Fibrinolysis

Fibrinolysis ( Fibrinspaltung ) is the name for the body's dissolution of a blood clot (thrombus ) by the enzyme plasmin. This plasmin cleaves fibrin polymers, which hold the thrombus into small fibrin degradation products, and the thrombus breaks.

The physiological fibrinolysis is mainly activated by the tissue-specific plasminogen activator and urokinase in the body. The most important non-physiological activators of plasminogen are staphylokinase and streptokinase, which can also be used therapeutically for the resolution of thrombus ( thrombolysis ). Both have in common that they themselves have no enzymatic activity, but form with plasminogen or plasmin a complex which is able to activate plasminogen. Be therapeutically today in addition to urokinase and recombinant used activators ( man-made ) ( rt- PA, alteplase ).

Activation of fibrinolysis

Fibrinolysis is activated simultaneously with blood clotting ( hemostasis ), but uses slower and thus effects, in addition to other anti-clotting factors that hemostasis is regulated.

The activation of the fibrinolysis is far less complex than the activation of the blood clotting cascade and contains substantially only the conversion of the inactive precursor protein, plasminogen into the active serine protease plasmin. The plasminogen activation, a distinction between the physiological activation by endogenous activators and the non-physiological activation by exogenous substances.

Inhibitors of fibrinolysis

Up to now could be identified four different inhibitors of plasminogen activators, all of which belong to the serpin family and are referred to as PAI- 1 to PAI -4 ( plasminogen activator inhibitor). PAI-1 is the most important inhibitor which inhibits both in normal blood to tissue-specific plasminogen activator and urokinase. PAI -1 is a 52,000 dalton large glycoprotein which is produced by the endothelial cells. The inhibition by PAI -1 follows the general reaction mechanism of serpins. Most of the PAI-1 ( about 90% of the entire PAI-1 in the blood ) is stored by the platelets. If the platelet is activated, they put the PAI -1 molecules freely and provide for a greatly increased concentration of PAI -1 at the site of thrombus formation, which increases the stability of the thrombus compared with fibrinolysis.

Cleavage of fibrin

Once active plasmin incurred, it binds to the fibrin and cross-linked fibrin polymers in cleaves the soluble fibrin degradation products (FDP, Eng. Fibrin degredation products ). The amino acid chains of fibrin contain various plasminsensitive interfaces and there, there are different degradation products with different structure and composition. The soluble fibrin degradation products are transported through the blood circulation, and then removed from the bloodstream.

Inhibitors of fibrinolysis

The inhibition of fibrinolysis is based, together with the inhibition of fibrinolysis, mainly through inhibition of the active plasmin. The most important inhibitor of plasmin is the enzyme alpha -2- plasmin inhibitor ( antiplasmin ). In the blood plasma plasmin is practically inhibited immediately by the alpha -2- plasmin inhibitor and rendered harmless, whereas fibrin-bound plasmin compared with the alpha -2- plasmin inhibitor is better protected and has a much longer half-life. However, during the coagulation of the alpha -2- plasmin inhibitor is cross-linked by the enzyme Factor XIII in the fibrin of the thrombus, causing the thrombus with respect to the resolution is stabilized by fibrinolysis. In addition, platelets may provide on its surface a catalytic environment, which allows the cross-linking of the alpha -2- plasmin inhibitor to the thrombus without the action of factor XIII. Another inhibitor of plasmin is macroglobulin.

Artificial inhibitors of plasmin or plasminogen are the ε -amino carboxylic acids ε -aminocaproic acid, para- aminomethyl benzoic acid ( PAMBA ) and tranexamic acid. All of these substances have a similar spatial arrangement of the two functional groups of amino- and carboxy group such as lysine. They bind to the lysine binding site of plasmin, which is thus inactivated. When drugs are therefore among the ε -amino carboxylic acids to the group of anti-fibrinolytics.

Diagnostics

The resulting fibrin degradation products (FDP) inhibit thrombin and thus slowing the conversion of fibrinogen to fibrin (ie slow clot formation ). In patients with active fibrinolysis this effect by means of the TCT (thrombin clotting time) can be demonstrated. However Concurrent heparin therapy affects the TCT, and makes this test so useless. FDPs also inhibit platelet function.

D-dimer, FDP, a specific, can be detected using an immunological test. Therefore the existence of fibrinolysis can be detected. Another test for the detection of fibrinolysis is the euglobulin lysis test (ELT ).

With thromboelastometry ( TEM) can be a very quick proof of purchase of fibrinolysis, especially hyperfibrinolysis be carried out even in heparinized patients.