Blood clotting serves as an ingredient for. External and internal pathways of blood coagulation

The process of blood clotting begins with blood loss, but massive blood loss, accompanied by a drop in blood pressure, leads to drastic changes in the entire hemostatic system.

Blood coagulation system (hemostasis)

The blood coagulation system is a complex multicomponent complex of human homeostasis, ensuring the preservation of the integrity of the body through the constant maintenance of the liquid state of the blood and the formation, if necessary, of various types of blood clots, as well as the activation of healing processes in places of vascular and tissue damage.

The functioning of the coagulation system is ensured by the continuous interaction of the vascular wall and circulating blood. Certain components are known that are responsible for the normal activity of the coagulological system:

• endothelial cells of the vascular wall,
• platelets,
• adhesive plasma molecules,
• plasma coagulation factors,
• fibrinolysis systems,
• systems of physiological primary and secondary anticoagulants-antiproteases,
• plasma system of physiological primary healing agents.

Any damage to the vascular wall, “blood trauma,” on the one hand, leads to bleeding of varying severity, and on the other, causes physiological and subsequently pathological changes in the hemostatic system, which can themselves lead to the death of the body. Naturally severe and frequent complications of massive blood loss include acute disseminated intravascular coagulation syndrome (acute DIC syndrome).

In case of acute massive blood loss, and it cannot be imagined without damage to blood vessels, local (at the site of damage) thrombosis almost always occurs, which, in combination with a drop in blood pressure, can trigger acute disseminated intravascular coagulation syndrome, which is the most important and pathogenetically most unfavorable mechanism of all the ills of acute massive blood loss. blood loss.

Endothelial cells

Endothelial cells of the vascular wall ensure the maintenance of the liquid state of the blood, directly influencing many mechanisms and links of thrombus formation, completely blocking or effectively restraining them. The vessels ensure laminarity of blood flow, which prevents the adhesion of cellular and protein components.

The endothelium carries a negative charge on its surface, as do cells circulating in the blood, various glycoproteins and other compounds. The similarly charged endothelium and circulating blood elements repel each other, which prevents the adhesion of cells and protein structures in the circulatory bed.

Maintaining blood fluidity

Maintaining the fluid state of the blood is facilitated by:

• prostacyclin (PGI 2),
• NO and ADPase,
• tissue thromboplastin inhibitor,
• glycosaminoglycans and, in particular, heparin, antithrombin III, heparin cofactor II, tissue plasminogen activator, etc.

Prostacyclin

Blockade of platelet agglutination and aggregation in the bloodstream is carried out in several ways. The endothelium actively produces prostaglandin I 2 (PGI 2), or prostacyclin, which inhibits the formation of primary platelet aggregates. Prostacyclin is able to “break up” early agglutinates and platelet aggregates, at the same time being a vasodilator.

Nitric oxide (NO) and ADPase

Platelet disaggregation and vasodilation are also carried out by the endothelium producing nitric oxide (NO) and the so-called ADPase (enzyme that breaks down adenosine diphosphate - ADP) - a compound produced by various cells and is an active agent that stimulates platelet aggregation.

Protein C system

The protein C system has a restraining and inhibitory effect on the blood coagulation system, mainly on its internal activation pathway. The complex of this system includes:

1. thrombomodulin,
2. protein C,
3. protein S,
4. thrombin as an activator of protein C,
5. protein C inhibitor.

Endothelial cells produce thrombomodulin, which, with the participation of thrombin, activates protein C, converting it into protein Ca. Activated protein Ca, with the participation of protein S, inactivates factors Va and VIIIa, suppressing and inhibiting the internal mechanism of the blood coagulation system. In addition, activated protein Ca stimulates the activity of the fibrinolytic system in two ways: by stimulating the production and release of tissue plasminogen activator from endothelial cells into the bloodstream, and also by blocking tissue plasminogen activator inhibitor (PAI-1).

Pathology of the protein C system

Often observed hereditary or acquired pathology of the protein C system leads to the development of thrombotic conditions.

Fulminant purpura

Homozygous protein C deficiency (purpura fulminans) is an extremely severe pathology. Children with fulminant purpura are practically not viable and die at an early age from severe thrombosis, acute disseminated intravascular coagulation syndrome and sepsis.

Thrombosis

Heterozygous hereditary deficiency of protein C or protein S contributes to the occurrence of thrombosis in young people. Thrombosis of the main and peripheral veins, pulmonary embolism, early myocardial infarction, and ischemic strokes are more often observed. In women with protein C or S deficiency who take hormonal contraceptives, the risk of thrombosis (usually thrombosis of cerebral vessels) increases 10-25 times.

Since proteins C and S are vitamin K-dependent proteases produced in the liver, treatment of thrombosis with indirect anticoagulants such as syncumar or pelentan in patients with hereditary deficiency of protein C or S may lead to aggravation of the thrombotic process. In addition, in some patients, when treated with indirect anticoagulants (warfarin), peripheral skin necrosis may develop (“ warfarin necrosis"). Their appearance almost always means the presence of heterozygous protein C deficiency, which leads to a decrease in fibrinolytic activity of the blood, local ischemia and skin necrosis.

V factor Leiden

Another pathology directly related to the functioning of the protein C system is called hereditary resistance to activated protein C, or factor V Leiden. In fact, V factor Leiden is a mutant V factor with a point replacement of arginine at the 506th position of factor V with glutamine. Factor V Leiden has increased resistance to the direct action of activated protein C. If hereditary deficiency of protein C in patients predominantly with venous thrombosis occurs in 4-7% of cases, then factor V Leiden, according to various authors, occurs in 10-25%.

Tissue thromboplastin inhibitor

Vascular endothelium can also inhibit thrombus formation when activated. Endothelial cells actively produce tissue thromboplastin inhibitor, which inactivates the tissue factor-factor VIIa (TF-VIIa) complex, which leads to blockade of the extrinsic blood coagulation mechanism, which is activated when tissue thromboplastin enters the bloodstream, thereby maintaining blood fluidity in the circulatory system.

Glucosaminoglycans (heparin, antithrombin III, heparin cofactor II)

Another mechanism for maintaining a fluid state of blood is associated with the production of various glycosaminoglycans by the endothelium, among which heparan and dermatan sulfate are known. These glycosaminoglycans are similar in structure and function to heparins. Produced and released into the bloodstream, heparin binds to antithrombin III (AT III) molecules circulating in the blood, activating them. In turn, activated AT III captures and inactivates factor Xa, thrombin and a number of other factors of the blood coagulation system. In addition to the mechanism of coagulation inactivation through AT III, heparins activate the so-called heparin cofactor II (CH II). Activated KG II, like AT III, inhibits the functions of factor Xa and thrombin.

In addition to influencing the activity of physiological anticoagulant-antiproteases (AT III and CG II), heparins are able to modify the functions of such adhesive plasma molecules as von Willebrand factor and fibronectin. Heparin reduces the functional properties of von Willebrand factor, helping to reduce the thrombotic potential of the blood. Fibronectin, as a result of heparin activation, binds to various target objects of phagocytosis - cell membranes, tissue detritus, immune complexes, fragments of collagen structures, staphylococci and streptococci. Due to heparin-stimulated opsonic interactions of fibronectin, the inactivation of phagocytosis targets in the organs of the macrophage system is activated. Cleaning the circulatory system from target objects of phagocytosis helps maintain the liquid state and fluidity of the blood.

In addition, heparins are able to stimulate the production and release into the circulation of tissue thromboplastin inhibitor, which significantly reduces the likelihood of thrombosis during external activation of the blood coagulation system.

The process of blood clotting - thrombus formation

Along with what was described above, there are mechanisms that are also related to the state of the vascular wall, but do not contribute to maintaining the liquid state of the blood, but are responsible for its coagulation.

The process of blood clotting begins with damage to the integrity of the vascular wall. At the same time, the external mechanisms of the process of thrombus formation are also distinguished.

With the internal mechanism, damage to only the endothelial layer of the vascular wall leads to the fact that the blood flow comes into contact with the structures of the subendothelium - with the basement membrane, in which the main thrombogenic factors are collagen and laminin. Von Willebrand factor and fibronectin in the blood interact with them; A platelet thrombus is formed, and then a fibrin clot.

It should be noted that blood clots that form under conditions of rapid blood flow (in the arterial system) can exist almost only with the participation of von Willebrand factor. On the contrary, both von Willebrand factor, fibrinogen, fibronectin, and thrombospondin are involved in the formation of blood clots at relatively low blood flow rates (in the microvasculature, venous system).

Another mechanism of thrombus formation is carried out with the direct participation of von Willebrand factor, which, when the integrity of the vessels is damaged, increases significantly in quantitative terms due to the entry from the Weibol-Pallada bodies of the endothelium.

Blood clotting systems and factors

Thromboplastin

The most important role in the external mechanism of thrombus formation is played by tissue thromboplastin, which enters the bloodstream from the interstitial space after rupture of the integrity of the vascular wall. It induces thrombus formation by activating the blood coagulation system with the participation of factor VII. Since tissue thromboplastin contains a phospholipid part, platelets participate little in this mechanism of thrombosis. It is the appearance of tissue thromboplastin in the bloodstream and its participation in pathological thrombus formation that determines the development of acute disseminated intravascular coagulation syndrome.

Cytokines

The next mechanism of thrombus formation is realized with the participation of cytokines - interleukin-1 and interleukin-6. The tumor necrosis factor formed as a result of their interaction stimulates the production and release of tissue thromboplastin from the endothelium and monocytes, the significance of which has already been discussed. This explains the development of local blood clots in various diseases that occur with clearly defined inflammatory reactions.

Platelets

Specialized blood cells involved in the process of blood clotting are platelets - anucleate blood cells that are fragments of the cytoplasm of megakaryocytes. The production of platelets is associated with a certain thrombopoietin, which regulates thrombocytopoiesis.

The number of platelets in the blood is 160-385×10 9 /l. They are clearly visible in a light microscope, therefore, when carrying out differential diagnosis of thrombosis or bleeding, microscopy of peripheral blood smears is necessary. Normally, the size of a platelet does not exceed 2-3.5 microns (about ⅓-¼ the diameter of a red blood cell). Under light microscopy, intact platelets appear as round cells with smooth edges and red-violet granules (α-granules). The lifespan of platelets is on average 8-9 days. Normally they are discoid in shape, but when activated they take the shape of a sphere with a large number of cytoplasmic protrusions.

There are 3 types of specific granules in platelets:

• lysosomes containing large quantities of acid hydrolases and other enzymes;
• α-granules containing many different proteins (fibrinogen, von Willebrand factor, fibronectin, thrombospondin, etc.) and stained purple-red according to Romanovsky-Giemsa;
• δ-granules are dense granules containing large amounts of serotonin, K + ions, Ca 2+, Mg 2+, etc.

α-granules contain strictly specific platelet proteins, such as platelet factor 4 and β-thromboglobulin, which are markers of platelet activation; their determination in blood plasma can help in the diagnosis of ongoing thrombosis.

In addition, the structure of platelets contains a system of dense tubes, which is like a depot for Ca 2+ ions, as well as a large number of mitochondria. When platelets are activated, a series of biochemical reactions occur, which, with the participation of cyclooxygenase and thromboxane synthetase, lead to the formation of thromboxane A 2 (TXA 2) from arachidonic acid, a powerful factor responsible for irreversible platelet aggregation.

The platelet is covered with a 3-layer membrane; on its outer surface there are various receptors, many of which are glycoproteins and interact with various proteins and compounds.

Platelet hemostasis

The glycoprotein Ia receptor binds to collagen, the glycoprotein Ib receptor interacts with von Willebrand factor, and glycoproteins IIb-IIIa interact with fibrinogen molecules, although it can bind to both von Willebrand factor and fibronectin.

When platelets are activated by agonists - ADP, collagen, thrombin, adrenaline, etc. - the 3rd lamellar factor (membrane phospholipid) appears on their outer membrane, activating the rate of blood clotting, increasing it 500-700 thousand times.

Plasma coagulation factors

Blood plasma contains several specific systems involved in the blood coagulation cascade. These are the systems:

• adhesion molecules,
• blood clotting factors,
• fibrinolysis factors,
• factors of physiological primary and secondary anticoagulants-antiproteases,
• factors of physiological primary reparative-healing agents.

Plasma Adhesive Molecule System

The system of plasma adhesive molecules is a complex of glycoproteins responsible for intercellular, cell-substrate and cell-protein interactions. These include:

1. von Willebrand factor,
2. fibrinogen,
3. fibronectin,
4. thrombospondin,
5. vitronectin.

von Willebrand factor

Von Willebrand factor is a high molecular weight glycoprotein with a molecular weight of 10 3 kDa or more. The von Willebrand factor performs many functions, but the main ones are two:

• interaction with factor VIII, due to which antihemophilic globulin is protected from proteolysis, which increases its life expectancy;
• ensuring the processes of adhesion and aggregation of platelets in the circulatory system, especially at high blood flow rates in the vessels of the arterial system.

A decrease in von Willebrand factor levels below 50%, as observed in von Willebrand disease or syndrome, results in severe petechial bleeding, usually of the microcirculatory type, manifested by bruising in minor injuries. However, in severe von Willebrand disease, a hematoma type of bleeding, similar to hemophilia, may be observed ().

On the contrary, a significant increase in the concentration of von Willebrand factor (more than 150%) can lead to a thrombophilic state, which is often clinically manifested by various types of thrombosis of peripheral veins, myocardial infarction, thrombosis of the pulmonary artery system or cerebral vessels.

Fibrinogen - factor I

Fibrinogen, or factor I, is involved in many cell-cell interactions. Its main functions are participation in the formation of a fibrin thrombus (thrombus reinforcement) and the process of platelet aggregation (attachment of one platelet to another) thanks to specific platelet receptors of glycoproteins IIb-IIIa.

Plasma fibronectin

Plasma fibronectin is an adhesive glycoprotein that interacts with various blood clotting factors. Also, one of the functions of plasma fibronectin is the repair of vascular and tissue defects. It has been shown that the application of fibronectin to areas of tissue defects (trophic ulcers of the cornea, erosions and ulcers of the skin) helps stimulate reparative processes and faster healing.

The normal concentration of plasma fibronectin in the blood is about 300 mcg/ml. In severe injuries, massive blood loss, burns, prolonged abdominal operations, sepsis, acute disseminated intravascular coagulation syndrome, the level of fibronectin drops as a result of consumption, which reduces the phagocytic activity of the macrophage system. This may explain the high incidence of infectious complications in people who have suffered massive blood loss, and the advisability of prescribing transfusions of cryoprecipitate or fresh frozen plasma containing large amounts of fibronectin to patients.

Thrombospondin

The main functions of thrombospondin are to ensure complete platelet aggregation and bind them to monocytes.

Vitronectin

Vitronectin, or glass binding protein, is involved in several processes. In particular, it binds the AT III-thrombin complex and subsequently removes it from the circulation through the macrophage system. In addition, vitronectin blocks the cell-lytic activity of the final cascade of complement system factors (C 5 -C 9 complex), thereby preventing the implementation of the cytolytic effect of activation of the complement system.

Clotting factors

The system of plasma coagulation factors is a complex multifactorial complex, the activation of which leads to the formation of a persistent fibrin clot. It plays a major role in stopping bleeding in all cases of damage to the integrity of the vascular wall.

Fibrinolysis system

The fibrinolysis system is the most important system that prevents uncontrolled blood clotting. Activation of the fibrinolysis system is realized by an internal or external mechanism.

Internal activation mechanism

The internal mechanism of fibrinolysis activation begins with the activation of plasma factor XII (Hageman factor) with the participation of high molecular weight kininogen and the kallikrein-kinin system. As a result, plasminogen transforms into plasmin, which splits fibrin molecules into small fragments (X, Y, D, E), which are opsonized by plasma fibronectum.

External activation mechanism

The external pathway of activation of the fibrinolytic system can be carried out by streptokinase, urokinase, or tissue plasminogen activator. The external pathway of activation of fibrinolysis is often used in clinical practice to lyse acute thrombosis of various locations (pulmonary embolism, acute myocardial infarction, etc.).

System of primary and secondary anticoagulants-antiproteases

A system of physiological primary and secondary anticoagulants-antiproteases exists in the human body to inactivate various proteases, plasma coagulation factors and many components of the fibrinolytic system.

Primary anticoagulants include a system including heparin, AT III and CG II. This system predominantly inhibits thrombin, factor Xa and a number of other factors of the blood coagulation system.

The protein C system, as already noted, inhibits plasma coagulation factors Va and VIIIa, which ultimately inhibits blood coagulation by an internal mechanism.

The tissue thromboplastin inhibitor system and heparin inhibit the extrinsic pathway of blood coagulation activation, namely the TF-VII factor complex. Heparin in this system plays the role of an activator of the production and release into the bloodstream of an inhibitor of tissue thromboplastin from the endothelium of the vascular wall.

PAI-1 (tissue plasminogen activator inhibitor) is the primary antiprotease that inactivates tissue plasminogen activator activity.

Physiological secondary anticoagulants-antiproteases include components whose concentration increases during blood clotting. One of the main secondary anticoagulants is fibrin (antithrombin I). It actively sorbs on its surface and inactivates free thrombin molecules circulating in the bloodstream. Derivatives of factors Va and VIIIa can also inactivate thrombin. In addition, thrombin in the blood is inactivated by circulating molecules of soluble glycocalycin, which are remnants of the platelet receptor glycoprotein Ib. Glycocalycin contains a certain sequence - a “trap” for thrombin. The participation of soluble glycocalycin in the inactivation of circulating thrombin molecules makes it possible to achieve self-limitation of thrombus formation.

System of primary reparative-healers

Blood plasma contains certain factors that promote the processes of healing and repair of vascular and tissue defects - the so-called physiological system of primary healing agents. This system includes:

• plasma fibronectin,
• fibrinogen and its derivative fibrin,
• transglutaminase or blood coagulation factor XIII,
• thrombin,
• platelet growth factor - thrombopoietin.

The role and significance of each of these factors separately has already been discussed.

Blood clotting mechanism

There are internal and external mechanisms of blood coagulation.

Intrinsic blood clotting pathway

The internal mechanism of blood clotting involves factors found in the blood under normal conditions.

Along the internal pathway, the blood coagulation process begins with contact or protease activation of factor XII (or Hageman factor) with the participation of high molecular weight kininogen and the kallikrein-kinin system.

Factor XII turns into XIIa (activated) factor, which activates factor XI (the precursor of plasma thromboplastin), converting it into factor XIa.

The latter activates factor IX (antihemophilic factor B, or Christmas factor), converting it, with the participation of factor VIIIa (antihemophilic factor A), into factor IXa. Ca 2+ ions and platelet factor 3 are involved in the activation of factor IX.

The complex of factors IXa and VIIIa with Ca 2+ ions and platelet factor 3 activates factor X (Stewart factor), converting it into factor Xa. Factor Va (proaccelerin) also takes part in the activation of factor X.

The complex of factors Xa, Va, Ca ions (IV factor) and platelet factor 3 is called prothrombinase; it activates prothrombin (or factor II), converting it into thrombin.

The latter breaks down fibrinogen molecules, converting it into fibrin.

Fibrin from a soluble form under the influence of factor XIIIa (fibrin-stabilizing factor) is converted into insoluble fibrin, which directly reinforces (strengthens) the platelet thrombus.

Extrinsic blood clotting pathway

The external mechanism of blood coagulation occurs when tissue thromboplastin (or tissue factor III) enters the circulation from tissues.

Tissue thromboplastin binds to factor VII (proconvertin), converting it to factor VIIa.

The latter activates the X factor, transforming it into the Xa factor.

Further transformations of the coagulation cascade are the same as during activation of plasma coagulation factors by the internal mechanism.

The mechanism of blood clotting briefly

In general, the blood coagulation mechanism can be briefly represented as a series of successive stages:

1. as a result of disruption of normal blood flow and damage to the integrity of the vascular wall, an endothelial defect develops;
2. von Willebrand factor and plasma fibronectin adhere to the exposed basement membrane of the endothelium (collagen, laminin);
3. circulating platelets also adhere to basement membrane collagen and laminin, and then to von Willebrand factor and fibronectin;
4. platelet adhesion and aggregation lead to the appearance of the 3rd lamellar factor on their outer surface membrane;
5. with the direct participation of the 3rd lamellar factor, plasma coagulation factors are activated, which leads to the formation of fibrin in the platelet thrombus - the reinforcement of the thrombus begins;
6. the fibrinolysis system is activated both internally (through factor XII, high-molecular kininogen and the kallikrein-kinin system) and externally (under the influence of tPA) mechanisms, stopping further thrombus formation; in this case, not only lysis of blood clots occurs, but also the formation of a large amount of fibrin degradation products (FDP), which in turn block pathological thrombus formation, having fibrinolytic activity;
7. reparation and healing of the vascular defect begins under the influence of physiological factors of the reparative-healing system (plasma fibronectin, transglutaminase, thrombopoietin, etc.).

In acute massive blood loss complicated by shock, the balance in the hemostatic system, namely between the mechanisms of thrombus formation and fibrinolysis, is quickly disrupted, since consumption significantly exceeds production. The developing depletion of blood coagulation mechanisms is one of the links in the development of acute disseminated intravascular coagulation syndrome.

Blood clotting

Blood coagulation is the most important stage of the hemostasis system, which is responsible for stopping bleeding when the vascular system of the body is damaged. Blood coagulation is preceded by the stage of primary vascular-platelet hemostasis. This primary hemostasis is almost entirely due to vasoconstriction and mechanical occlusion of platelet aggregates at the site of damage to the vascular wall. The characteristic time for primary hemostasis in a healthy person is 1-3 minutes. Blood coagulation (hemocoagulation, coagulation, plasma hemostasis, secondary hemostasis) is a complex biological process of formation of fibrin protein threads in the blood, which polymerizes and forms blood clots, as a result of which the blood loses its fluidity, acquiring a cheesy consistency. Blood clotting in a healthy person occurs locally, at the site of formation of the primary platelet plug. The characteristic time for the formation of a fibrin clot is about 10 minutes.

Physiology

A fibrin clot produced by adding thrombin to whole blood. Scanning electron microscopy.

The process of hemostasis comes down to the formation of a platelet-fibrin clot. It is conventionally divided into three stages:

1. Temporary (primary) vasospasm;
2. Formation of a platelet plug due to adhesion and aggregation of platelets;
3. Retraction (contraction and compaction) of the platelet plug.

Vascular damage is accompanied by immediate activation of platelets. Adhesion (sticking) of platelets to connective tissue fibers at the edges of the wound is caused by the glycoprotein von Willebrand factor. Simultaneously with adhesion, platelet aggregation occurs: activated platelets attach to damaged tissues and to each other, forming aggregates that block the path to blood loss. A platelet plug appears
From platelets that have undergone adhesion and aggregation, various biologically active substances (ADP, adrenaline, norepinephrine, etc.) are intensely secreted, which lead to secondary, irreversible aggregation. Simultaneously with the release of platelet factors, thrombin is formed, which acts on fibrinogen to form a fibrin network in which individual red and white blood cells get stuck - a so-called platelet-fibrin clot (platelet plug) is formed. Thanks to the contractile protein thrombostenine, platelets are pulled towards each other, the platelet plug contracts and thickens, and its retraction occurs.

Blood clotting process

Classic blood coagulation scheme according to Morawitz (1905)

The process of blood coagulation is predominantly a proenzyme-enzyme cascade in which proenzymes, passing into an active state, acquire the ability to activate other blood coagulation factors. In its simplest form, the blood clotting process can be divided into three phases:

1. the activation phase includes a complex of sequential reactions leading to the formation of prothrombinase and the transition of prothrombin to thrombin;
2. coagulation phase - formation of fibrin from fibrinogen;
3. retraction phase - formation of a dense fibrin clot.

This scheme was described back in 1905 by Morawitz and has not yet lost its relevance.

There has been significant progress in the detailed understanding of blood clotting since 1905. Dozens of new proteins and reactions involved in the blood coagulation process, which has a cascade nature, have been discovered. The complexity of this system is due to the need to regulate this process. A modern representation of the cascade of reactions accompanying blood coagulation is shown in Fig. 2 and 3. Due to the destruction of tissue cells and activation of platelets, phospholipoprotein proteins are released, which, together with plasma factors X a and Va, as well as Ca 2+ ions, form an enzyme complex that activates prothrombin. If the coagulation process begins under the influence of phospholipoproteins released from cells of damaged vessels or connective tissue, we are talking about external blood coagulation system(extrinsic coagulation activation pathway, or tissue factor pathway). The main components of this pathway are 2 proteins: factor VIIa and tissue factor, the complex of these 2 proteins is also called the extrinsic tenase complex.
If initiation occurs under the influence of coagulation factors present in the plasma, the term is used internal coagulation system. The complex of factors IXa and VIIIa that forms on the surface of activated platelets is called intrinsic tenase. Thus, factor X can be activated by both the VIIa-TF complex (extrinsic tenase) and the IXa-VIIIa complex (intrinsic tenase). The external and internal blood coagulation systems complement each other.
During the process of adhesion, the shape of platelets changes - they become rounded cells with spiny processes. Under the influence of ADP (partially released from damaged cells) and adrenaline, the ability of platelets to aggregate increases. At the same time, serotonin, catecholamines and a number of other substances are released from them. Under their influence, the lumen of damaged vessels narrows, and functional ischemia occurs. Eventually the vessels become occluded by a mass of platelets adhering to the edges of the collagen fibers at the edges of the wound.
At this stage of hemostasis, thrombin is formed under the influence of tissue thromboplastin. It is he who initiates irreversible platelet aggregation. By reacting with specific receptors in the platelet membrane, thrombin causes phosphorylation of intracellular proteins and the release of Ca 2+ ions.
In the presence of calcium ions in the blood, under the influence of thrombin, polymerization of soluble fibrinogen occurs (see fibrin) and the formation of a structureless network of insoluble fibrin fibers. Starting from this moment, the formed elements of blood begin to be filtered in these threads, creating additional rigidity for the entire system, and after some time forming a platelet-fibrin clot (physiological thrombus), which clogs the rupture site, on the one hand, preventing blood loss, and on the other - blocking the entry of external substances and microorganisms into the blood. Blood clotting is affected by many conditions. For example, cations speed up the process, and anions slow it down. In addition, there are substances that completely block blood clotting (heparin, hirudin, etc.) and those that activate it (viper poison, feracryl).
Congenital disorders of the blood clotting system are called hemophilia.

Methods for diagnosing blood clotting

The whole variety of clinical tests of the blood coagulation system can be divided into 2 groups: global (integral, general) tests and “local” (specific) tests. Global tests characterize the result of the entire coagulation cascade. They are suitable for diagnosing the general condition of the blood coagulation system and the severity of pathologies, while simultaneously taking into account all the influencing factors. Global methods play a key role at the first stage of diagnosis: they provide an integral picture of the changes occurring in the coagulation system and make it possible to predict the tendency to hyper- or hypocoagulation in general. “Local” tests characterize the result of the work of individual parts of the cascade of the blood coagulation system, as well as individual coagulation factors. They are indispensable for possible clarification of the localization of pathology with an accuracy of the coagulation factor. To obtain a complete picture of the patient's hemostasis, the doctor must be able to choose which test he needs.
Global tests:

• Determination of clotting time of whole blood (Mas-Magro method or Morawitz method)
• Thrombin generation test (thrombin potential, endogenous thrombin potential)

"Local" tests:

• Activated partial thromboplastin time (aPTT)
• Prothrombin time test (or Prothrombin test, INR, PT)
• Highly specialized methods for identifying changes in the concentration of individual factors

All methods that measure the time interval from the moment of adding a reagent (an activator that starts the coagulation process) until the formation of a fibrin clot in the plasma under study belong to clotting methods (from the English “clot” - clot).

see also

Notes

Links

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Baseball at the 1996 Summer Olympics - BLOOD CLOTTING, the transformation of liquid blood into an elastic clot as a result of the transition of the fibrinogen protein dissolved in the blood plasma into insoluble fibrin; a protective reaction of the body that prevents blood loss when blood vessels are damaged. Time… …

Modern encyclopedia BLOOD CLOTTING - transformation of liquid blood into an elastic clot as a result of the transition of fibrinogen dissolved in blood plasma into insoluble fibrin; a protective reaction of animals and humans that prevents blood loss when the integrity of blood vessels is violated...

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Modern encyclopedia- blood coagulation, the transition of blood from a liquid state to a gelatinous clot. This property of blood (clotting) is a protective reaction that prevents the body from blood loss. S. to. proceeds as a sequence of biochemical reactions,... ... Veterinary encyclopedic dictionary

Modern encyclopedia- transformation of liquid blood into an elastic clot as a result of the transition of the fibrinogen protein dissolved in the blood plasma into insoluble fibrin when blood flows from a damaged vessel. Fibrin, polymerizing, forms thin threads that hold... ... Natural science. encyclopedic Dictionary

Clotting factors- Scheme of interaction of coagulation factors during activation of hemocoagulation. Blood coagulation factors are a group of substances contained in blood plasma and platelets and providing ... Wikipedia

Blood clotting- Blood coagulation (hemocoagulation, part of hemostasis) is a complex biological process of the formation of fibrin protein filaments in the blood, forming blood clots, as a result of which the blood loses its fluidity, acquiring a cheesy consistency. In good condition... ... Wikipedia

Table of contents of the topic "Eosinophils. Monocytes. Thrombocytes. Hemostasis. Blood coagulation system. Anticoagulation system.":
1. Eosinophils. Functions of eosinophils. Functions of eosinophilic leukocytes. Eosinophilia.
2. Monocytes. Macrophages. Functions of monocytes - macrophages. Normal number of monocytes - macrophages.
3. Regulation of granulocytopoiesis and monocytopoiesis. Granulocyte colony-stimulating factors. Keylons.
4. Platelets. Platelet structure. Functions of platelets. Functions of glycoproteins. Zone of sol - gel of hyaloplasm.
5. Thrombocytopoiesis. Regulation of thrombocytopoiesis. Thrombopoietin (thrombocytopoietin). Megakaryocytes. Thrombocytopenia.
6. Hemostasis. Mechanisms of blood clotting. Platelet hemostasis. Platelet reaction. Primary hemostasis.
7. Blood coagulation system. Extrinsic pathway for activation of blood coagulation. Blood clotting factors.

9. Anticoagulant blood system. Anticoagulant mechanisms of blood. Antithrombin. Heparin. Proteins. Prostacyclin. Thrombomodulin.
10. Tissue plasminogen activator. Ectoenzymes. The role of the endothelium in the anticoagulant system. Tissue factor. Plasminogen activator inhibitor. von Willebrand factor. Anticoagulants.

Destruction of platelets and red blood cells or contact of these cells with the subendothelium of the damaged vessel activates factor XII. Factor XIIa (a-activated), interacting with high molecular weight plasma kininogen, converts factor XI into factor XIa. The reaction is accelerated by plasma prekallikrein. XIa activates factor IX (plasma thromboplastin), the resulting factor IXa forms a complex: “factor IXa + factor VIII (antihemophilic factor) + platelet phospholipid (platelet factor 3) + calcium ions.”
This complex activates factor X. Factors Xa and Va, interacting with the phospholipid surface of the cell in the presence of Ca 2+, form a new complex called blood prothrombinase, which converts prothrombin into thrombin. Platelet factor 3 plays a special role in increasing prothrombinase activity. Its absence reduces prothrombinase activity by 1000 times!

Blood contains non-enzymatic proteins- accelerators or factors V and VII, which, when interacting with the phospholipid surfaces of platelets and areas of the membranes of other damaged cells, accelerate the blood coagulation reaction many thousands of times. Platelet factor III deficiency leads to hemorrhagic diathesis, factor IX deficiency causes hemophilia B, and factor VIII deficiency causes hemophilia A.

Rice. 7.9. The sequence of formation and fixation of a blood clot with the help of plasma coagulation factors during the “internal” pathway of blood coagulation activation. Time indicates the duration of the process after blood contacts the subendothelium.

Factor VIII circulates in the blood, being bound to its carrier protein - von Willebrand factor. The latter stabilizes the factor VIII molecule, increases its life span inside the vessel and promotes the transfer of factor VIII to the site of vessel damage. Activated factor VIII can exert its effect only by detaching from the carrier protein. This “operation” with the factor VIII - von Willebrand factor complex occurs under the influence of thrombin, trace amounts of which are constantly formed in the blood as a consequence of the destruction of aging blood cells.

Extrinsic pathway of blood coagulation activation takes about 15 s, and interior- 2-10 min. Both of them culminate in the conversion of prothrombin to thrombin. Prothrombin is synthesized in the liver; for its formation, as well as for the formation of factors IX, X, VII and II, vitamin K is required, which enters the body with food, is deposited in the liver and activates the synthesis of the above blood clotting factors in it. Therefore, liver damage or vitamin K deficiency occurring in the body are accompanied by bleeding. The amount of thrombin formed during the activation of blood coagulation is directly proportional to the number of complexes that activate it.

Thrombin- an active proteolytic enzyme that cleaves 4 monomer peptides from the fibrinogen molecule. Each monomer has 4 free bonds. By connecting them to each other: end to end, side to side, the monomers form a network of fibrin fibers within a few seconds. Under the influence of the fibrin-stabilizing factor (factor XIII), additional disulfide bonds are formed in fibrin, and the network of fibrin fibers becomes strong. Platelets, leukocytes, red blood cells and plasma proteins are retained in this network, forming a fibrin thrombus.

After the formation of a clot, its contraction begins after 30-60 minutes, or retraction. Retraction occurs due to contraction of platelet actin and myosin filaments, as well as fibrin filaments under the influence of thrombin and Ca2+ ions. As a result fibrin clot retraction compresses into a dense mass, the thrombus becomes denser and becomes impermeable to both cells and blood plasma. The continuation of blood coagulation in the bloodstream after the formation of a fibrin thrombus is prevented by the anticoagulation system of the blood.

There are three main stages of hemocoagulation:

1. formation of blood thromboplastin and tissue thromboplastin;

2. formation of thrombin;

3. formation of a fibrin clot.

There are 2 mechanisms of hemocoagulation: internal coagulation mechanism(factors located inside the vascular bed are involved) and extrinsic coagulation mechanism(in addition to intravascular factors, external factors also participate in it).

Internal blood coagulation mechanism (contact)

The internal mechanism of hemocoagulation is triggered when the vascular endothelium is damaged (for example, with atherosclerosis, under the influence of high doses of catecholamines) in which collagen and phospholipids are present. Factor XII (trigger factor) is attached to the changed area of ​​the endothelium. Interacting with the altered endothelium, it undergoes conformational structural changes and becomes a very powerful active proteolytic enzyme. Factor XIIa simultaneously participates in the coagulation system, the anticoagulation system, and the kinin system:

1. activates the blood coagulation system;
2. activates the anticoagulation system;
3. activates platelet aggregation;
4. activates the kinin system;

Stage 1 internal mechanism of blood coagulation - formation of complete blood thromboplastin.

Factor XII, in contact with damaged endothelium, becomes active XII. XIIa activates prekallikrein (XIY), which activates kininogen (XY). Kinins, in turn, increase the activity of factor XII.

Factor XII activates factor XI, which then activates factor IX (Christmas factor). Factor IXa interacts with factor YIII and calcium ions. As a result, a complex is formed that includes an enzyme, coenzyme, and calcium ions (phase IXa, phase YIII, Ca 2+). This complex activates factor X with the participation of platelet factor P 3 . As a result, active blood thromboplastin, including f.Xa, f.Y, Ca 2+ and P 3 .

P 3 - is a fragment of platelet membranes, contains lipoproteins, and is rich in phospholipids.

Stage 2 – thrombin formation.

Active blood thromboplastin triggers stage 2 of blood coagulation, activating the transition of prothrombin to thrombin (phase II → phase II a). Thrombin activates the external and internal mechanisms of hemocoagulation, as well as the anticoagulation system, platelet aggregation and the release of platelet factors.

Active thrombin triggers stage 3 of blood clotting.

Stage 3 is formation of insoluble fibrin(I factor). Under the influence of thrombin, soluble fibrinogen is successively converted into fibrin monomer, and then into insoluble fibrin polymer.

Fibrinogen is a water-soluble protein that consists of 6 polypeptide chains, including 3 domains. Under the influence of thrombin, peptides A and B are cleaved from fibrinogen, and aggregation sites are formed in it. Fibrin threads are first connected into linear chains, and then covalent interchain cross-links are formed. Factor XIIIa (fibrin stabilizing), which is activated by thrombin, is involved in their formation. Under the influence of factor XIIIa, which is a transamidinase enzyme, bonds between glutamine and lysine appear in fibrin during its polymerization.

The essence and significance of blood coagulation.

If the blood released from the blood vessel is left for some time, then from the liquid it first turns into jelly, and then a more or less dense clot is organized in the blood, which, by contracting, squeezes out a liquid called blood serum. This is plasma devoid of fibrin. The described process is called blood clotting (by hemocoagulation). Its essence lies in the fact that the fibrinogen protein dissolved in plasma under certain conditions becomes insoluble and precipitates in the form of long fibrin filaments. In the cells of these threads, as in a mesh, cells get stuck and the colloidal state of the blood as a whole changes. The significance of this process is that coagulated blood does not flow out of the wounded vessel, preventing the body from dying from blood loss.

Blood coagulation system. Enzymatic theory of coagulation.

The first theory explaining the process of blood clotting by the work of special enzymes was developed in 1902 by the Russian scientist Schmidt. He believed that coagulation occurs in two phases. First, one of the plasma proteins prothrombin under the influence of enzymes released from blood cells destroyed during injury, especially platelets ( thrombokinase) And Ca ions goes into enzyme thrombin. At the second stage, under the influence of the enzyme thrombin, fibrinogen dissolved in the blood is converted into insoluble fibrin, which causes the blood to clot. In the last years of his life, Schmidt began to distinguish 3 phases in the process of hemocoagulation: 1- formation of thrombokinase, 2- formation of thrombin. 3- formation of fibrin.

Further study of the coagulation mechanisms showed that this representation is very schematic and does not fully reflect the entire process. The main thing is that there is no active thrombokinase in the body, i.e. an enzyme capable of converting prothrombin into thrombin (according to the new nomenclature of enzymes, this should be called prothrombinase). It turned out that the process of prothrombinase formation is very complex; a number of so-called proteins are involved in it. thrombogenic enzyme proteins, or thrombogenic factors, which, interacting in a cascade process, are all necessary for blood clotting to occur normally. In addition, it was discovered that the coagulation process does not end with the formation of fibrin, because its destruction begins at the same time. Thus, the modern blood coagulation scheme is much more complicated than Schmidt’s.

The modern blood coagulation scheme includes 5 phases, successively replacing each other. These phases are as follows:

1. Formation of prothrombinase.

2. Thrombin formation.

3. Fibrin formation.

4. Fibrin polymerization and clot organization.

5. Fibrinolysis.

Over the past 50 years, many substances involved in blood clotting have been discovered, proteins, the absence of which in the body leads to hemophilia (inability to clot blood). Having considered all these substances, the international conference of hemocoagulologists decided to designate all plasma coagulation factors in Roman numerals, and cellular coagulation factors in Arabic numerals. This was done in order to eliminate confusion in names. And now in any country, after the generally accepted name of the factor (they can be different), the number of this factor according to the international nomenclature must be indicated. In order for us to consider the folding pattern further, let us first give a brief description of these factors.

A. Plasma clotting factors .

I. Fibrin and fibrinogen . Fibrin is the end product of the blood clotting reaction. The coagulation of fibrinogen, which is its biological feature, occurs not only under the influence of a specific enzyme - thrombin, but can be caused by the venoms of some snakes, papain and other chemicals. Plasma contains 2-4 g/l. Place of formation: reticuloendothelial system, liver, bone marrow.

II. Thrombin and prothrombin . Only traces of thrombin are normally found in circulating blood. Its molecular weight is half the molecular weight of prothrombin and is equal to 30 thousand. The inactive precursor of thrombin - prothrombin - is always present in the circulating blood. This is a glycoprotein consisting of 18 amino acids. Some researchers believe that prothrombin is a complex compound of thrombin and heparin. Whole blood contains 15-20 mg% prothrombin. This content in excess is enough to convert all fibrinogen in the blood into fibrin.

The level of prothrombin in the blood is a relatively constant value. Among the factors that cause fluctuations in this level, menstruation (increases) and acidosis (decreases) should be pointed out. Taking 40% alcohol increases the prothrombin content by 65-175% after 0.5-1 hour, which explains the tendency to thrombosis in people who regularly drink alcohol.

In the body, prothrombin is constantly used and synthesized at the same time. Antihemorrhagic vitamin K plays an important role in its formation in the liver. It stimulates the activity of liver cells that synthesize prothrombin.

III. Thromboplastin . This factor is not present in active form in the blood. It is formed when blood cells and tissues are damaged and can be, respectively, blood, tissue, erythrocyte, platelet. Its structure is a phospholipid, similar to the phospholipids of cell membranes. According to thromboplastic activity, tissues of various organs are arranged in descending order: lungs, muscles, heart, kidneys, spleen, brain, liver. Sources of thromboplastin are also human milk and amniotic fluid. Thromboplastin is involved as an essential component in the first phase of blood coagulation.

IV. Ionized calcium, Ca++. The role of calcium in the process of blood clotting was known to Schmidt. It was then that they were offered sodium citrate as a blood preservative - a solution that bound Ca++ ions in the blood and prevented its clotting. Calcium is necessary not only for the conversion of prothrombin to thrombin, but for other intermediate stages of hemostasis, in all phases of coagulation. The content of calcium ions in the blood is 9-12 mg%.

V and VI. Proaccelerin and accelerin (AS-globulin ). Formed in the liver. Participates in the first and second phases of coagulation, while the amount of proaccelerin decreases and accelerin increases. Essentially V is a precursor to factor VI. Activated by thrombin and Ca++. It is an accelerator (accelerator) of many enzymatic coagulation reactions.

VII. Proconvertin and convertin . This factor is a protein found in the beta globulin fraction of normal plasma or serum. Activates tissue prothrombinase. Vitamin K is required for the synthesis of proconvertin in the liver. The enzyme itself becomes active upon contact with damaged tissues.

VIII. Antihemophilic globulin A (AGG-A). Participates in the formation of blood prothrombinase. Capable of providing clotting of blood that has not had contact with tissues. The absence of this protein in the blood causes the development of genetically determined hemophilia. It has now been obtained in dry form and is used in the clinic for its treatment.

IX. Antihemophilic globulin B (AGG-B, Christmas factor , plasma component of thromboplastin). Participates in the coagulation process as a catalyst, and is also part of the blood thromboplastic complex. Promotes activation of X factor.

X. Koller factor, Steward-Prower factor . The biological role is reduced to participation in the formation of prothrombinase, since it is its main component. When rolled up it is disposed of. Named (like all other factors) after the names of patients in whom a form of hemophilia was first discovered, associated with the absence of the specified factor in their blood.

XI. Rosenthal factor, plasma thromboplastin precursor (PPT) ). Participates as an accelerator in the formation of active prothrombinase. Refers to beta globulins in the blood. Reacts in the first stages of phase 1. Formed in the liver with the participation of vitamin K.

XII. Contact factor, Hageman factor . Plays the role of a trigger in blood clotting. Contact of this globulin with a foreign surface (roughness of the vessel wall, damaged cells, etc.) leads to activation of the factor and initiates the entire chain of coagulation processes. The factor itself is adsorbed on the damaged surface and does not enter the bloodstream, thereby preventing the generalization of the coagulation process. Under the influence of adrenaline (under stress), it is partially able to activate directly in the bloodstream.

XIII. Fibrin stabilizer Lucky-Loranda . Necessary for the formation of terminally insoluble fibrin. This is a transpeptidase that cross-links individual fibrin strands with peptide bonds, promoting its polymerization. Activated by thrombin and Ca++. In addition to plasma, it is found in formed elements and tissues.

The 13 factors described are the generally accepted basic components necessary for the normal blood clotting process. The various forms of bleeding caused by their absence belong to different types of hemophilia.

B. Cellular coagulation factors.

Along with plasma factors, cellular factors released from blood cells also play a primary role in blood coagulation. Most of them are found in platelets, but they are also found in other cells. It’s just that during hemocoagulation, platelets are destroyed in greater quantities than, say, erythrocytes or leukocytes, so platelet factors are of greatest importance in coagulation. These include:

1f. AC platelet globulin . Similar to V-VI blood factors, performs the same functions, accelerating the formation of prothrombinase.

2f. Thrombin accelerator . Accelerates the action of thrombin.

3f. Thromboplastic or phospholipid factor . It is found in granules in an inactive state and can only be used after platelets have been destroyed. Activated upon contact with blood, necessary for the formation of prothrombinase.

4f. Antiheparin factor . Binds heparin and delays its anticoagulant effect.

5f. Platelet fibrinogen . Necessary for the aggregation of blood platelets, their viscous metamorphosis and the consolidation of the platelet plug. Found both inside and outside the platelet. promotes their gluing.

6f. Retractozyme . Provides compaction of the blood clot. Several substances are determined in its composition, for example thrombostenin + ATP + glucose.

7f. Antifibinosilin . Inhibits fibrinolysis.

8f. Serotonin . Vasoconstrictor. Exogenous factor, 90% is synthesized in the gastrointestinal mucosa, the remaining 10% in platelets and the central nervous system. Released from cells when they are destroyed, it promotes spasm of small vessels, thereby helping to prevent bleeding.

In total, up to 14 factors are found in platelets, such as antithromboplastin, fibrinase, plasminogen activator, AC globulin stabilizer, platelet aggregation factor, etc.

Other blood cells contain mainly these same factors, but normally they do not play a significant role in hemocoagulation.

WITH. Tissue coagulation factors

Participate in all phases. These include active thromboplastic factors like plasma factors III, VII, IX, XII, and XIII. Tissues contain activators of factors V and VI. There is a lot of heparin, especially in the lungs, prostate gland, and kidneys. There are also antiheparin substances. In inflammatory and cancerous diseases, their activity increases. There are many activators (kinins) and inhibitors of fibrinolysis in tissues. The substances contained in the vascular wall are especially important. All these compounds constantly flow from the walls of blood vessels into the blood and regulate coagulation. The tissues also ensure the removal of coagulation products from the vessels.

Modern hemostasis scheme.

Let us now try to combine all coagulation factors into one common system and analyze the modern hemostasis scheme.

The chain reaction of blood coagulation begins from the moment blood comes into contact with the rough surface of a wounded vessel or tissue. This causes activation of plasma thromboplastic factors and then the gradual formation of two prothrombinases, clearly different in their properties - blood and tissue - occurs.

However, before the chain reaction of prothrombinase formation ends, processes associated with the participation of platelets (the so-called vascular-platelet hemostasis). Due to their ability to adhesion, platelets stick to the damaged area of ​​the vessel, stick to each other, sticking together with platelet fibrinogen. All this leads to the formation of the so-called. lamellar thrombus (“Gayem’s platelet hemostatic nail”). Platelet adhesion occurs due to ADP released from the endothelium and erythrocytes. This process is activated by wall collagen, serotonin, factor XIII and contact activation products. At first (within 1-2 minutes) blood still passes through this loose plug, but then the so-called viscose degeneration of the blood clot, it thickens and the bleeding stops. It is clear that such an end to events is only possible when small vessels are injured, where blood pressure is not able to squeeze out this “nail”.

1st coagulation phase . During the first phase of coagulation, education phase prothrombinase, there are two processes that occur at different speeds and have different meanings. This is the process of formation of blood prothrombinase, and the process of formation of tissue prothrombinase. The duration of phase 1 is 3-4 minutes. however, the formation of tissue prothrombinase takes only 3-6 seconds. The amount of tissue prothrombinase produced is very small, it is not enough to convert prothrombin into thrombin, however, tissue prothrombinase acts as an activator of a number of factors necessary for the rapid formation of blood prothrombinase. In particular, tissue prothrombinase leads to the formation of a small amount of thrombin, which converts internal coagulation factors V and VIII into an active state. A cascade of reactions ending in the formation of tissue prothrombinase ( external mechanism of hemocoagulation), as follows:

1. Contact of destroyed tissues with blood and activation of factor III - thromboplastin.

2. III factor translates VII to VIIa(proconvertin to convertin).

3. A complex is formed (Ca++ + III + VIIIa)

4. This complex activates a small amount of X factor - X goes to Ha.

5. (Ha + III + Va + Ca) form a complex that has all the properties of tissue prothrombinase. The presence of Va (VI) is due to the fact that there are always traces of thrombin in the blood, which activates V factor.

6. The resulting small amount of tissue prothrombinase converts a small amount of prothrombin into thrombin.

7. Thrombin activates a sufficient amount of V and VIII factors necessary for the formation of blood prothrombinase.

If this cascade is turned off (for example, if, with all precautions using paraffin needles, you take blood from a vein, preventing its contact with tissues and with a rough surface, and place it in a paraffin tube), the blood clots very slowly, within 20-25 minutes or longer.

Well, normally, simultaneously with the process already described, another cascade of reactions associated with the action of plasma factors is launched, ending with the formation of blood prothrombinase in an amount sufficient to convert a large amount of prothrombin from thrombin. These reactions are as follows ( interior mechanism of hemocoagulation):

1. Contact with a rough or foreign surface leads to the activation of factor XII: XII - XIIa. At the same time, a Gayem hemostatic nail begins to form (vascular-platelet hemostasis).

2. Active factor XII converts factor XI into an active state and a new complex is formed XIIa + Ca++ + XIa+ III(f3)

3. Under the influence of the specified complex, factor IX is activated and a complex is formed IXa + Va + Ca++ +III(f3).

4. Under the influence of this complex, a significant amount of X factor is activated, after which the last complex of factors is formed in large quantities: Xa + Va + Ca++ + III(ph3), which is called blood prothrombinase.

This entire process normally takes about 4-5 minutes, after which the coagulation moves into the next phase.

Coagulation phase 2 - thrombin generation phase lies in the fact that under the influence of the enzyme prothrombinase, factor II (prothrombin) goes into an active state (IIa). This is a proteolytic process, the prothrombin molecule is split into two halves. The resulting thrombin goes to the implementation of the next phase, and is also used in the blood to activate more and more accelerin (V and VI factors). This is an example of a positive feedback system. The thrombin generation phase lasts several seconds.

3rd phase of coagulation - fibrin formation phase- also an enzymatic process, as a result of which a piece of several amino acids is split off from fibrinogen due to the action of the proteolytic enzyme thrombin, and the remainder is called fibrin monomer, which in its properties differs sharply from fibrinogen. In particular, it is capable of polymerization. This connection is designated as Im.

4 coagulation phase- fibrin polymerization and clot organization. It also has several stages. Initially, in a few seconds, under the influence of blood pH, temperature, and ionic composition of the plasma, long fibrin polymer filaments are formed Is which, however, is not yet very stable, since it can dissolve in urea solutions. Therefore, at the next stage, under the influence of the fibrin stabilizer Lucky-Loranda ( XIII factor) fibrin is finally stabilized and converted into fibrin Ij. It falls out of solution in the form of long threads that form a network in the blood, in the cells of which cells get stuck. Blood changes from a liquid state to a jelly-like state (coagulates). The next stage of this phase is the retraction (compaction) of the clot, which lasts quite a long time (several minutes), which occurs due to the contraction of fibrin threads under the influence of retractozyme (thrombostenin). As a result, the clot becomes dense, the serum is squeezed out of it, and the clot itself turns into a dense plug that blocks the vessel - a thrombus.

5 coagulation phase- fibrinolysis. Although it is not actually associated with the formation of a blood clot, it is considered the last phase of hemocoagulation, since during this phase the thrombus is limited to only the area where it is actually needed. If the thrombus has completely closed the lumen of the vessel, then during this phase this lumen is restored (there is thrombus recanalization). In practice, fibrinolysis always occurs in parallel with the formation of fibrin, preventing the generalization of coagulation and limiting the process. Fibrin dissolution is ensured by a proteolytic enzyme plasmin (fibrinolysin) which is contained in plasma in an inactive state in the form plasminogen (profibrinolysine). The transition of plasminogen to the active state is carried out by a special activator, which in turn is formed from inactive precursors ( proactivators), released from tissues, vessel walls, blood cells, especially platelets. In the processes of transferring proactivators and plasminogen activators into an active state, acid and alkaline blood phosphatases, cell trypsin, tissue lysokinases, kinins, environmental reaction, and factor XII play an important role. Plasmin breaks down fibrin into individual polypeptides, which are then utilized by the body.

Normally, a person’s blood begins to clot within 3-4 minutes after leaving the body. After 5-6 minutes it completely turns into a jelly-like clot. You will learn how to determine bleeding time, blood clotting rate and prothrombin time in practical classes. All of them have important clinical significance.

Coagulation inhibitors(anticoagulants). The constancy of blood as a liquid medium under physiological conditions is maintained by a set of inhibitors, or physiological anticoagulants, that block or neutralize the action of coagulants (clotting factors). Anticoagulants are normal components of the functional hemocoagulation system.

It has now been proven that there are a number of inhibitors for each blood coagulation factor, and, however, the most studied and of practical importance is heparin. Heparin- is a powerful brake on the conversion of prothrombin to thrombin. In addition, it affects the formation of thromboplastin and fibrin.

There is a lot of heparin in the liver, muscles and lungs, which explains the non-coagulability of blood in the small bleeding circle and the associated danger of pulmonary hemorrhages. In addition to heparin, several more natural anticoagulants with antithrombin action have been discovered; they are usually designated by ordinal Roman numerals:

I. Fibrin (because it absorbs thrombin during the coagulation process).

II. Heparin.

III. Natural antithrombins (phospholipoproteins).

IV. Antiprothrombin (preventing the conversion of prothrombin to thrombin).

V. Antithrombin in the blood of patients with rheumatism.

VI. Antithrombin resulting from fibrinolysis.

In addition to these physiological anticoagulants, many chemical substances of various origins have anticoagulant activity - dicoumarin, hirudin (from leech saliva), etc. These drugs are used clinically in the treatment of thrombosis.

Prevents blood clotting and fibrinolytic blood system. According to modern ideas, it consists of profibrinolysin (plasminogen), proactivator and plasma and tissue systems plasminogen activators. Under the influence of activators, plasminogen transforms into plasmin, which dissolves the fibrin clot.

Under natural conditions, the fibrinolytic activity of the blood depends on the plasminogen depot, the plasma activator, on the conditions that ensure activation processes, and on the entry of these substances into the blood. Spontaneous activity of plasminogen in a healthy body is observed during a state of excitement, after an injection of adrenaline, during physical stress and in conditions associated with shock. Among artificial blockers of fibrinolytic activity of the blood, gamma aminocaproic acid (GABA) occupies a special place. Normally, plasma contains an amount of plasmin inhibitors that is 10 times greater than the level of plasminogen reserves in the blood.

The state of hemocoagulation processes and the relative constancy or dynamic balance of coagulation and anticoagulation factors is associated with the functional state of the organs of the hemocoagulation system (bone marrow, liver, spleen, lungs, vascular wall). The activity of the latter, and consequently the state of the hemocoagulation process, is regulated by neurohumoral mechanisms. Blood vessels have special receptors that sense the concentration of thrombin and plasmin. These two substances program the activity of these systems.

Regulation of hemocoagulation and antigoagulation processes.

Reflex influences. Painful irritation occupies an important place among the many irritants that affect the body. Pain leads to changes in the activity of almost all organs and systems, including the coagulation system. Short-term or long-term painful stimulation leads to an acceleration of blood clotting, accompanied by thrombocytosis. Adding a feeling of fear to the pain leads to an even more dramatic acceleration of coagulation. Painful stimulation applied to the anesthetized area of ​​skin does not accelerate coagulation. This effect is observed from the first day of birth.

The duration of painful stimulation is of great importance. With short-term pain, the changes are less pronounced and the return to normal occurs 2-3 times faster than with prolonged irritation. This gives reason to believe that in the first case only the reflex mechanism takes part, and with prolonged painful stimulation the humoral link is also activated, determining the duration of the onset of changes. Most scientists believe that adrenaline is such a humoral link during painful stimulation.

Significant acceleration of blood clotting occurs reflexively also when the body is exposed to heat and cold. After the cessation of thermal irritation, the recovery period to the initial level is 6-8 times shorter than after cold irritation.

Blood coagulation is a component of the indicative reaction. A change in the external environment, the unexpected appearance of a new stimulus, causes an indicative reaction and at the same time an acceleration of blood clotting, which is a biologically expedient protective reaction.

Influence of the autonomic nervous system. When the sympathetic nerves are stimulated or after an injection of adrenaline, coagulation is accelerated. Irritation of the parasympathetic part of the NS leads to a slowdown in coagulation. It has been shown that the autonomic nervous system influences the biosynthesis of procoagulants and anticoagulants in the liver. There is every reason to believe that the influence of the sympathetic-adrenal system extends mainly to blood clotting factors, and the parasympathetic system - mainly to factors that prevent blood clotting. During the period of stopping bleeding, both sections of the ANS act synergistically. Their interaction is primarily aimed at stopping bleeding, which is vital. Subsequently, after reliable stopping of bleeding, the tone of the parasympathetic nervous system increases, which leads to an increase in anticoagulant activity, which is so important for the prevention of intravascular thrombosis.

Endocrine system and coagulation. Endocrine glands are an important active link in the mechanism for regulating blood coagulation. Under the influence of hormones, blood clotting processes undergo a number of changes, and hemocoagulation either accelerates or slows down. If we group hormones according to their effect on blood coagulation, then accelerating coagulation will include ACTH, STH, adrenaline, cortisone, testosterone, progesterone, extracts of the posterior lobe of the pituitary gland, pineal gland and thymus gland; Thyroid-stimulating hormone, thyroxine and estrogens slow down coagulation.

In all adaptive reactions, especially those occurring with the mobilization of the body's defenses, in maintaining the relative constancy of the internal environment in general and the blood coagulation system in particular, the pituitary-anrenal system is the most important link in the neurohumoral regulatory mechanism.

There is a significant amount of evidence indicating the influence of the cerebral cortex on blood coagulation. Thus, blood coagulation changes when the cerebral hemispheres are damaged, during shock, anesthesia, or an epileptic seizure. Of particular interest are changes in the rate of blood clotting in hypnosis, when a person is told that he is injured, and at this time clotting increases as if it were actually happening.

Anticoagulant blood system.

Back in 1904, the famous German scientist and coagulologist Morawitz first suggested the presence in the body of an anticoagulation system that keeps blood in a liquid state, and also that the coagulation and anticoagulation systems are in a state of dynamic equilibrium.

Later, these assumptions were confirmed in the laboratory headed by Professor Kudryashov. In the 30s, thrombin was obtained, which was administered to rats in order to induce blood clotting in the vessels. It turned out that the blood in this case stopped clotting altogether. This means that thrombin activated some kind of system that prevents blood clotting in the vessels. Based on this observation, Kudryashov also came to the conclusion about the presence of an anticoagulant system.

The anticoagulant system should be understood as a set of organs and tissues that synthesize and utilize a group of factors that ensure the liquid state of blood, that is, preventing blood clotting in blood vessels. Such organs and tissues include the vascular system, liver, some blood cells, etc. These organs and tissues produce substances that are called blood clotting inhibitors or natural anticoagulants. They are constantly produced in the body, unlike artificial ones, which are introduced in the treatment of prethrombic conditions.

Blood clotting inhibitors act in phases. It is assumed that their mechanism of action is either the destruction or binding of blood coagulation factors.

In phase 1, the following are used as anticoagulants: heparin (a universal inhibitor) and antiprothrombinases.

In phase 2, thrombin inhibitors are triggered: fibrinogen, fibrin with its breakdown products - polypeptides, thrombin hydrolysis products, prethrombin 1 and II, heparin and natural antithrombin 3, which belongs to the group of glycosaminoglycans.

In some pathological conditions, for example, diseases of the cardiovascular system, additional inhibitors appear in the body.

Finally, enzymatic fibrinolysis takes place (fibrinolytic system) occurring in 3 phases. So, if a lot of fibrin or thrombin is formed in the body, then the fibrinolytic system immediately turns on and fibrin hydrolysis occurs. Non-enzymatic fibrinolysis, which was mentioned earlier, is of great importance in maintaining the liquid state of the blood.

According to Kudryashov, two anticoagulant systems are distinguished:

The first one is of a humoral nature. It works constantly, releasing all of the anticoagulants already listed, with the exception of heparin. II - emergency anticoagulant system, which is caused by nervous mechanisms associated with the functions of certain nerve centers. When an alarming amount of fibrin or thrombin accumulates in the blood, the corresponding receptors are irritated, which activates the anticoagulant system through the nerve centers.

Both the coagulation and anticoagulation systems are regulated. It has long been noted that under the influence of the nervous system, as well as certain substances, either hyper- or hypocoagulation occurs. For example, with severe pain that occurs during childbirth, thrombosis in the blood vessels may develop. Under the influence of stress, blood clots can also form in blood vessels.

The coagulation and anticoagulation systems are interconnected and are under the control of both nervous and humoral mechanisms.

It can be assumed that there is a functional system that ensures blood coagulation, which consists of a perceptive unit represented by special chemoreceptors embedded in vascular reflexogenic zones (aortic arch and sinocarotid zone), which capture factors that ensure blood coagulation. The second link of the functional system is regulation mechanisms. These include the nerve center, which receives information from reflexogenic zones. Most scientists assume that this nerve center, which regulates the coagulation system, is located in the hypothalamus. Experiments on animals show that when the posterior part of the hypothalamus is irritated, hypercoagulation occurs more often, and when the anterior part is irritated, hypocoagulation occurs. These observations prove the influence of the hypothalamus on the process of blood coagulation, and the presence of corresponding centers in it. Through this nerve center the synthesis of factors that ensure blood clotting is controlled.

Humoral mechanisms include substances that change the rate of blood clotting. These are primarily hormones: ACTH, growth hormone, glucocorticoids, which accelerate blood clotting; Insulin acts biphasically - during the first 30 minutes it accelerates blood clotting, and then over the course of several hours it slows it down.

Mineralocorticoids (aldosterone) reduce the rate of blood clotting. Sex hormones act in different ways: male hormones accelerate blood clotting, female hormones act in two ways: some of them increase the rate of blood clotting - hormones of the corpus luteum. others slow it down (estrogens)

The third link is the performing organs, which primarily include the liver, which produces coagulation factors, as well as cells of the reticular system.

How does a functional system work? If the concentration of any factors that ensure the blood clotting process increases or decreases, then this is perceived by chemoreceptors. Information from them goes to the center for regulating blood coagulation, and then to the performing organs, and according to the feedback principle, their production is either inhibited or increased.

The anticoagulation system, which keeps the blood fluid, is also regulated. The perceptive link of this functional system is located in the vascular reflexogenic zones and is represented by specific chemoreceptors that detect the concentration of anticoagulants. The second link is represented by the nerve center of the anticoagulant system. According to Kudryashov, it is located in the medulla oblongata, which is proven by a number of experiments. If, for example, you turn it off with substances such as aminosine, methylthiuracil and others, then the blood begins to clot in the vessels. The executive links include organs that synthesize anticoagulants. These are the vascular wall, liver, blood cells. A functional system that prevents blood clotting is triggered as follows: a lot of anticoagulants - their synthesis is inhibited, a little - it increases (feedback principle).