Plasminogen Activators and Plasminogen Activator Inhibitors in Liver Deficiencies Caused by Chronic Alcoholism or Infectious Hepatitis

Trân-Thang, C; Fasel-Felley, Josette; Pralong, G.; Hofstetter, J R; Bachmann, Fédor; Kruithof, Egbert K. O.

doi:10.1055/s-0038-1646877

Cited by 66 publications

(33 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our results lend further support to numerous previous reports showing that fibrinolysis is up-regulated in cirrhotic patients [1][2][3][4][5][6] and provide for the first time evidence suggesting that a defect in the TAFI pathway, because of a deficiency of circulating TAFI and probably, at least in the more severe cases, because of impaired thrombin generation, may contribute to hyperfibrinolysis and possibly to bleeding associated with cirrhosis. Hyperfibrinolysis, either assessed by global fibrinolytic assays or by plasma levels of fibrin(ogen) degradation products plus t-PA antigen or activity, has been reported to be a predictor of bleeding in cirrhotic patients, [33][34][35] and there is evidence that antifibrinolytic drugs may be effective for the treatment of bleeding complications.…”

Section: Discussionsupporting

confidence: 79%

“…1 Of particular relevance to hyperfibrinolysis are the imbalance between tissue plasminogen activator (t-PA) and its specific inhibitor (PAI-1), which results in an enhancement of free t-PA in the circulation and the reduction of ␣ 2 -plasmin inhibitor (␣ 2 -PI). [2][3][4][5][6] In recent years, a new plasma protein has been identified that may play an important regulatory role in fibrinolysis. It is a procarboxypeptidase synthesized by the liver and named thrombin activatable fibrinolysis inhibitor (TAFI) or procarboxypeptidase B or U.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

et al. 2003

View full text Add to dashboard Cite

Hyperfibrinolysis is thought to contribute to bleeding associated with advanced cirrhosis. Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma precursor of a carboxypeptidase (TAFIa) with antifibrinolytic activity and was recently shown to be reduced in cirrhosis. In this study, we evaluated the influence of TAFI deficiency on in vitro fibrinolysis in cirrhotic patients. Fifty-three patients with cirrhosis and 43 healthy controls were studied. TAFI antigen was measured by enzyme-linked immunosorbent assay and TAFI activity by chromogenic assay. Fibrinolysis was evaluated as tissue plasminogen activator-induced plasma clot lysis time in the absence and in the presence of a specific inhibitor of TAFIa. TAFI antigen and activity levels were markedly reduced in cirrhotic patients (P < .0001). In these patients, the lysis time of plasma clots was shorter than in controls (median, interquartile range: 25 minutes, 21-36 minutes vs. 48 minutes, 40-60 minutes, respectively; P < .0001) and was poorly influenced by the TAFIa inhibitor. Accordingly, TAFIa and thrombin activity, generated in cirrhotic samples during clot lysis, were significantly lower than in control samples. Addition of purified TAFI to cirrhotic plasma prolonged the lysis time and enhanced the response to TAFIa inhibitor in a dose-dependent manner. In conclusion, our results indicate that in vitro plasma hyperfibrinolysis in cirrhosis is largely due to a defective TAFIa generation resulting from low TAFI levels and probably from impaired thrombin generation. Impairment of the antifibrinolytic TAFI pathway might contribute to bleeding associated with this disease. (HEPATOLOGY 2003;38:230-237.) H yperfibrinolysis is a common finding in cirrhosis and is thought to contribute to the bleeding tendency associated with this disease by causing a premature removal of the hemostatic plug at sites of vascular injury. The abnormalities of the fibrinolytic system encountered in cirrhosis are complex and result from both impaired synthesis and altered clearance of the fibrinolytic factors. 1 Of particular relevance to hyperfibrinolysis are the imbalance between tissue plasminogen activator (t-PA) and its specific inhibitor (PAI-1), which results in an enhancement of free t-PA in the circulation and the reduction of ␣ 2 -plasmin inhibitor (␣ 2 -PI). [2][3][4][5][6] In recent years, a new plasma protein has been identified that may play an important regulatory role in fibrinolysis. It is a procarboxypeptidase synthesized by the liver and named thrombin activatable fibrinolysis inhibitor (TAFI) or procarboxypeptidase B or U. 7-9 Upon activation by thrombin or plasmin, it is converted to an enzyme (TAFIa) with carboxypeptidase B-like activity that inhibits fibrinolysis through the removal of C-terminal lysines from partially degraded fibrin. 10,11 In so doing, TAFIa reduces the cofactor function of fibrin in the plasminogen activation catalyzed by t-PA, thereby decreasing plasmin generation. The most likely physiologic activator of TAFI is thrombin, 12,13 whi...

show abstract

Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

et al. 2003

View full text Add to dashboard Cite

show abstract

“…Indeed, PAI-1 levels during disease development are a predictor of later severity [79]. A recent human study further supports the hypothesis that PAI-1 plays a critical role in ALD [80].…”

Section: Fibrin/clottingmentioning

confidence: 50%

Advances in alcoholic liver disease

Arteel

Marsano

Méndez

et al. 2003

Best Practice & Research Clinical Gastroenterology

127

View full text Add to dashboard Cite

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. In studies from the Veterans Administration, patients with cirrhosis and superimposed alcoholic hepatitis had greater than 60% mortality over a 4-year period, with most of those deaths occurring in the first month. Thus, the prognosis for this disease is more ominous than for many common types of cancer (eg, breast, prostate, and colon). Moreover, ALD imposes a significant economic burden from lost wages, health care costs, and lost productivity. Unfortunately, there is still no Food and Drug Administration-approved or widely accepted drug therapy for any stage of ALD. Thus, a pressing need exists for a more detailed understanding of mechanisms of liver injury. This article reviews recent advances in mechanisms and therapy related to five major areas of direct relevance to ALD: oxidative stress; gut-liver axis and cytokine signaling; malnutrition; fibrin/clotting; and stellate cell activation/fibrosis. We also review why therapies related to these mechanisms have performed well in experimental animals and in vitro systems, but have not necessarily translated into effective therapy for humans with ALD.

show abstract

“…There is general agreement that pa tients with liver cirrhosis had increased val ues of t-PA antigen [71][72][73][74] probably depen dent on reduced hepatic clearance [75,76] while the measure of PAI gave conflicting results. Tran-Thanget al [77] found high val ues of PAI in LC but they did not distinguish between the patients according to the severity of liver failure. Boks et al [72] found a con siderable variability of fast-acting PA inhibi tor, which was higher in cirrhotic patients than in normal subjects; however, in patients with more severe liver insufficiency very low values of PAI were observed.…”

Section: Hyperfibrinolytic Syndromementioning

confidence: 99%

Clotting Abnormalities in Chronic Liver Disease

Violi

Ferro

Quintarelli

et al. 1992

Dig Dis

View full text Add to dashboard Cite

In patients with chronic liver disease (CLD), several clotting changes can be observed. The most frequent abnormality is the reduced synthesis of many clotting factors, including vitamin-K-dependent and vitamin-K-independent ones. A low platelet count is another frequent feature of patients with CLD, which, however, is not always associated with the prolongation of bleeding time. Hyperfibrinolytic syndrome is usually seen in patients with decompensated state, and may further deteriorate the clotting abnormalities and favor bleeding complications. The assessment of the clotting system may be a useful approach to evaluate liver function and predict prognosis of patients with CLD.

show abstract

Plasminogen Activators and Plasminogen Activator Inhibitors in Liver Deficiencies Caused by Chronic Alcoholism or Infectious Hepatitis

Cited by 66 publications

References 7 publications

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

Advances in alcoholic liver disease

Clotting Abnormalities in Chronic Liver Disease

Contact Info

Product

Resources

About