Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event

Chaireti, Roza; Rajani, Rupesh; Bergquist, Annika; Melin, Tor; Friis-Liby, Ingalill; Kapraali, Marjo; Kechagias, Stergios; Lindahl, Tomas; Almér, Sven

doi:10.1016/j.thromres.2014.05.012

Cited by 18 publications

(20 citation statements)

References 30 publications

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“…Nevertheless, we show that prothrombin conversion and thrombin inactivation are severely attenuated in cirrhosis, which provides experimental evidence that supports the hypothesis of rebalanced thrombin generation in cirrhosis. Similar to the prothrombin-antithrombin balance, we reckon with the possibility that the decrease of the factor V is compensated for by the decrease of the delimiting factors protein C and protein S. This is supported by the finding of thrombomodulin resistance in liver cirrhosis patients [35,36,42]. …”

Section: Discussionmentioning

confidence: 92%

Decreased prothrombin conversion and reduced thrombin inactivation explain rebalanced thrombin generation in liver cirrhosis

et al. 2017

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Impaired coagulation factor synthesis in cirrhosis causes a reduction of most pro- and anticoagulant factors. Cirrhosis patients show no clear bleeding or thrombotic phenotype, although they are at risk for both types of hemostatic event. Thrombin generation (TG) is a global coagulation test and its outcome depends on underlying pro- and anticoagulant processes (prothrombin conversion and thrombin inactivation). We quantified the prothrombin conversion and thrombin inactivation during TG in 30 healthy subjects and 52 Child-Pugh (CP-) A, 15 CP-B and 6 CP-C cirrhosis patients to test the hypothesis that coagulation is rebalanced in liver cirrhosis patients. Both prothrombin conversion and thrombin inactivation are reduced in cirrhosis patients. The effect on pro- and anticoagulant processes partially cancel each other out and as a result TG is comparable at 5 pM tissue factor between healthy subjects and patients. This supports the hypothesis of rebalanced hemostasis, as TG in cirrhosis patients remains within the normal range, despite large changes in prothrombin conversion and thrombin inactivation. Nevertheless, in silico analysis shows that normalization of either prothrombin conversion or thrombin inactivation to physiological levels, by for example the administration of prothrombin complex concentrates would cause an elevation of TG, whereas the normalization of both simultaneously maintains a balanced TG. Therefore, cirrhosis patients might require adapted hemostatic treatment.

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Section: Discussionmentioning

confidence: 92%

Decreased prothrombin conversion and reduced thrombin inactivation explain rebalanced thrombin generation in liver cirrhosis

et al. 2017

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“…By contrast, they can all be considered in thrombin generation assays (TGA) 10 that therefore, are closer to the in vivo coagulation conditions. Thrombin generation (TG) in plasma of patients with cirrhosis is increased in the presence of thrombomodulin (TM) (ie, if endogenous protein C is activated) 11‐16 . Low protein C (PC) levels and high plasma factor VIII (FVIII) levels are probably involved in this hypercoagulable phenotype 13,17,18 .…”

Section: Introductionmentioning

confidence: 99%

Hypercoagulability (thrombin generation) in patients with cirrhosis is detected with ST‐Genesia

Talon

Sinegre

Lecompte

et al. 2020

Journal of Thrombosis and Haemostasis

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Background Thrombin generation assays (TGAs) performed with calibrated automated thrombography (CAT) in the presence of thrombomodulin (TM) indicate plasma hypercoagulability in cirrhosis. Objective To evaluate, in the presence of TM, the new ST‐Genesia automated device developed for improving TGA vs the previously used CAT method, with plasma samples of patients with cirrhosis. Patients/Methods Platelet‐poor plasma samples were prepared from citrated blood samples of 52 healthy controls and 85 patients with cirrhosis (severity evaluated using the Child‐Pugh score [CP]). TGAs were performed using CAT with PPP‐Reagent and ST‐Genesia with the STG‐ThromboScreen reagent, in the presence of TM. Endogenous thrombin potential (ETP) was chosen as the main parameter. Results Whatever the method, ETP values were higher in patients than in healthy controls. All patients identified as hypercoagulable with ST‐Genesia and STG‐ThromboScreen were found hypercoagulable with CAT and PPP‐Reagent. Conversely, eight and ten patients in the CP‐A and CP‐B classes respectively were identified as hypercoagulable only with CAT. The use of ST‐Genesia with the STG‐ThromboScreen reagent with TM led to a bias, with higher ETP values for healthy controls and lower for patients compared with CAT. Crossover analysis (CAT with the STG‐ThromboScreen reagent) evidenced a substantial effect of the STG‐ThromboScreen reagent; the analyzer (including calibration and data analysis) plays a lesser role. Conclusion ST‐Genesia evidences hypercoagulability in patients with cirrhosis when TG is studied in the presence of TM, but the results are not interchangeable with those obtained with CAT.

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“…30,33,34,37,38,40,47,51 Many recent studies have reported a hypercoagulable phenotype in plasma from patients with cirrhosis, based on ETP values in the presence of TM, that increases with the disease in severity, in contrast to the initial observations by Tripodi et al The growing consensus is that patients with cirrhosis, even with severe disease, display a hypercoagulable phenotype when tested by TGA with TM. 36,38,40,41,48,52 This hypercoagulable phenotype was found using different analytical conditions, such as low or high TF concentrations, and various TM concentrations. 47 The hypercoagulable phenotype was also detected when Protac was used as activator of the PC pathway.…”

Section: Results Interpretationmentioning

confidence: 99%

“…18 Some studies on patients with cirrhosis used one single centrifugation, [25][26][27][28][29][30][31] and others a double centrifugation. 19,[32][33][34][35][36][37][38][39][40][41] The centrifugation conditions were not always specified (e.g., temperature was sometimes missing), with differences in terms of g force, time, and temperature. Only one study used filtration (0.22 μm pore diameter) after a single centrifugation to exclude residual platelets and large cellular debris, 25 but filtration could also remove adhesive proteins such as von Willebrand factor, and thus lowers FVIII.…”

Section: Preanalytical and Analytical Conditions For Thrombin Generatmentioning

confidence: 99%

“…Delahousse et al 33 used a different diluted PTreagent as a source of TF. Commercially available reagents, which allow a better assay standardization, have been used since the study by Youngwon et al 30,[34][35][36][37][38][39]47,48 The PPP low reagent and the PPP reagent (Stago) have different final (nominal) concentrations of TF, 1 and 5 PM, respectively. Of note, details on the PL composition in these reagents are not provided by the manufacturers, or how TF concentration was estimated.…”

Section: Measuring Protein C Contributionmentioning

confidence: 99%

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Thrombin Generation and Cirrhosis: State of the Art and Perspectives

Lebreton

Sinegre

Lecompte

et al. 2020

Semin Thromb Hemost

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Epidemiological and laboratory studies performed in the last decades have changed our understanding of coagulopathy in cirrhosis, from a condition at increased risk of hemorrhagic events to one at higher thrombotic risk. However, it is not clear whether the decrease in factors that promote (except factor [F] VIII) versus inhibit coagulation in patients with cirrhosis results in a rebalanced state or in a hypercoagulable phenotype. This issue can be partially addressed using thrombin generation assays (TGA), which unlike routine clotting tests (prothrombin time or activated partial thromboplastin time) are sensitive to both procoagulant factors and coagulation inhibitors. However, many preanalytical issues and variable analytical methodologies used in TGAs complicate data analysis and interlaboratory comparisons. The introduction of TGAs in which activators of the protein C pathway (particularly soluble forms of thrombomodulin [TM]) are added has allowed detection of a reduced anticoagulant effect of TM or even a hypercoagulable phenotype as judged by endogenous thrombin potential. However, inter- and intra-assay variability may be greater with this TGA variant compared with “standard” TGAs. TGAs also allowed identifying main determinants of the hypercoagulability phenotype in the presence of TM: acquired antithrombin and protein C deficiencies, and elevated FVIII levels. The aim of this narrative review is to summarize the preanalytical and methodological variables of TGAs and also the findings of the main studies that have evaluated TGAs in patients with cirrhosis. The review also provides some propositions for future studies and outlines some perspectives on the potential implementation of this promising tool in clinical practice for the study of coagulation in patients with cirrhosis.

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Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event

Cited by 18 publications

References 30 publications

Decreased prothrombin conversion and reduced thrombin inactivation explain rebalanced thrombin generation in liver cirrhosis

Decreased prothrombin conversion and reduced thrombin inactivation explain rebalanced thrombin generation in liver cirrhosis

Hypercoagulability (thrombin generation) in patients with cirrhosis is detected with ST‐Genesia

Thrombin Generation and Cirrhosis: State of the Art and Perspectives

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