Liver International ISSN 1478-3223

Editorial DOI:10.1111/liv.12477 Liver Int. 2014: 34: 652–654

Does balanced haemostasis equate to normal coagulation in patients with acute liver failure? Patients with liver disease whether acute or chronic suffer from a coagulopathy and this, in the past, has been associated with a bleeding phenotype. Laboratory investigations typically reveal a high Prothrombin Time (PT)/International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) and sometimes a low fibrinogen level. The high PT was noted since the inception of the test by Armand Quick (1). It was later realized that this test was exquisitely sensitive to low factor VII levels. The PT/INR became established tests to monitor coumarin anticoagulant therapy and as high PT/INR values correlate with an increased risk of bleeding in patients on similar drugs, the raised PT in patients with liver disease was considered to indicate a state of ‘autoanticoagulation’. This notion has been challenged over the past decade. Interest in the coagulopathy of liver disease started accruing momentum in 2005 when Tripodi et al. showed that using a novel assay of coagulation, the thrombin generation test (TGT), people with cirrhotic liver disease generated similar amounts of thrombin as a normal control population (2). One has to point out that the normal values came after the thrombin receptor, thrombomodulin, was added to the assay which makes the system sensitive to some of the natural anticoagulants. In vivo, thrombin binds to the endothelial cell surface receptor thrombomodulin. This interaction neutralises thrombin’s procoagulant activity and allows its active site to target Protein C (PC) and activate the latter to Activated Protein C (APC). APC is a very potent anticoagulant which targets the clotting cascade at least in two crucial points, by inactivating both the propagation and amplification loops through its activity on activated Factor V (FVa) and activated Factor VIII (FVIIIa) respectively. Tripodi’s work which has since been replicated by other groups (3), demonstrated that as the levels of PC and Protein S (PS) are reduced in liver disease, there is less APC production and less inactivation of coagulation. This has been interpreted as ‘balanced coagulation’ as we have a reduction in both the pro-coagulants such as FI, FII, FV, FVII, FIX, FX and FXI and the anticoagulants namely PC, PS and also Protein Z and antithrombin (AT). Not only that, but Factor VIII and Von Willebrand Factor are almost invariably increased in these patients. As a natural progression in research, groups started looking at a different cohort of patients, those with


acute liver failure (ALF). Lisman et al. and Agarwal et al. both showed that the coagulopathy in these cases is similar to that in patients with cirrhosis with some differences (4, 5). Patients with ALF tend to have higher INR levels. In these patients, the unmodified TG assay shows that the patient group does not generate as much thrombin as the normal cohorts. This has been replicated by Habib et al. in this edition of the Journal (6). What has not been replicated is the increased velocity of thrombin generation in the patients with ALF for unclear reasons. Again, it has been shown that the patients are highly resistant to APC after an empiric concentration of soluble thrombomodulin is added to the test. The patients also generate as much thrombin as their matched normal counterparts after the inclusion of this thrombin receptor. Does this mean that patients with ALF have a normal coagulation potential resulting in a normal bleeding risk when exposed to haemostatic challenges? Does this mean that clinicians do not need to try to correct the ‘coagulopathy’ of liver disease? We could try to answer these questions by drawing comparison with coumarin anticoagulation. The INR in patients on warfarin correlates strongly with TGT (7). It shows a parabolic curve with increasing INRs with a plateau being reached at INR of around 4.0 (7, 8). The maximum amount of thrombin generated in the TGT or the endogenous thrombin potential (ETP) goes down to 28.2% of normal in patients with INRs in the therapeutic range of 2.4–2.6 and goes down to 22% in those with INRs of 2.9–3.0. In the ALF cohort presented in the Journal, the median INR was 3.36 with an interquartile range of 2.67–7.01. So, allowing for differences in the PT reagent (STA-Neoplastine) used in this study which has an ISI of ~1.3 and would be expected to yield higher INR values than the human recombinant TF reagents such as Innovin and Recombiplastin (ISI ~1.0), Habib et al.’s ALF patients should have shown an ETP of less than 22% of normal. Instead, dividing the mean patient ETP by the mean normal ETP gives a value of 55.5% normal. This is high, despite these patients having FII, FVII and FV levels

Does balanced haemostasis equate to normal coagulation in patients with acute liver failure?

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