In this article we will look at the answer to the question of what fibrinolysis is. Here we will try to study the definition this term, its significance in the life of living beings, phases of the process and some features. The article will also pay special attention to the issue of its norm in the body, in particular during pregnancy.
Introduction
Fibrinolysis is a process during which blood clots and/or blood clots are dissolved. It is an integral part of the homeostasis mechanism and is always accompanied by the coagulation of fluid - blood. This process includes many cultivating factors that accompany it.
Fibrinolysis is one of the most important defensive reactions body, preventing fibrin from clogging the vessels that serve as a highway for blood movement. Another one important function- recanalization, which can be observed after the bleeding has stopped. Fibrinolysis includes the breakdown of fibrin, which is carried out through the use of plasmin. The plasmin protein exists in the blood, but in an inactive form called plasminogen.
External activation
The phases of fibrinolysis are divided according to the form of activation, which is divided into external and internal.
An external activation mechanism is possible only if there is a set of tissue activators. As a rule, the latter are synthesized in the vascular endothelium. These types of molecules include the following substances:
- Urokinase is a human serine protease encoded by the PLAU gene (chromosome 10).
- TAP - tissue activator plasminogens.
Internal activation
Internal activation occurs through the use of plasma activators and formed blood elements, such as leukocytes, erythrocytes and platelets. Internal system The activation mechanism is divided into Hageman-dependent and independent forms. The last type (independent) occurs only in the presence of proteins C and S, which have a direct effect on it. Dependent fibrinolysis is caused by the presence of kallikrein, which causes the transformation of plasminogens into plasmin. The main purpose of the Hageman-dependent form is to cleanse the vascular bed from fibrin in an unstable form.
Inhibition process
Fibrinolysis is a process that, together with a number of certain inhibitory and activating substances, determines the phenomenon of fibrinolytic activity and determines its properties through the relationship between them.
Blood plasma includes a set of inhibitors that slow down the process of fibrinolysis. One of the most significant inhibitors is alpha2-plasmin, which binds plasmin, trypsin, kallikrein, urokinase and tPA. Other strong inhibitory substances are: C1-protease inhibitor and many others. They can be produced not only by blood plasma, but also by fibroblasts, macrophages and monocytes.
Form of regulation
The processes of coagulation and fibrinolysis are in constant equilibrium with each other.
The phenomenon of increased fibrinolysis is caused by changes in the sympathetic nervous system(increased tone) and increased release of hormones such as adrenaline and norepinephrine. These three reasons lead to the activation of the Hageman factor. The latter, in turn, triggers both internal and external mechanisms. The main efferent regulators of the processes of fibrinolysis and blood coagulation are the vascular walls.
Indicators during pregnancy
The rate of fibrinolysis during pregnancy is very important point, which the expectant mother should pay attention to. This will avoid unnecessary complications that may occur in the fetus if its norm is exceeded or decreased.
Fibrinolysis is the phenomenon of dissolving blood clots and blood clots. It directly affects the formation of a human child in the womb. After conception, the indicator of fibrinogen, associated with the phenomenon of fibrinolysis, can change its value in the body from extremely small to huge values. To clearly determine its level, it is necessary to do a clinical study.
Childbirth is accompanied by large blood loss and in the absence of sufficient fibrinogen, this can lead to the loss of large blood resources. The process of fibrinolysis is extremely important for the activity of the placenta, as is the content of fibrinogen itself. Both factors can cause extremely undesirable complications, such as delayed fetal development.
Based on data on the level of fibrinogen and the rate of fibrinolysis, doctors can draw conclusions about whether the mother has severe inflammatory processes, as well as necrotic tissue configuration. Nature decided this problem by increasing fibrinogen levels during pregnancy.
Fibrinogen norm
The norm for women before pregnancy is two to four grams per liter. After the fetus has been conceived, this figure increases to six grams. This figure is still considered the norm. A significant excess of fibrinogen is observed in the third trimester.
Despite the fact that an increase in fibrinogen during pregnancy is normal reaction body on the formation of the fetus, its value (fibrinogen) still has its own limit, the presence of which may indicate the formation pathological processes. In such cases, patients are examined using a hemostasiogram.
Fibrinolysis - what does it mean? Having answered this question, we also touched on the concept of fibrinogen. So what are the consequences of a decrease in fibrinogen and changes in the process of fibrinolysis?
The above-mentioned changes in the mother's body can lead to premature detachment of the placental tissues that form its walls, as well as cause hypoxia and malnutrition of the fetus.
Low value fibrinogen can cause the following painful conditions:
- hepatitis;
- acute lack of vitamins B2 and C;
- gestosis;
- intravascular disseminated coagulation.
As a rule, the lack of the blood component fibrinogen is caused by the phenomenon of late toxicosis - gestosis.
The term "fibrinolysis" refers to the process of dissolving a blood clot. During the coagulation process, fibrinolysis prevents disruption of microcirculation in regions of the body outside the damage zone, and after bleeding stops, recanalization of the thrombus and restoration of blood supply in tissues distal to the site of thrombus formation. the process of destruction (lysis) of a blood clot is associated with the breakdown of fibrin and fibrinogen by a system of enzymes, the active components of which are plasmin. Plasmin hydrolyzes fibrin, fibrinogen, factors V, VII, XII, prothrombin.
Plasmin in the blood is in an inactive state in the form of plasminogen and is activated by tissue and blood activators. Tissue plasminogen activators are synthesized by the vascular endothelium. Highest value among them are tissue plasminogen activator (tPA) and urokinase, which is produced in the kidney by the juxtagiomerular apparatus.
The intrinsic activation pathway is divided into Hageman-dependent and Hageman-independent. Hageman-dependent is carried out by f XIIa, VMC and caplicrein. Hageman-independent proceeds through the mechanism of urgent reactions and is carried out by plasma proteinases. Plasma contains fibrinolysis inhibitors: a2 - antiplasmin, C1 and a1-protease inhibitors, a2 - macroglobulin. The activators are: a specific activator from endothelial cells; activated factor XII when interacting with kallikrein and high molecular weight kininogen; urokinase, produced by the kidney; bacterial streptokinase.
A disruption of the blood coagulation process occurs when there is a deficiency or absence of any factor involved in homeostasis. For example, the hereditary disease hemophilia is known, which occurs only in men and is characterized by frequent and prolonged bleeding. This disease is caused by a deficiency of factors VIII and IX, which are called antihemophilic factors.
Blood clotting can occur under the influence of factors that accelerate and slow down this process.
Factors that accelerate the blood clotting process:
Destruction of blood cells and tissue cells (increases the output of factors involved in blood clotting);
Calcium ions (participate in all main phases of blood clotting);
Thrombin;
Vitamin K (participates in the synthesis of prothrombin);
Heat (blood clotting is an enzymatic process);
Adrenalin.
Under normal conditions, the blood in the vessels is always in a liquid state, although conditions for the formation of intravascular blood clots constantly exist. Maintaining the liquid state of blood is ensured by self-regulation mechanisms due to the existence of appropriate functional systems. The main links in maintaining the fluid state of blood are the coagulation and anticoagulation systems. Currently, it is customary to distinguish two anticoagulant systems - the first and the second.
The first anticoagulant system (PAC) neutralizes thrombin in the circulating blood provided that it is formed slowly and in small quantities. Neutralization of thrombin is carried out by anticoagulants, which are constantly in the blood and therefore the PPS functions constantly. Such substances include:
Fibrin, which adsorbs part of thrombin;
Antithrombins prevent the conversion of prothrombin to thrombin;
Heparin blocks the transition phase of prothrombin to thrombin and fibrinogen to fibrin, and also inhibits the first phase of blood coagulation;
Lysis products (destruction of fibrin), which have antithrombin activity, inhibit the formation of prothrombinase;
Cells of the reticuloendothelial system absorb thrombin from blood plasma.
With a rapid increase in the amount of thrombin in the blood, PPS cannot prevent the formation of intravascular thrombi. In this case, the second anticoagulant system (ACS) comes into play, which ensures the maintenance of the liquid state of blood in the vessels through a reflex-humoral pathway. A sharp increase in the concentration of thrombin in the circulating blood leads to irritation of vascular chemoreceptors. Impulses from them enter the giant cell nucleus of the reticular formation of the medulla oblongata, and then along the efferent pathways to the reticuloendothelial system (liver, lungs, etc.). Heparin and substances that carry out and stimulate fibrinolysis (for example, plasminogen activators) are released into the blood in large quantities.
Heparin inhibits the first three phases of blood coagulation and interacts with substances that take part in blood coagulation. The resulting complexes with thrombin, fibrinogen, adrenaline, serotonin, factor X11I, etc. have anticoagulant activity and a lytic effect on unstabilized fibrin.
Regulation of blood clotting
Regulation of blood coagulation is carried out using neuro-humoral mechanisms. Excitation of the sympathetic department of the autonomic nervous system, which occurs during fear, pain, and stressful conditions, leads to a significant acceleration of blood clotting, which is called hypercoagulation. The main role in this mechanism belongs to adrenaline and norepinephrine. Adrenaline triggers a number of plasma and tissue reactions: the release of thromboplastin from the vascular wall, which quickly turns into tissue prothrombinase; adrenaline activates factor XII, which initiates the formation of blood prothrombinase; adrenaline activates tissue lipases, which break down fats and thereby increases the content of fatty acids in the blood, which have thromboplastic activity; adrenaline enhances the release of phospholipids from blood cells, especially from red blood cells.
Irritation of the vagus nerve or the administration of acetylcholine leads to the release of substances from the walls of blood vessels similar to those released under the action of adrenaline. Consequently, in the process of evolution, only one protective-adaptive reaction was formed in the hemocoagulation system - hypercoagulemia, aimed at urgently stopping bleeding. The identity of hemocoagulation shifts upon stimulation of the sympathetic and parasympathetic parts of the autonomic nervous system indicates that primary hypocoagulation does not exist, it is always secondary and develops after primary hypercoagulation as a result (consequence) of the consumption of part of the blood coagulation factors.
Acceleration of hemocoagulation causes increased fibrinolysis, which ensures the breakdown of excess fibrin. Activation of fibrinolysis is observed during physical work, emotions, and painful stimulation.
Blood coagulation is influenced by the higher parts of the central nervous system, including the cerebral cortex, which is confirmed by the possibility of changing hemocoagulation conditionally. It exerts its influence through the autonomic nervous system and endocrine glands, the hormones of which have a vasoactive effect. Impulses from the central nervous system arrive to the hematopoietic organs, to the organs that store blood and cause an increase in blood output from the liver, spleen, and activation of plasma factors. This leads to the rapid formation of prothrombinase. Then they turn on humoral mechanisms, which support and continue the activation of the coagulation system and at the same time reduce the effects of the anticoagulation system. The significance of conditioned reflex hypercoagulation appears to be in preparing the body to protect itself from blood loss.
The blood coagulation system is part of a larger system - the system for regulating the state of aggregation of blood and colloids (PACK), which maintains the constancy of the internal environment of the body and its state of aggregation at a level that is necessary for normal life by maintaining the fluid state of the blood and restoring the properties of the walls vessels that change even during their normal functioning. The blood coagulation system in the body is always in an active state, which is due to the continuous release of thromboplastin from naturally degrading cells. Hypercoagulation develops in states of pain and emotional stress, which occurs with activation of the sympathetic division of the autonomic nervous system. Catecholamines promote the release of thromboplastin from the walls. Adrenaline directly activates the Hageman factor and activates tissue lipases, which increases thromboplastic activity. Stimulation of the vagus nerve produces effects similar to those of adrenaline.
Fibrinolysis system- an enzymatic system that breaks down fibrin strands that are formed during blood clotting into soluble complexes. The fibrinolysis system is completely opposite to the blood coagulation system. Fibrinolysis limits the spread of blood coagulation through the vessels, regulates the permeability of blood vessels, restores their patency and ensures the liquid state of the blood in the vascular bed. The fibrinolysis system includes the following components:
1) fibrinolysin (plasmin). It is found inactive in the blood in the form of profibrinolysin (plasminogen). It breaks down fibrin, fibrinogen, some plasma factors blood clotting;
2) plasminogen activators (profibrinolysin). They belong to the globulin fraction of proteins. There are two groups of activators: direct action and indirect action. Direct-acting activators directly convert plasminogen into its active form - plasmin. Direct-acting activators - trypsin, urokinase, acid and alkaline phosphatase. Indirect-acting activators are in the blood plasma in an inactive state in the form of a proactivator. To activate it, tissue and plasma lysokinase is required. Some bacteria have lysokinase properties. There are tissue activators in the tissues, especially many of them are found in the uterus, lungs, thyroid gland, prostate;
3) fibrinolysis inhibitors (antiplasmins) - albumins. Antiplasmins inhibit the action of the enzyme fibrinolysin and the conversion of profibrinolysin to fibrinolysin.
The fibrinolysis process occurs in three phases.
During phase I, lysokinase, entering the blood, brings the plasminogen proactivator into an active state. This reaction occurs as a result of the cleavage of a number of amino acids from the proactivator.
Phase II – conversion of plasminogen to plasmin due to the cleavage of the lipid inhibitor under the influence of the activator.
During phase III, under the influence of plasmin, fibrin is broken down into polypeptides and amino acids. These enzymes are called fibrinogen/fibrin degradation products and have a pronounced anticoagulant effect. They inhibit thrombin and inhibit the formation of prothrombinase, suppress the process of fibrin polymerization, platelet adhesion and aggregation, enhance the effect of bradykinin, histamine, angeotensin on the vascular wall, which promotes the release of fibrinolysis activators from the vascular endothelium.
Distinguish two types of fibrinolysis– enzymatic and non-enzymatic.
Enzymatic fibrinolysis carried out with the participation of the proteolytic enzyme plasmin. Fibrin is broken down into degradation products.
Non-enzymatic fibrinolysis carried out by complex compounds of heparin with thrombogenic proteins, biogenic amines, hormones, conformational changes occur in the fibrin-S molecule.
The process of fibrinolysis occurs through two mechanisms - external and internal.
Along the external pathway, activation of fibrinolysis occurs due to tissue lysokinases and tissue plasminogen activators.
In inner path activation, proactivators and activators of fibrinolysis take part, capable of converting proactivators into plasminogen activators or acting directly on the proenzyme and converting it into plasmin.
Leukocytes play a significant role in the process of fibrin clot dissolution due to their phagocytic activity. Leukocytes take up fibrin, lyse it and secrete it into environment products of its degradation.
The process of fibrinolysis is considered in close connection with the process of blood coagulation. Their relationships are carried out at the level common paths activations in the reaction of the enzyme cascade, as well as due to neurohumoral regulatory mechanisms.
Fibrinolysis is the process of splitting a fibrin clot, as a result of which the lumen of a vessel blocked by a thrombus is restored. Fibrinolysis begins simultaneously with clot retraction, but proceeds more slowly. This is also an enzymatic process, which is carried out under the influence of the proteolytic enzyme - plasmin (fibrinolysin).
Plasmin is found in the blood plasma in an inactive state in the form of plasminogen. Plasminogen is synthesized in the liver, bone marrow, kidneys and other organs. Under the influence of blood and tissue activators, its activation occurs - the transition to plasmin. Plasmin breaks down fibrin into individual polypeptide chains, resulting in lysis (dissolution) of the fibrin clot (Fig. 4)
Fig.4.
Activation of plasminogen, like the formation of protrambinase, can occur via external and internal pathways. External path Plasminogen activation is carried out using tissue activators. These include primarily tissue plasminogen activator (t-PA), which is produced by endothelial cells of various tissues and is located mainly in the walls of blood vessels(mainly in veins and venules), and urokinase (and - RA), synthesized mainly by the kidneys and fibroblasts. Tissue plasminogen activator takes part in the dissolution of fibrin found in plasma. Urokinase is involved in the dissolution of fibrin located on the surface of cells, including endothelial cells. The internal pathway of plasminogen activation involves blood activators, for example, activated Hageman factor, kallikrein, proteins C and S. Some exogenous substances, for example, streptokinase of streptococci, and some drugs also have the ability to activate plasminogen.
Physiological inhibitors of fibrinolysis are also found in blood plasma. Some inhibitors (activators) neutralize the effect of plasminogen activators, while others (antiplasmins) inhibit plasmin itself. Among antiactivators, 3 types of inhibitors have been identified. B 2 - antiplasmin (b 2 -globulin) and b 2 -macroglobulin have an antiplasmin effect. First of all, plasmin is inactivated by b 2 - antiplasmin, which can neutralize 2/3 of all plasmin that can be formed in the blood from existing plasminogen. Therefore, it quickly disappears from the bloodstream and exerts its effect locally in the blood clot. If plasmin is produced excessively, depletion of b2-antiplasmin may occur. Then b 2 -macroglobulin, which is a less specific plasmin inhibitor, is included in the inhibition. B 1 - antitrypsin is also a plasminogen inhibitor.
There is also a non-plasmin version of fibrinolysis, which is carried out by fibryolytic proteases of leukocytes, platelets, erythrocytes and antithrombin III in combination with heparin, which can directly break down fibrin. All substances involved in the process of fibrinolysis are united by the fibrinolytic system. In addition to dissolving blood clots and removing fibrin deposits, components of the fibrinolytic system also take part in other physiological processes: wound healing, regulation of growth, division and migration of cells, muscle regeneration, growth of neuronal axons, ovulation processes, fertilization, etc. The process of fibrinolysis lasts several days and its result is recanalization of the vessel, i.e. restoration of its patency. Blood clot retraction and fibrinolysis are distinguished as additional phases of blood coagulation. We emphasize that the existing two types of coagulation lead to the formation of two types of blood clots - platelet and plasma.
During the formation of a hemostatic plug, mechanisms are activated aimed at limiting the growth of a blood clot, dissolving it and restoring blood flow. All this is performed by the fibrinolysis system. Fibrinolysis is the process of lysis of a thrombus or fibrin clot.
Fibrinolysis system consists of enzymes, non-enzymatic protein cofactors And inhibitors fibrinolysis. The ultimate goal of this system is the formation of the fibrinolytic enzyme plasmin and the destruction of the fibrin clot. The system normally provides strictly local action, because its components are adsorbed on fibrin threads. The system includes 18 proteins and among them:
1. Plasminogen is a proenzyme from which the protein plasmin is formed, which breaks down fibrin. Activated by plasminogen activators (PA) and factor XIIa.
2. Tissue-type plasminogen activators (t-PA, tissue plasminogen activator) and urokinase ( u-PA, urokinase, urokinase plasminogen activator) – enzymes (serine proteases) that convert plasminogen into plasmin.
- tissue plasminogen activator (t-PA) is secreted by endothelium, monocytes, megakaryocytes,
- urokinase plasminogen activator (u-PA) is produced by renal duct epithelial cells, juxtaglomerular cells, fibroblasts, macrophages, and endothelial cells.
3. Factor XII (Hageman factor) – contact factor, activator of plasminogen and prekallikrein.
4. Prekallikrein is a contact factor, Fletcher factor, proenzyme of kallikrein, which catalyzes the formation of kinins, but for this it must first be activated by the Hageman factor (f. XIIa).
5. High molecular weight kininogen(VMC, Fitzgerald factor) - in the bloodstream is in complex with factor XII, is a receptor for prekallikrein.
Conversion of plasminogen to plasmin
The key enzyme is plasmin, which hydrolyzes fibrin into soluble products. Transformation activators plasminogen is formed into plasmin vascular wall (internal activation) or tissues ( external activation).
Internal activation mechanism divided into Hageman-dependent (XIIa-dependent) and Hageman-independent (XIIa-independent):
- Hageman addict fibrinolysis occurs under the influence of factor XIIa, kallikrein and high molecular weight kininogen (HMK). This path carries urgent nature and is necessary for cleaning the vascular bed from unstabilized fibrin, which is formed during the process of intravascular coagulation.
- Hageman-independent fibrinolysis is carried out by kallikrein and VMC, but without Hageman factor.
External activation path, dominant, is carried out with the participation of plasminogen activators t-PA and u-PA (urokinase).
The binding of plasminogen and its activators occurs on the fibrin clot. There is a lysine-binding site necessary for the activation of plasminogen by t-PA, which ensures the local formation of plasmin.
Regulation of plasmin synthesis from plasminogen
Breakdown of fibrin and fibrinogen
Plasmin is a very active and at the same time relatively non-specific serine protease that destroys fibrin and fibrinogen. The molecules formed as a result, having different molecular weights, are designated as fibrin degradation products. They are mainly complexesDDE And D-dimers.
Some degradation products have pronounced physiological activity - they reduce platelet aggregation and disrupt the polymerization of fibrin monomers, being, in essence, anticoagulants.
Fibrinolysis reactions
Fibrinolysis inhibitors
Plasminogen activator inhibitor type 1(PAI-1, plasmaminogen activator inhibitor-1) is the main inhibitor of fibrinolysis, synthesized by the vascular endothelium. The protein specifically inhibits the effect t-PA And u-RA, preventing their interaction with plasminogen. In turn, PAI-1 itself is inhibited protein C. Thus, protein C not only suppresses coagulation (through inactivation of factors Va and VIIIa), but also enhances fibrinolysis.
α2-Antiplasmin is an enzyme (serine protease), a fast-acting inhibitor of plasmin. It prevents plasminogen from being adsorbed on fibrin, reducing the amount of plasmin formed on the surface of the clot and thereby sharply slowing down fibrinolysis.
α2-Macroglobulin– inactivates thrombin, XIIa and plasmin. The mechanism of inhibition is the formation of an [α2-macroglobulin protease] complex, which is then transported to the liver.
Thrombin-activated fibrinolysis inhibitor (TAFI, thrombin-activatable fibrinolysis inhibitor, carboxypeptidase Y), is activated by the thrombin-thrombomodulin complex. TAFI is destroying catalytic surface fibrin (lysine-binding site), necessary for the action of t-PA. In addition, at higher concentrations, TAFI directly inhibits plasminogen, which prevents premature thrombus lysis.
