Plasma hypercoagulability in the presence of thrombomodulin but not of activated protein C in patients with cirrhosis

Lebreton, Aurélien; Sinegre, Thomas; Pereira, Bruno; Lamblin, Géraldine; Duron, Cédric; Abergel, A.

doi:10.1111/jgh.13493

Cited by 26 publications

(54 citation statements)

References 27 publications

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“…However, plasma hypercoagulability persisted in the CTP‐B and CTP‐C groups, indicating that PC normalization alone is not sufficient. This is consistent with the observation that plasma hypercoagulability increases with disease severity .…”

Section: Discussionsupporting

confidence: 93%

“…For each assay, the ETP (n m min) was the primary endpoint, because it represents the whole thrombin that the plasma under study can generate. The results of TG evaluation with CAT were previously reported for 26 healthy controls and 56 patients; however, all of these subjects were retested for this study, and the agreement between previous and current results was very good (data not shown).…”

Section: Methodssupporting

confidence: 70%

“…The APC pathway plays a central role in rebalancing the coagulation of patients with cirrhosis. Previous studies showed that, in experimental conditions that allow PC activation by generated thrombin, TG is normal or even increased, depending on the experimental conditions and the studied patients . Here, we report that the ETP decreased after normalization of FVIII (by addition of an inhibitory antibody) or PC (by addition of PC), and that a normal coagulation phenotype could be fully restored after normalization of both FVIII and PC levels.…”

Section: Discussionmentioning

confidence: 49%

“…PC levels were < 70% in 88 patients, FVIII levels were > 150% in 48 patients, and both alterations were present in 43 patients. The median age (59 years for patients and 41 years for controls) and sex ratio (83% men in the cirrhosis group and 100% in the control group) were significantly different between patients and controls ( P < 0.001), but we previously showed that age is not a strong determinant of TG variation when healthy controls and patients with cirrhosis are compared . The causes of cirrhosis were alcohol (38%), hepatitis C virus infection (32%), or various combinations (30%).…”

Section: Resultsmentioning

confidence: 80%

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Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis

Sinegre

Duron

Lecompte

et al. 2018

Journal of Thrombosis and Haemostasis

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Background In cirrhosis, thrombin generation (TG) studied in the presence of thrombomodulin (TM) indicates plasma hypercoagulability. Although the role of protein C (PC) deficiency has been investigated, the influence of an increase in the factor VIII level has never been addressed. Objectives We investigated the roles of high FVIII and low PC levels in increased TG in the presence of TM. Methods Blood samples were prospectively collected from 35 healthy controls and 93 patients with cirrhosis (Child-Turcotte-Pugh [CTP]-A, n = 61; CTP-B, n = 19; and CTP-C, n = 13) and FVIII levels > 150% (n = 48) and/or PC levels < 70% (n = 88). TG was performed with tissue factor (5 pm), phospholipids, and TM (4 nm). FVIII and PC levels were normalized by adding an inhibitory anti-FVIII antibody and exogenous PC, respectively. Results The endogenous thrombin potential (ETP) in the presence of TM was higher in patients than in controls. After FVIII normalization, the ETP (median) decreased from 929 nm min to 621 nm min (CTP-A), 1122 nm min to 1082 nm min (CTP-B), and 1221 nm min to 1143 nm min (CTP-C); after PC normalization, it decreased from 776 nm min to 566 nm min (CTP-A), 1120 nm min to 790 nm min (CTP-B), and 995 nm min to 790 nm min (CTP-C). The ETP was reduced by 17% and 30%, respectively, but normal TG was not restored. When both FVIII and PC levels were normalized, the ETP decreased from 929 nm min to 340 nm min (CTP-A), 1122 nm min to 506 nm min (CTP-B), and 1226 nm min to 586 nm min (CTP-C), becoming similar to control levels. Conclusion Cirrhosis-induced plasma hypercoagulability, as demonstrated in these experimental conditions, can be partly explained by opposite changes in two factors: PC level (decrease) and FVIII level (increase).

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Section: Discussionsupporting

confidence: 93%

Section: Methodssupporting

confidence: 70%

Section: Discussionmentioning

confidence: 49%

Section: Resultsmentioning

confidence: 80%

See 2 more Smart Citations

Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis

Sinegre

Duron

Lecompte

et al. 2018

Journal of Thrombosis and Haemostasis

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“…Using the near patient WB‐TG assay, we observed that the endogenous thrombin generating potential (ETPp) values of patients with cirrhosis, regardless of the presence/absence of TM, were in the same range as in healthy controls, suggesting that these patients had normal thrombin‐generating capacity. The standard PPP‐TG results add to the growing literature that hypocoagulable state is suggested when TG is tested without activating the protein C pathway, whereas hypercoagulable state is found when the function of the anticoagulant protein C pathway is included in TG by adding TM into the test . These results indicate that cirrhosis does not necessarily result in a hypocoagulable state as suggested by their lower procoagulant factor levels and prolonged PT and APTT, thus reinforcing that prophylactic administration of fresh‐frozen plasma according to their PT/APTT is not required …”

Section: Discussionmentioning

confidence: 55%

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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Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases

Lisman

Porte

2017

Research and Practice in Thrombosis and Haemostasis

107

131

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Essentials Patients with liver diseases may acquire substantial changes in all components of hemostasis.Hemostasis is in unstable balance due to simultaneous changes in pro‐ and antihemostatic systems.Intrahepatic activation of hemostasis may contribute to disease progression.Optimal strategies for prevention and treatment of bleeding and thrombosis are currently unknown. Patients with liver diseases may develop alterations in all components of the hemostatic system. Thrombocytopenia, low levels of coagulation factors and inhibitors, low levels of fibrinolytic proteins, and increased levels of endothelial‐derived proteins such as von Willebrand factor are all part of the coagulopathy of liver disease. Due to concomitant changes in pro‐ and antihemostatic drivers, the net effects of these complex hemostatic changes have long been unclear. According to current concepts, the hemostatic system of patients with liver disease is in an unstable balance, which explains the occurrence of both bleeding and thrombotic complications. This review will discuss etiology and management of bleeding and thrombosis in liver disease and will outline unsolved clinical questions. In addition, we will discuss the role of intrahepatic activation of coagulation for progression of liver disease, a novel paradigm with potential consequences for the general management of patients with liver disease.

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Plasma hypercoagulability in the presence of thrombomodulin but not of activated protein C in patients with cirrhosis

Abstract: In the presence of activated protein C, no hypercoagulability was observed, adding to the current evidence that acquired protein C deficiency plays a key role in the coagulation imbalance.

Cited by 26 publications

References 27 publications

Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis

Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis

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

Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases

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