Plasminogen activators in alcoholic cirrhosis: demonstration of increased tissue type and urokinase type activator.

Booth, Nuala A.; Anderson, John M.; Bennett, Bruce

doi:10.1136/jcp.37.7.772

Cited by 95 publications

(41 citation statements)

References 22 publications

(2 reference statements)

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“…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.…”

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confidence: 99%

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Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis

et al. 2003

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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...

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis

et al. 2003

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“…Zymography for PA [2] and PA1 [14] was as described previously. The gels was washed for 90 min in 2 x 500 ml 2.5% (w/v) aqueous Triton X-100, rinsed in distilled water and then applied to a detector gel.…”

Section: Sds-pagementioning

confidence: 99%

Plasminogen activator inhibitor from human endothelial cells. Purification and partial characterization

et al. 1987

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An inhibitor of plasminogen activator was purified to apparent homogeneity from human umbilical vein endothelial cell conditioned medium. The purification was achieved by a speedy and simple two-step procedure, without the use of denaturants. The purified protein was a single-chain glycoprotein with apparent molecular mass of 48 kDa.The purified inhibitor had a specific activity of 8500 U/mg protein and the activity could be stimulated about fourteenfold by treatment with denaturants.An antiserum to the purified inhibitor was raised in rabbits. It recognised plasminogen activator inhibitor from platelets and plasma as well as from cultured endothelial cells. The immunoglobulin fraction of the antiserum neutralised the functional activity of the inhibitor from all these sources.The activity of the fibrinolytic system depends on the cleavage of the zymogen plasminogen to form plasmin by plasminogen activators. Two major immunologically distinct types of plasminogen activator, tissue-type (tPA) and urokinase (u-PA) have been identified (reviewed in [l]). t-PA is present in normal resting plasma at a molecular mass of about 110 kDa [2 -41, in contrast to the 65-kDa form isolated from tissues [5]. The high-molecular-mass t-PA in plasma is now known to be an equimolar complex of t-PA with a plasminogen activator inhibitor (PAI) [3, 41. Inhibitors active against both t-PA and u-PA have been discovered in bovine [6] and human [7 -91 endothelial cells, in platelets [lo, 111 and in plasma [3, 12 -141. Immunological cross-reactivity between the bovine endothelial and human platelet inhibitor has been established [15] and this type of PA1 is now designated PAI-1 [16].The bovine endothelial cell PA1 is in an inactive or latent form that is converted to an active form in the presence of denaturants such as SDS and guanidinium hydrochloride [17]. This inhibitor has been purified using SDS/polyacrylamide gel electrophoresis (SDS-PAGE) as the final preparative step; thus the purified product was active [18].In the study reported here, we aimed to purify PA1 from human endothelial cells in the absence of denaturants. T h s Correspondence to

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“…Plasmin-a 2 -antiplasmin complexes were determined as described previously (Booth & Bennett, 1982). SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and zymography were performed according to the method of Booth et al (1984). Alkaline phosphatase-anti-alkaline phosphatase (APAAP) immunocytochemical staining was by the method of Cordell et al (1984).…”

Section: Methodsmentioning

confidence: 99%

Tumour cell u‐PA as a cause of fibrinolytic bleeding in metastatic disease

et al. 1997

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Tumour cells may express urokinase type plasminogen activator (u‐PA). This may influence the invasive properties of the cells but has seldom been implicated in production of a systemic bleeding state. Two patients are described in whom severe bleeding occurred in association with disseminated malignancies. Thrombin generation was little disturbed and platelet numbers were insufficient to account for the bleeding. Florid plasmin generation was evident in the circulation and the fibrinolytic inhibitor tranexamic acid controlled the bleeding well. Free active u‐PA was demonstrated in the circulation and u‐PA antigen on the malignant cells which invaded the marrow of one of the patients. Tumour cell u‐PA may occasionally be responsible for a bleeding state.

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Plasminogen activators in alcoholic cirrhosis: demonstration of increased tissue type and urokinase type activator.

Cited by 95 publications

References 22 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

Plasminogen activator inhibitor from human endothelial cells. Purification and partial characterization

Tumour cell u‐PA as a cause of fibrinolytic bleeding in metastatic disease

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