Thrombin activation and increased fibrinolysis in patients with chronic liver disease

Ja, Páramo; Rifón, J.; Fernández, J; Cuesta, B; Rocha, E.

doi:10.1097/00001721-199104000-00002

Cited by 25 publications

(16 citation statements)

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“…We found an increase of FI + 2 and T A T suggesting specific enzymatic activity of factor X upon prothrombin and thrombin generation [29][30][31][32][33][34]. Other authors suggest, however, that evidence implicating D IC is indirect in liver cirrhosis and the increased levels of prethrombotic markers would only reflect a decreased clearance [35,36], Fibrinolysis parameters showed the typical pattern of liver failure with a significant in crease of t-PA activity and antigen and de crease of plasminogen and cii-antiplasmin in patients as compared to controls, suggesting that extensive alterations of the fibrinolytic system are commonly present in chronic liver disease [34,[37][38][39], The lack of differences in PAI-1 activity between patients and controls could be related to the increased t-PA concen trations since other authors have found ele vated concentrations of PAI-1 antigen [38].…”

Section: Discussionmentioning

confidence: 99%

Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

Páramo

Sangro²,

Prosper³

et al. 1995

Pathophysiol Haemos Thromb

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Abnormal cytokine levels have been described in patients with chronic liver disease, but studies correlating cytokine homeostasis with abnormalities in coagulation and fibrinolysis are lacking. In order to establish a link between cytokines and the hemostatic changes the following parameters were determined in 44 patients with cirrhosis (alcoholic =15, postnecrotic = 22, others = 7): TNF-α, IL·6, thrombin-antithrombin (TAT) complexes, prothrombin fragment 1 + 2 (F1 + 2) and t-PA by using enzyme-linked immunosorbent assays, and PAI-1, plasminogen and α₂-antiplasmin (α₂-AP) by using chromogenic substrates. All patients were at stages B and C of Child’s classification when entering the study. Mean cytokine concentrations were significantly higher in cirrhotic patients as compared to age- and sex-matched controls (p < 0.009). There was a significant increase of TAT (p < 0.02) and F1 + 2 (p < 0.001) in the patients groups, suggesting a grade of intravascular coagulation. A hyperfibrinolytic state as demonstrated by an increase of t-PA and decrease of plasminogen and α₂-AP was also observed (p < 0.001). We could define a subgroup of patients with cytokine values higher than 20 pg/ml. Interestingly, in this group there was a significant increase of TAT (p < 0.04) and t-PA (p < 0.02) levels and a decrease of plasminogen and α₂-AP (p < 0.02) as compared to values observed in patients with cytokines lower than 20 pg/ml. We conclude that high levels of TNF-α and IL-6 may contribute to hyperfibrinolysis and intravascular coagulation in patients with liver cirrhosis, as assessed by the increase of TAT and t-PA levels and the reduction of plasminogen and α₂-AP.

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Section: Discussionmentioning

confidence: 99%

Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

Páramo

Sangro²,

Prosper³

et al. 1995

Pathophysiol Haemos Thromb

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“…A parallel extension would suggest that uncontrolled fibrinolysis could contribute to the progression of liver disease. Clinical studies suggest exaggerated fibrinolysis in patients with liver disease, as indicated by elevated D-dimer levels, a product of fibrin degradation (Paramo et al, 1991;Pernambuco et al, 1993;Violl et al, 1996). Moreover, reductions in the primary inhibitors of fibrinolysis: thrombin-activatable fibrinolysis inhibitor and a2-antiplasmin, have been noted in patients with liver disease ( Gresele et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

Joshi

Kopec

Towery

et al. 2014

J Pharmacol Exp Ther

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Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant a-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1 2/2 mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

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“…With the use of these tests, it has been possible to detect accelerated intravascular coagulation and fibrinolysis (AICF) more definitively in patients with liver cirrhosis (12)(13)(14)(15)(16)(17)(18)(19)(20). Unfortunately, in most of these studies, the terms DIC or low grade DIC are used frequently for AICF, which is confusing.…”

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confidence: 99%

“…In most studies (16 -19), the extent of AICF seemed to be related to the severity of cirrhosis. In some studies, AICF was observed only in patients with decompensated, end stage cirrhosis (16,17), or complications such as sepsis, shock, or malignancy (13). In two studies in which this was examined, the presence and severity of AICF seemed related to the reduction in the levels of AT III (13) and/or protein C and protein S (15).…”

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confidence: 99%

“…Thus, the results of this study add further support to the concept, based on a large amount of published evidence, that AICF is not a common feature in patients with nonadvanced, stable liver cirrhosis without complications. However, because relatively few patients with end stage cirrhosis were enrolled and patients with complications such as recent esophageal or gastric bleeding and coexisting conditions such as shock, infection, recent surgery, trauma, and malignancy were excluded, the results of the study by Ben Ari et al (22) do not refute extensive, previously published evidence (12)(13)(14)(15)(16)(17)(18)(19)(20) that such patients may be prone to develop AICF and DIC as manifestations of a systemic hypercoagulable state with, perhaps, preferential expression in the portal circulation (23). This concept is supported by the findings that large vessel thrombosis, particularly portal vein thrombosis, may occur in 15% of patients with cirrhosis (24) and microvascular thrombosis in one or multiple organs was observed in 50% and 2%, respectively in one anatomic/pathologic study of 184 cases with liver disease (25).…”

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confidence: 99%

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AICF and DIC in Liver Cirrhosis: Expressions of a Hypercoagulable State

Joist

1999

American Journal of Gastroenterology

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Thrombin activation and increased fibrinolysis in patients with chronic liver disease

Cited by 25 publications

References 0 publications

Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

Increased Concentrations of Tumor Necrosis Factor and lnterleukin-6 Contribute to the Hemostatic Abnormalities in Advanced Liver Disease

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

AICF and DIC in Liver Cirrhosis: Expressions of a Hypercoagulable State

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