Once the restitutio ad integrum of the injured vessel has been achieved, the clot no longer has any reason to exist and must, therefore, be removed to restore patency and canalization of the vessel. The process that determines the lysis of the clot is defined as fibrinolysis (Fig. 1). The major components of the fibrinolytic system are plasminogen, which is converted to plasmin by plasminogen activators known as t-PA and urokinase (u-PA). Plasmin is the main enzyme responsible for clot dissolution and works by degrading stabilized fibrin (but also fibrinogen and insoluble fibrin) into degradation products also known as fibrinogen/fibrin degradation products (FDP). The process of fibrin degradation begins at the α, β, and γ chains, generating C-terminal lysine residues that are in turn capable of promoting the conversion of further plasminogen molecules into plasmin. The progressive action of plasminogen releases, therefore, a wide and heterogeneous (both in terms of structure and molecular weight) series of degradation products, containing variable combinations of the central E and lateral D domains. The degradation of stabilized fibrin, but not of soluble fibrin or fibrinogen, determines the formation of FDP containing the so-called D-dimer, represented by degradation molecules of various structures and molecular weights that contain two lateral D units linked by a stable covalent bond. It is therefore evident that the determination of the D-dimer is useful in the laboratory to testify that the lysis of a stabilized clot has occurred (as it happens, e.g., in thrombotic processes), while the determination of the total FDP does not allow one to distinguish whether the action of plasmin has addressed only the stabilized fibrin or has also affected the fibrinogen and/or soluble fibrin (as it usually happens in primary fibrinogenolysis or in disseminated intravascular coagulation). This mechanism explains the higher diagnostic specificity of D-dimer compared to FDP for the diagnosis of venous thromboembolism.

Fig1. Fibrinoformation and fibrinolysis. (Copyright EDISES 2021. Reproduced with permission)

As with the coagulation cascade, the progression of fibrinolysis is modulated by specific inhibitors. In the latter case, plasminogen activators are inhibited by PAI-1 (plasminogen activator inhibitor-1), α2-antiplasmin, and α2-macroglobulin.

TAFI (Thrombin Activatable Fibrinolysis Inhibitor), a metalloprotease of hepatic origin, acts as a bridge between the coagulation cascade and fibrinolysis. The activation of TAFI (bound to thrombomodulin) by thrombin promotes the degradation of carboxy-terminal residues of lysine and argi nine on the fibrin surface, thus preventing the binding of fibrin itself to plasminogen. In summary, activated TAFI, in addition to inactivating partially degraded fibrin, also acts as a cofactor for plasmin generation, ultimately inhibiting fibrinolysis as a whole. Considering that thrombin is the activator of TAFI, it is therefore legitimate to conclude that the coagulation cascade regulates fibrinolysis as well. Therefore, a defect in thrombin generation is inevitably reflected in increased fibrinolytic power. The clinical consequences are easily predictable when the thrombin generation guaranteed by the TF pathway alone (the extrinsic pathway) is insufficient to activate such a quantity of TAFI as to inhibit fibrinolysis. A “useful” concentration of TAFI is obtained only when the thrombin burst is fully functional. Defects in the factors involved in this process (i.e., essentially FXI, FIX, and FVIII) not only lead to hemorrhagic diathesis due to insufficient fibrin generation but also to inefficient activation of TAFI. It could therefore be concluded that hemophiliacs bleed not only due to insufficient clot generation but also due to excessive lysis of the small clot that has formed.

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