Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism

Mario Colucci, Bianca M. Binetti, Armando Tripodi, Veena Chantarangkul, Nicola Semeraro

Research output: Contribution to journalArticle

Abstract

The prothrombin gene mutation G20210A is a common risk factor for thrombosis and is associated with increased prothrombin levels. However, the mechanism whereby hyperprothrombinemia predisposes to thrombosis remains unclear. Because thrombin is the physiologic activator of TAFI (thrombin activatable fibrinolysis inhibitor), the precursor of an antifibrinolytic carboxypeptidase (TAFIa), we evaluated the influence of hyperprothrombinemia on fibrinolysis. Thirty-two heterozygous carriers of the G20210A mutation and 30 noncarriers were studied. Plasma fibrinolytic factors and TAFI levels were similar in the 2 groups. Mean lysis time of tissue factor-induced plasma clots exposed to 25 ng/mL exogenous tissue-type plasminogen activator (t-PA) was significantly longer in 20210A carriers than in control donors. This difference disappeared on addition of a specific inhibitor of TAFIa. Determination of thrombin and TAFIa activity, generated during clot lysis, revealed that G20210A mutation was associated with a significant enhancement of late thrombin formation and an increase in TAFI activation. Plasma prothrombin level was highly significantly correlated with both clot lysis time and TAFI activation. The addition of purified prothrombin, but not of factors X or VIIa, to normal plasma caused a concentration-dependent, TAFI-mediated inhibition of fibrinolysis. These findings provide a new mechanism that might contribute to the thrombotic risk in prothrombin 20210A carriers.

Original languageEnglish
Pages (from-to)2157-2161
Number of pages5
JournalBlood
Volume103
Issue number6
DOIs
Publication statusPublished - Mar 15 2004

ASJC Scopus subject areas

  • Hematology

Fingerprint Dive into the research topics of 'Hyperprothrombinemia associated with prothrombin G20210A mutation inhibits plasma fibrinolysis through a TAFI-mediated mechanism'. Together they form a unique fingerprint.

  • Cite this