The effect of fibrin(ogen) on thrombin generation and decay

Defibrination causes a similar to 30% decrease of thrombin generation (TG) which can be restored by adding native fibrinogen in its original concentration (3 mg/ml). The fibrinogen variant gamma A/gamma', which binds thrombin with high affinity, is over four times more efficient in this respect than the more common gamma A/gamma A 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 alpha 2-macroglobulin-dependent decay constants at a series of concentrations of native, gamma A/gamma A and gamma A/gamma' 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 alpha 2-macroglobulin, where the gamma A/gamma' form is much more active than the gamma A/gamma A form. AT-dependent decay is somewhat decreased by gamma A/gamma' fibrinogen but hardly by the gamma A/gamma A 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.