title: 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.
authors.affiliation: Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy. mario.colucci@dimo.uniba.it
authors.forename: Mario
authors.initials: M
authors.lastname: Colucci
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Binetti
authors.forename: Maria G
authors.initials: MG
authors.lastname: Branca
authors.forename: Carlo
authors.initials: C
authors.lastname: Clerici
authors.forename: Antonio
authors.initials: A
authors.lastname: Morelli
authors.forename: Nicola
authors.initials: N
authors.lastname: Semeraro
authors.forename: Paolo
authors.initials: P
authors.lastname: Gresele
mesh_terms: D000328:Adult; D000368:Aged; D001778:Blood Coagulation Disorders / Q000378:metabolism; D025901:Carboxypeptidase B2 / Q000097:blood / Q000172:deficiency* / Q000494:pharmacology; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006470:Hemorrhage / Q000378:metabolism*; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018180:Thrombomodulin / Q000378:metabolism
chemical_list: D018180:Thrombomodulin; D025901:Carboxypeptidase B2