Fibrinolysis is characterized by the dissolution of fibrin by the enzyme plasmin. It is subject to complicated regulatory mechanisms in the organism and is in balance with hemostasis (blood clotting). Disturbance of this balance can lead to severe bleeding or thrombosis as well as embolism.
What is fibrinolysis?
The function of fibrinolysis is to limit the process of blood clotting during injury. The term fibrinolysis refers to the enzymatic breakdown of fibrin. Fibrin is a protein that is insoluble in water and plays a major role in blood clotting. It represents a cross-linked system of several polypeptide chains. The cross-links between the individual polypeptide chains are formed via covalent peptide bonds. As the main component of blood clots (thromboses), fibrin is responsible for their stability. During fibrinolysis, the cross-links of the network are dissolved, producing water-soluble fragments. These fragments are then transported away via the bloodstream. When injuries occur, hemostasis (blood clotting) always occurs first to stop bleeding. However, hemostasis also immediately leads to the activation of fibrinolysis. When the process of wound healing is complete, the balance shifts in favor of fibrinolysis.
Function and task
The function of fibrinolysis is to limit the process of blood clotting during injury. Otherwise, hemostasis would continue until the injured blood vessel was blocked. The result would be thrombosis, which could easily lead to a fatal embolism. The wound healing process thus takes place within the framework of a precisely coordinated balance between thrombus formation and thrombus degradation. In this process, fibrinolysis can be activated or inhibited. At the same time, however, fibrinolysis activation can also be inhibited. Hemostasis is also controlled by activating and inhibiting processes. This complicated balance ensures an undisturbed wound healing process. Both endogenous and exogenous enzymes are involved in the activation of fibrinolysis. Endogenous activators of fibrinolysis include tissue-specific plasminogen activator (tPA) and urokinase (uPA). Endogenous activator enzymes are produced by staphylococci and streptococci. Tissue-specific plasminoactivator originates from endothelial cells of the vessel wall. Its release is initiated by a complicated regulatory mechanism through activation of the plasmatic coagulation system in a somewhat delayed fashion. The tissue-specific plasmin activator is a serine protease that controls the conversion of plasminogen to plasmin. Plasmin, in turn, is the actual fibrin-degrading enzyme. The other endogenous fibrinolysis activator urokinase (uPA) also converts plasminogen to plasmin. Urokinase was first discovered in human urine. The fibrinolysis activators staphylokinase and streptokinase are produced by the corresponding bacterial strains and also convert plasminogen to plasmin. The hemolytic effect here leads to further spread of infection. However, all four enzymes are also used as active ingredients in drugs for the treatment of thrombosis. The plasmin formed has the task of breaking down fibrin. In the process, the thrombus dissolves. However, in order to limit fibrinolysis, both inhibitors of fibrinolysis activation and direct plasmin inhibitors are formed in the organism. To date, four different inhibitors of fibrinolysis activators have been discovered. They all belong to the serpin family and are designated PAI-1 through PAI-4 (plasminogen activator inhibitor). These inhibitors are stored in platelets. Upon platelet activation, they are released and in turn inhibit fibrinolysis activators. Plasmin can also be inhibited directly. This is mainly done by the enzyme alpha-2-antiplasmin. In the course of blood clotting, this enzyme is cross-linked with the fibrin polymers so that the thrombus is stabilized against fibrinolysis. Another plasmin inhibitor is macroglobulin. There are also artificial plasmin inhibitors. These agents include epsilon-aminocarboxylic acids and epsilon-aminocaproic acids. Furthermore, para-aminomethylbenzoic acid (PAMBA) and tranexamic acid are also each artificial plasmin inhibitors. Some of these agents are used as antifibrinolytics to treat increased fibrinolysis.
Diseases and ailments
As mentioned, hemostasis and fibrinolysis are in balance. Fine-tuned processes regulate activation and inhibition of thrombus formation and degradation. Any disturbance of this balance can lead to serious diseases. For example, if increased blood clotting occurs without adequate fibrinolysis, thrombosis may result. Detached blood clots can travel to the lungs, brain or heart and cause embolisms, strokes or heart attacks. The causes of an increased tendency to thrombosis are manifold. In addition to increased blood clotting due to underlying diseases and genetic predispositions, disorders in fibrinolysis are often responsible. It has been found that impaired fibrinolysis accounts for 20 percent of the causes of thrombosis or embolism. Plasminogen deficiency, tPA deficiency, low activity of tPA and protein-C deficiency are discussed for the lower activity of fibrinolysis (hypofibrinolysis). Protein-C inactivates coagulation factors Va and VIIIa by their degradation, inducing thrombus dissolution. Hypofibrinolysis is often treated by drug administration of plasminogen activators. In addition to hypofibrinolysis, however, there is also the clinical picture of hyperfibrinolysis. In this case, there is an increased degradation of fibrin. The result is an increased tendency to bleed. In hyperfibrinolysis, an increased spontaneous formation of plasminogen is often observed. The effect is further enhanced by the cleavage products of fibrin, because they additionally inhibit the cross-linking of fibrin molecules. Another cause of increased fibrinolysis may be the inhibition of alpha-2-antiplasmin, the enzyme that deactivates the fibrin-degrading plasmin. If deactivation ceases, fibrin degradation is no longer stopped. Treatment of hyperfibrinolysis is usually by administration of artificial plasmin inhibitors.
