelet/fibrinogen interaction and reflects overall clot strength, that demonstrates a correlation with increasing severity of cirrhosis and thrombocytopenia. Why the authors chose to only look at this parameter and compare it with thrombin generation tests is perplexing, as the two are essentially measuring very different aspects of the haemostatic process. It would be far more appropriate to compare thrombin generation tests with viscoelastic parameters that are related to plasmatic coagulation and thrombin generation, that is the clotting time, clot formation time and α angle, and also parameters of the first derivative ROTEM (TEM International, GmbH, Munich, Germany) curve as described by Sorensen et al.4 Although Tripodi et al.2 demonstrated that maximum clot firmness is a good discriminator between cirrhotic and healthy individuals, they found that clotting time does not differentiate, and indeed 70% of patients with cirrhosis have no prolongation of the clotting time despite abnormal PT (Prothrombin Time)/INR (International Normalised Ratio). It should be noted that when using viscoelastic tests, it is conventionally the clotting time that is used as a basis for administering fresh frozen plasma, and not maximum clot firmness.5 Using viscoelastic tests rather than conventional coagulation tests to determine whether to administer clotting factor support, has been shown to significantly reduce transfusion of fresh frozen plasma in patients with cirrhosis.6,7 It is known that despite prolonged PT/INR and low platelet counts, viscoelastic tests are within normal range in many patients with both acute and chronic liver disease, commensurate with the concept of re-balanced haemostasis, and in keeping with the fact that many cirrhotic patients now undergo invasive interventions and liver transplantation without the need for blood or blood products.5–9 The patients in this observational series are not fully representative of the wide spectrum of liver disease and coagulopathy that is seen in clinical practice as patients with infection, inflammation, prior or existing thrombosis, immune disorders and malignancy, were all excluded.1 All these conditions can be associated with an increase in maximum clot firmness because of elevated fibrinogen levels, and in some cases increased platelet reactivity. Thrombin generation tests have given important insight into the complexity of the haemostatic changes in liver disease, and the fact that thrombin generation is normal or even increased, when the protein C pathway is activated by thrombomodulin or protac.8 The fact that many of these patients have a pro-thrombotic tendency despite the elevated INR is because the latter is only responsive to procoagulant activity but not the associated changes in anticoagulant levels. Thrombin generation tests, however, are complex tests that are not routinely available, they are not yet well standardised and they are usually performed in platelet-poor plasma. Consequently, they do not reflect the important contribution of platelets and other cells, such as tissue factor-bearing monocytes, to thrombin generation. Notably, thrombin generation studies using platelet-rich plasma demonstrated that thrombin generation is highly dependent on platelet count – in particular in patients with thrombocytopenia below 60 × 109 l−1.10–11 This is of particular importance for the interpretation of the Lentschener et al.1 study results, as 80% of the patient population was thrombocytopenic and 22.5% had even a platelet count below 60 × 109 l−1. Accordingly, it can be expected that performing thrombin generation tests in platelet-rich plasma from cirrhotic patients with severe thrombocytopenia would result in decreased thrombin generation compared with healthy volunteers.10,11 In contrast to thrombin generation tests performed in platelet-poor plasma, viscoelastic tests use whole blood to assess haemostasis and include both plasmatic and cellular contributions to the coagulation process. Accordingly, Tripodi et al.12 showed that ROTEM is superior to thrombin generation tests in demonstrating hypercoagulability in patients after splenectomy. To summarise, we feel this study is in many ways comparing apples with oranges by using different blood samples (platelet-poor plasma in thrombin generation tests vs. whole blood in ROTEM), different types of parameters (thrombin generation in thrombin generation tests vs. maximum clot firmness in ROTEM) and different additives (thrombin generation tests with thrombomodulin vs. ROTEM without thrombomodulin). Consequently, the conclusion of the authors that ROTEM is not appropriate for assessing haemostasis in cirrhosis and could lead to unnecessary transfusion of fresh frozen plasma is misleading to the general reader. Ultimately, the clinical relevance of diagnostic tests can only be proven by demonstrating a correlation to clinical outcomes such as bleeding or thrombosis, and as the authors themselves point out, another limitation of this study is the lack of any clinical outcome data to support their contention. However, we fully agree with the authors that there is no need for haemostatic interventions in non-bleeding patients with stable cirrhosis. Acknowledgements relation to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: KG works as the medical director of Tem International since July 2012. Comment from the editor: Tem Innovations GmbH deals with the development and production of ROTEM diagnostic equipment and reagents. The affiliate company Tem International GmbH handles the distribution, marketing and customer service for the product range worldwide (https://www.rotem-usa.com/company/about-us/).