Lysine antifibrinolytic activity

As fibrin is formed during the clotting cascade the fribri-nolytic enzyme plasmin is formed in tandem and breaks down fibrin. Thus, if dot formation is defective, it is necessary to inhibit the action of plasmin. The amino add lysine (Fig. 19.1) was observed to have antifibrinolytic activity and e-aminocaproic add (Fig. 19.1) was found to have even greater activity. Screening of analogues of e-aminocaproic add resulted in the discovery of tranexamic acid (Fig. 19.1), which is a potent inhibitor of the conversion of plasminogen into plasmin. 

Tranexamic acid produces an antifibrinolytic effect by blocking the lysine binding site on plasminogen which is essential for binding to fibrin and thereby prevents the activation of plasminogen on the surface of fibrin. 

Figure 17.4 Antifibrinolytic action of the lysine analogues. Normally, plasminogen binds to fibrin at a lysine-binding site and is converted in the presence of tissue plasminogen activator (tPA) to piasmin. The lysine analogues block the lysine-bIndIng site and prevent access of plasminogen to tfie fibrin molecule. Reproduced from Dunn O, Goa KL. Drugs 1999 57 1005-32, with permission.)...

Various other compounds are used clinically as antifibrinolytics. As mentioned above, aprotinin, a small polypeptide that inhibits plasmin, trypsin and kallikrein, is often used in coagulation tlierapy and in fibrin sealant formulations (Trautschold et al, 1967). In the latter applications, the aprotinin serves to delay the fibrinolytic action of plasmin until the fibrin has fiilfilled its function. A monoamino carboxylic acid, e-amino caproic acid, is similar in structure to lysine and interacts with the active kringles or lysine-binding sites of plasminogen and plasminogen activators to inhibit their binding to fibrin and thus their fibrinolytic actions (Thorsen, 1992). This compound is also used in some clinical applications. 

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