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

Abstract

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...

Effects of dietary protein restriction on albumin and fibrinogen synthesis in macroalbuminuric type 2 diabetic patients

“…Serum albumin concentration was determined by standard Bromcresol Green method [18] (ALB plus; Roche Diagnostics, Mannheim, Germany) on a Hitachi 747 (Milan, Italy). Plasma chronometric determination of fibrinogen was obtained in citrate plasma using the clotting method of Clauss [19] on a Hemolab Fibrinomat (bioMérieux, Lyon, France) [20]. Serum samples for IL-6 and C-reactive protein (CRP) were determined in duplicate using commercially available immunosorbent kits (Human IL-6 ELISA; Diaclone Tepnel Lifecodes, Stamford, CT, USA; CRP Ultra; Abbott Diagnostics, Abbott Laboratories, Abbott Park, IL, USA).…”

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

“…Cirrhosis has been associated with laboratory changes suggesting hyperfibrinolysis (i.e., increased t-PA and reduced PI or TAFI), but also with changes suggesting hypofibrinolysis (i.e., reduced plasminogen and increased PAI). Despite conflicting data, the balance of fibrinolysis is likely restored by concomitant changes in the pro-and anti-fibrinolytic drivers [3,32,33].…”

Metabolic Syndrome Accompanied by Hypercholesterolemia Is Strongly Associated With Proinflammatory State and Impairment of Fibrinolysis in Patients With Type 2 Diabetes

“…The patients had been referred to the diabetes outpatient clinic at the Dokkyo University Hospital to optimize glycemic control. Excluded from the study were patients with known liver disease, because TAFI is produced mainly by the liver (14). Patients with medications that could affect the coagulation or fibrinolytic systems (such as anticoagulants and antiplatelet agents) were excluded from study.…”

“…One possible explanation for this weak correlation between two fibrinolysis inhibitors is a difference in production sites of each fibrinolysis inhibitor. PAI is produced mainly by adipose tissues and vascular endothelial cells (21), while TAFI is produced exclusively by the liver (14). Another possibility is that plasma TAFI concentrations may be regulated more strongly by genotype rather than metabolic factors as mentioned above (17).…”