Significance of Cross-Linking of α<sub>2</sub>-Plasmin Inhibitor to Fibrin in Inhibition of Fibrinolysis and in Hemostasis

Yoichi Sakata; Nobuo Aoki

doi:10.1172/JCI110479

Significance of Cross-Linking of α₂-Plasmin Inhibitor to Fibrin in Inhibition of Fibrinolysis and in Hemostasis

Published March 1, 1982 - More info

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Abstract

When blood is clotted, α₂-plasmin inhibitor (α₂PI) is cross-linked to fibrin by activated fibrin-stabilizing factor (activated coagulation Factor XIII, plasma transglutaminase). The amount of cross-linked α₂-PI is proportional to the amount of α₂PI present at the time of clotting. Plasma from a patient with congenital deficiency of α₂PI was supplemented with various amounts of purified α₂PI. Clots were prepared from these plasmas and were suspended in plasma containing a normal concentration of α₂PI, and spontaneous clot lysis was observed. When the clot was formed in the presence of calcium ions and thereby allowing cross-linking to occur, the rate and extent of fibrinolysis were found to be inversely proportional to the concentrations of α₂PI present in the clot at the time of clotting. When the clot was formed in the absence of calcium ions so that no cross-linking occurred, the clot underwent fibrinolysis at similar rates, regardless of the concentrations of α₂PI in the clot. When the clot formed in the presence of calcium ions was squeezed and washed to remove unbound proteins before being suspended in plasma, the extent of fibrinolysis was also inversely proportional to the amount of α₂PI cross-linked to fibrin. Similar results were obtained when the clot was suspended in buffered saline instead of plasma. These observations suggest that spontaneous fibrinolysis is mainly carried out by plasminogen/plasminogen activator bound to fibrin, and this fibrinolysis caused by fibrin-associated activation of plasminogen was mainly inhibited by α₂PI cross-linked to fibrin. To further support this concept, α₂PI treated with activated fibrin-stabilizing factor and that had lost most of its cross-linking capacity was used in similar experiments. This modified α₂PI had the same inhibitory activity on plasmin as the native inhibitor, but gave significantly less inhibition of fibrinolysis in every experiment, particularly when the clot was compacted by platelet-mediated clot retraction or by squeezing. Thus, it was concluded that α₂PI cross-linked to fibrin plays a significant role in inhibition of physiologically occurring fibrinolysis. It is further suggested that the absence of cross-linked α₂PI contributes to accelerated fibrinolysis and hemorrhagic tendency in patients with congenital deficiency of fibrin-stabilizing factor.