Mechanisms of enhanced thrombin‐generating capacity in patients with cirrhosis

Lisman, Ton; Bos, Sophie; Intagliata, Nicolas M.

doi:10.1111/jth.14020

Cited by 23 publications

(16 citation statements)

References 19 publications

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“…The TM resistance in cirrhosis is most probably due to their reduced protein C and protein S, combined with the elevated FVIII levels. [43][44][45] The high dose of TM, however, did substantially prolong the lagtime of WB-TG in both patients and controls, but this effect may be not via the anticoagulant function of the protein C pathway, but rather because TM prevented thrombin from activating platelets and consequently limited the availability of procoagulant phospholipids. 46 This study has several limitations.…”

Section: Discussionmentioning

confidence: 88%

“…Conversely, a much lower dose of TM (10 nmol/L) exhibited a much stronger inhibitory effect on the ETP of PPP‐TG and the effect was five‐fold weaker in the patients than in controls. The TM resistance in cirrhosis is most probably due to their reduced protein C and protein S, combined with the elevated FVIII levels . The high dose of TM, however, did substantially prolong the lagtime of WB‐TG in both patients and controls, but this effect may be not via the anticoagulant function of the protein C pathway, but rather because TM prevented thrombin from activating platelets and consequently limited the availability of procoagulant phospholipids…”

Section: Discussionmentioning

confidence: 96%

“…Four patients were classified as Child-Pugh class A, 18 patients were in class B, and 12 patients in class C. The median Model for End-Stage Liver Disease (MELD) score of the patients was 17.5 (IQR: 14.3-23.8). Twenty-six patients had acutely decompensated (AD)cirrhosis, with a CLIF-AD score of 51(45)(46)(47)(48)(49)(50)(51)(52)(53). Six patients fulfilled criteria for chronic liver failure (ACLF), of which three patients had a CLIF-ACLF grade 2, three patients had grade 3 21,22.…”

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confidence: 99%

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Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay

Wan

Roberts

Hendrix

et al. 2020

Journal of Thrombosis and Haemostasis

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Background and Aims Patients with cirrhosis have a rebalanced hemostasis, often with normal or elevated thrombin‐generating (TG) capacity in plasma. Whole blood (WB) TG allows faster determination and, importantly, includes the influence of all circulating blood cells. We aimed to study the TG profile of patients with cirrhosis in WB and in platelet poor plasma. Methods Thrombin‐generating capacity in WB and plasma were assessed with a near‐patient WB‐TG assay and the calibrated automated thrombinography assay, respectively. TG assays were tested in presence and absence of thrombomodulin. Conventional coagulation tests were also performed. Results Thirty‐four patients with cirrhosis and twenty‐two controls were analyzed. Compared with controls, patients had substantially deranged results in conventional coagulation tests. Comparable WB‐TG capacity (endogenous thrombin potential until peak, ETPp) but significantly lower peak thrombin were found in patients, and these results persisted when thrombomodulin was present. TG of the patients was more resistant to thrombomodulin than controls in both WB and plasma, although the inhibitory effect of thrombomodulin was drastically weaker in WB than in plasma. The peak of WB‐TG in patients correlated moderately with their hematocrit and platelet count. Significant correlations were found between TG results in WB and plasma. Conclusions The WB‐TG assay shows a normal to hypocoagulable state in patients with cirrhosis with a decreased anticoagulant activity of TM compared to plasma‐TG. The clinical value of this assay needs further validation.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 96%

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confidence: 99%

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Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay

Wan

Roberts

Hendrix

et al. 2020

Journal of Thrombosis and Haemostasis

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“…For instance, normalization of AT levels also rescues thrombin generation. 53 The role of these proteins deserves additional studies, particularly prothrombin and AT, because the balance between thrombin formation and direct inhibition influences the coagulation profile of patients with cirrhosis, according to some authors. 37,53 There is still another issue to be properly addressed, which is the extent of the stability of the phenotype over months if patients are stable, or the worsening of hypercoagulability for one given patient due to the increased severity of cirrhosis.…”

Section: Results Interpretationmentioning

confidence: 99%

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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“…Cirrhosis is characterized by rebalanced haemostasis . This rebalanced haemostasis is fragile and dynamic with endothelial dysfunction and bacterial translocation associated with prothrombotic effects and bacterial infections or sepsis associated with bleeding . The rebalanced haemostasis explains the higher incidence of PVT, deep vein thrombosis and thromboembolic events in cirrhosis …”

Section: Introductionmentioning

confidence: 99%

Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: A prospective study

Ferreira

Marinho

Cortez‐Pinto

et al. 2019

Liver International

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Background and aims: The role of portal vein thrombosis (PVT) in the natural history of cirrhosis is controversial. There are few prospective studies validating risk factors for development of PVT. We analysed the incidence, factors associated with PVT development and its influence on cirrhosis decompensations and orthotopic liver transplant (OLT)-free survival. Methods: In this prospective observational study between January 2014 and March 2019, 445 consecutive patients with chronic liver disease were screened and finally 241 with cirrhosis included. Factors associated with PVT development and its influence on cirrhosis decompensations and OLT-free survival by time dependent covariate coding were analysed. Results: Majority of patients belonged to Child-Pugh class A 184 (76.3%) and the average MELD score was 10 ± 5. Previous cirrhosis decompensations occurred in 125 (52.1%), 63 (26.1%) were on NSBB and 59 (27.2%) had undergone banding for bleeding prophylaxis. Median follow-up was 29 (1-58) months. Cumulative incidence of PVT was 3.7% and 7.6% at 1 and 3 years. Previous decompensation of cirrhosis and low platelet counts but not NSBB independently predicted the development of PVT. During follow-up, 82/236 (34.7%) patients developed cirrhosis decompensations.OLT-free survival was 100% and 82.8% at 3 years, with and without PVT respectively. MELD score, but not PVT, independently predicted cirrhosis decompensations (HR 1.14; 95%CI:1.09-1.19) and OLT-free survival (HR 1.16;95%CI:1.11-1.21).

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Mechanisms of enhanced thrombin‐generating capacity in patients with cirrhosis

Cited by 23 publications

References 19 publications

Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay

Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay

Thrombin Generation and Cirrhosis: State of the Art and Perspectives

Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: A prospective study

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