Summary
Defibrination causes a ~30% decrease of thrombin generation (TG) which can be restored
by adding native fibrinogen in its original concentration (3 mg/ml). The fibrinogen
variant γA/γ′, which binds thrombin with high affinity, is over four times more efficient
in this respect than the more common γA/γA form. By using high tissue factor concentrations
we accelerated prothrombin conversion so as to obtain a descending part of the TG
curve that was governed by thrombin decay only. From that part we calculated the antithrombin
(AT)- and α2-macroglobulin- dependent decay constants at a series of concentrations
of native, γA/γA and γA/γ′ fibrinogen. We found that the increase of TG in the presence
of fibrinogen is primarily due to a dose-dependent decrease of thrombin inactivation
by α2-macroglobulin, where the γA/γ′ form is much more active than the γA/γA form.
AT-dependent decay is somewhat decreased by γA/γ′ fibrinogen but hardly by the γA/γA
form. We assume that binding of thrombin to fibrin(ogen) interferes with its binding
to inhibitors. Attenuation of decay only in part explains the stimulating effect of
fibrinogen on TG, as fibrinogen stimulates prothrombin conversion, regardless of the
fibrinogen variant.
Note: Part of this work was presented at the ISTH meeting in 2013.
Keywords
Fibrinogen - thrombin generation - gamma chain - thrombin decay - prothrombin conversion
