Evidence that α2-antiplasmin becomes covalently ligated to plasma fibrinogen in the circulation:: a new role for plasma factor XIII in fibrinolysis regulation

Background: Plasma alpha(2)-antiplasmin (alpha(2)AP) is a rapid and effective inhibitor of the fibrinolytic enzyme plasmin. Congenital alpha(2)AP deficiency results in a severe hemorrhagic disorder due to accelerated fibrinolysis. It is well established that in the presence of thrombin-activated factor XIII (FXIIIa), alpha(2)AP becomes covalently ligated to the distal alpha chains of fibrin or fibrinogen at lysine 303 (two potential sites per molecule). Some time ago we showed that alpha(2)AP is covalently linked to plasma fibrinogen . That singular observation led to our hypothesis that native plasma factor XIII (FXIII), which is known to catalyze covalent cross-linking of fibrinogen in the presence of calcium ions, can also incorporate alpha(2)AP into fibrinogen in the circulation. Results and Conclusions: We now provide evidence that FXIII incorporates I(125)-labelled alpha(2)AP into the A alpha-chain sites on fibrinogen or fibrin. We also measured the content of alpha(2)AP in isolated plasma fibrinogen fractions by ELISA and found that substantial amounts were present (1.2-1.8 moles per mole fibrinogen). We propose that alpha(2)AP becomes ligated to fibrinogen while in the circulation through the action of FXIII, and that its immediate presence in plasma fibrinogen contributes to regulation of in vivo fibrinolysis.