Inhibition of thrombin-mediated factor V activation contributes to the anticoagulant activity of fibrinogen γ′

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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 γA/γ′ fibrinogen isoform binds with high affinity to thrombin exosite II through the anionic carboxyl-terminal end of the γ′ 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 γ′ in plasma, and to verify whether the fibrinogen γ′ 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 γ′ carboxyl-terminal peptide (0–500 μmol 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 γ′ 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 γ′ peptide have an overall anticoagulant effect on thrombin generation determined at low TF. Inhibition of thrombin-mediated FV activation by the fibrinogen γ′ peptide is a novel mechanism of the anticoagulant activity of fibrinogen γ′.

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