Fibrinolysis
Fibrinolysis ( fibrin cleavage ) is the name given to the body's own dissolution of a blood clot ( thrombus ) by the enzyme plasmin . Plasmin splits the fibrin polymers that hold the thrombus together into small fibrin breakdown products and the thrombus breaks down.
As an important partial aspect of hemostasis (blood coagulation) , fibrinolysis is subject to complex regulation through opposing biochemical processes (activation, inhibition of activation, inactivation) in order to achieve the physiological optimum between the two disadvantageous extremes of bleeding and thrombosis .
Activation of fibrinolysis
The activation of fibrinolysis is far less complex than the activation cascade of blood coagulation and essentially only involves the conversion (activation) of the inactive precursor protein plasminogen into the active serine protease plasmin. Fibrinolysis is activated at the same time as blood clotting, but starts more slowly, which helps regulate hemostasis.
In plasminogen activation, a distinction is made between physiological activation by the body's own activators and non-physiological activation by substances foreign to the body.
There are two endogenous activators, the tissue-specific plasminogen activator (tPA) and the urokinase (uPA) . The main non-physiological activators of plasminogen are staphylokinase from staphylococci and streptokinase from streptococci . The two endogenous activators are also proteases, while the exogenous activators themselves have no enzymatic activity, but rather form a complex with plasminogen or plasmin, which then activates plasminogen.
All activators can also be used therapeutically for thrombolysis (dissolution of thrombi). In particular, genetically engineered (recombinant) tissue-specific plasminogen activator (rtPA, alteplase ) and urokinase are used.
Inhibitors of Fibrinolysis Activation
So far, 4 different inhibitors of plasminogen activators have been identified, all of which belong to the Serpine family and are referred to as PAI-1 to PAI-4 (plasminogen activator inhibitor). The most important inhibitor is PAI-1, which inhibits both the tissue-specific plasminogen activator and urokinase in normal blood . PAI-1 is a 52,000 dalton large glycoprotein that of the endothelial cells is established. Inhibition by PAI-1 follows the general reaction mechanism of serpins. Most of the PAI-1 (about 90% of the total PAI-1 in the blood) is stored by the platelets . If the platelets are activated, they release the PAI-1 molecules and thus ensure a greatly increased concentration of PAI-1 at the site of thrombus formation, which increases the stability of the thrombus against fibrinolysis.
Cleavage of the fibrin polymers
Once active plasmin has formed, it binds to the fibrin and splits the crosslinked fibrin polymers into soluble fibrin degradation products (FDP, fibrin degradation products). The amino acid chains of fibrin contain various plasmin-sensitive interfaces and various breakdown products with different structures and masses arise. The soluble fibrin breakdown products are carried away by the blood circulation and then removed from the bloodstream.
Inactivation of fibrinolysis
The inhibition of fibrinolysis is based, in addition to the inhibition of fibrinolysis activation, mainly on the 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 almost immediately inhibited and rendered harmless by the alpha-2 plasmin inhibitor, whereas fibrin-bound plasmin is better protected compared to the alpha-2 plasmin inhibitor and has a much longer half-life . During blood clotting , however, the alpha-2-plasmin inhibitor is cross-linked to the fibrin polymers of the thrombus by the enzyme factor XIII, whereby the thrombus is stabilized against dissolution by fibrinolysis. In addition, platelets can also provide a catalytic environment on their surface , which enables the alpha-2-plasmin inhibitor to cross-link to the thrombus without the action of factor XIII. Another inhibitor of plasmin is macroglobulin .
Artificial inhibitors of plasmin or plasminogen are the ε-aminocarboxylic acids ε-aminocaproic acid , para-aminomethylbenzoic acid ( PAMBA ) and tranexamic acid . All of these substances have a similar spatial arrangement of the two functional groups amino and carboxy groups as lysine . They bind to the lysine binding site of plasmin, which is then inactivated. As medicinal substances , ε-aminocarboxylic acids therefore belong to the group of antifibrinolytics .
Diagnosis
The resulting fibrin breakdown products (FDP) inhibit thrombin and thus slow down the conversion of fibrinogen into fibrin (i.e. slow down the formation of clots). In patients with active fibrinolysis, this effect can be demonstrated using TCT (thrombin clotting time). Simultaneous heparin therapy, however, influences the TCT and makes this test useless. FDPs also inhibit platelet function.
D-dimer , a specific FDP, can be detected using an immunological test. This allows the existence of fibrinolysis to be recognized. Another test for detecting fibrinolysis is the euglobulin lysis test (ELT).
With thromboelastometry (TEM) a very rapid detection of an existing fibrinolysis, in particular a hyperfibrinolysis, can be carried out even in heparinized patients.
Individual evidence
- ↑ K. Aktories, U. Förstermann, W. Forth: General and special pharmacology and toxicology. 9th edition, Elsevier, Urban & Fischer; 2006, p. 547, ISBN 9783437444906