Inhibition of thrombin-mediated factor V activation contributes to the anticoagulant activity of fibrinogen gamma '

F Omarova, Shirley Uitte de Willige, RAS Ariens, J Rosing, RM Bertina, E Castoldi

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Abstract

Background Besides its role in blood clotting, fibrinogen exerts a poorly understood anticoagulant function by binding thrombin and modulating its activity. In particular, the gamma A/gamma ' fibrinogen isoform binds with high affinity to thrombin exosite II through the anionic carboxyl-terminal end of the gamma ' chain. This interaction down-regulates thrombin-mediated factor VIII (FVIII) activation, but its effect on FV activation is unknown. Objectives To investigate the overall anticoagulant activity of fibrinogen and particularly of fibrinogen gamma ' in plasma, and to verify whether the fibrinogen gamma ' carboxyl-terminal peptide affects thrombin-mediated FV activation. Methods Thrombin generation was measured by calibrated automated thrombography in whole and defibrinated plasma and in plasma supplemented with the (sulfated) fibrinogen gamma ' carboxyl-terminal peptide (0-500 mu mol L-1). The effect of the peptide on thrombin-mediated FV activation was studied in model systems and in plasma. Results Total fibrinogen prolonged the lag time of thrombin generation at low tissue factor (TF) concentrations. The fibrinogen gamma ' peptide dose-dependently prolonged the lag time and decreased the peak height of thrombin generation at low TF, whereas a scrambled control peptide was ineffective. These effects persisted in the presence of an anti-FVIII antibody, suggesting that the peptide may also inhibit thrombin-mediated activation of FV. This was confirmed in model systems and in plasma. Conclusions Total fibrinogen and the fibrinogen gamma ' peptide have an overall anticoagulant effect on thrombin generation determined at low TF. Inhibition of thrombin-mediated FV activation by the fibrinogen gamma ' peptide is a novel mechanism of the anticoagulant activity of fibrinogen gamma '.
Original languageUndefined/Unknown
Pages (from-to)1669-1678
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume11
Issue number9
DOIs
Publication statusPublished - 2013

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