The blood clotting process begins with blood loss, but massive blood loss, accompanied by a drop in blood pressure, leads to dramatic changes in the entire hemostatic system.
Blood coagulation system (hemostasis)
The blood coagulation system is a complex multicomponent complex of human homeostasis, which ensures the preservation of the integrity of the body due to 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 repair-healers.
Any damage to the vascular wall, "trauma to the blood", on the one hand, lead to varying severity of bleeding, and on the other, cause physiological, and subsequently pathological changes in the hemostatic system, which can by themselves lead to the death of the body. The regular severe and frequent complications of massive blood loss include acute disseminated intravascular coagulation syndrome (acute disseminated intravascular coagulation).
In acute massive blood loss, and it cannot be imagined without damage to the vessels, there is almost always a local (at the site of injury) thrombosis, 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.
Endothelial cells
Endothelial cells of the vascular wall maintain the liquid state of the blood, directly affecting many mechanisms and links of thrombus formation, completely blocking or effectively restraining them. The vessels provide laminar blood flow, which prevents the adhesion of cellular and protein components.
The endothelium carries a negative charge on its surface, as well as the cells circulating in the blood, various glycoproteins and other compounds. Likely charged endothelium and circulating blood elements are repelled, which prevents cells and protein structures from sticking together in the circulatory bed.
Maintaining a liquid state of blood
The maintenance of the liquid state of the blood is facilitated by:
- prostacyclin (PGI 2),
- NO and ADPase,
- a tissue thromboplastin inhibitor,
- glucosaminoglycans and, in particular, heparin, antithrombin III, heparin cofactor II, tissue plasminogen activator, etc.
Prostacyclin
The 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
Disaggregation of platelets and vasodilation are also carried out by the endothelial production of nitric oxide (NO) and the so-called ADPase (an 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 pathway of activation. The complex of this system includes:
- thrombomodulin,
- protein C,
- protein S,
- thrombin as an activator of protein C,
- protein C inhibitor
Endothelial cells produce thrombomodulin, which, with the participation of thrombin, activates protein C, converting it, respectively, 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 fibrinolysis system in two ways: by stimulating the production and release of tissue plasminogen activator from endothelial cells into the bloodstream, and also by blocking the tissue plasminogen activator inhibitor (PAI-1).
Protein C system abnormalities
The 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 fulminant) is an extremely serious pathology. Children with purpura fulminant are practically unviable and die at an early age from severe thrombosis, acute disseminated intravascular coagulation and sepsis.
Thrombosis
Heterozygous hereditary deficiency of protein C or protein S contributes to thrombosis in young people. Thrombosis of the main and peripheral veins, thromboembolism of the pulmonary artery, early myocardial infarction, ischemic strokes are more common. In women with a deficiency of protein C or S, taking hormonal contraceptives, the risk of thrombosis (more often cerebrovascular thrombosis) increases 10-25 times.
Since proteins C and S are vitamin K-dependent proteases produced in the liver, the treatment of thrombosis with indirect anticoagulants such as syncumar or pelentan in patients with hereditary protein C or S deficiency can lead to an aggravation of the thrombotic process. In addition, a number of patients during treatment with indirect anticoagulants (warfarin) may develop peripheral skin necrosis (“ warfarin necrosis"). Their appearance almost always means the presence of a heterozygous protein C deficiency, which leads to a decrease in the 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 V factor Leiden. In fact, factor V Leiden is a mutant factor V with a point substitution of arginine at the 506th position of factor V for 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 V factor Leiden, according to different authors, is 10-25%.
Tissue thromboplastin inhibitor
The vascular endothelium can also inhibit thrombus formation when activated. Endothelial cells actively produce an inhibitor of tissue thromboplastin, which inactivates the tissue factor - factor VIIa (TF-VIIa) complex, which leads to a blockage of the external mechanism of blood coagulation, which is activated when tissue thromboplastin enters the bloodstream, thereby maintaining blood flow in the circulatory bed.
Glucosaminoglycans (heparin, antithrombin III, heparin cofactor II)
Another mechanism for maintaining the liquid state of the blood is associated with the production of various glucosaminoglycans by the endothelium, among which heparan and dermatan sulfate are known. These glucosaminoglycans are similar in structure and function to heparins. Produced and released into the bloodstream, heparin binds to the 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 inactivation of coagulation, carried out through AT III, heparins activate the so-called heparin cofactor II (CG II). Activated CG II, like AT III, inhibits the functions of factor Xa and thrombin.
In addition to affecting the activity of physiological anticoagulants-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. As a result of heparin activation, fibronectin binds to various targets of phagocytosis - cell membranes, tissue detritus, immune complexes, fragments of collagen structures, staphylococci and streptococci. As a result of heparin-stimulated opsonic interactions of fibronectin, inactivation of phagocytosis targets in the organs of the macrophage system is activated. Clearing the circulatory bed from the target objects of phagocytosis contributes to the preservation of the liquid state and blood flow.
In addition, heparins are able to stimulate the production and release into the circulatory bed of a tissue thromboplastin inhibitor, which significantly reduces the likelihood of thrombosis with external activation of the blood coagulation system.
Blood clotting process - thrombus formation
Together with the above, there are mechanisms that are also associated with the state of the vascular wall, but they do not contribute to the maintenance of the liquid state of the blood, but are responsible for its coagulation.
The blood clotting process 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 an internal mechanism, damage to only the endothelial layer of the vascular wall leads to the fact that the blood flow is in contact with the structures of the subendothelium - with the basement membrane, in which collagen and laminin are the main thrombogenic factors. The 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 practically only with the participation of von Willebrand factor. On the contrary, both von Willebrand factor and fibrinogen, fibronectin, thrombospondin are involved in the formation of blood clots at relatively low blood flow velocities (in the microvasculature, venous system).
Another mechanism of thrombus formation is carried out with the direct participation of the von Willebrand factor, which, when the integrity of the vessels is damaged, significantly increases in quantitative terms due to the intake of endothelium from the Weibol-Pallas corpuscles.
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 are little involved in this mechanism of thrombus formation. It is the appearance of tissue thromboplastin in the bloodstream and its participation in pathological thrombus formation that determine the development of acute disseminated intravascular coagulation.
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 mentioned. This explains the development of local blood clots in various diseases occurring with pronounced inflammatory reactions.
Platelets
Specialized blood cells involved in the process of blood clotting are platelets - non-nuclear blood cells, which are fragments of the cytoplasm of megakaryocytes. Platelet production is associated with a specific - 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 the 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-the diameter of an erythrocyte). On light microscopy, unchanged platelets appear as rounded cells with smooth edges and red-violet granules (α-granules). The life span of platelets is on average 8-9 days. They are normally discoid, 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 a large amount of acid hydrolases and other enzymes;
- α-granules containing many different proteins (fibrinogen, von Willebrand factor, fibronectin, thrombospondin, etc.) and stained according to Romanovsky-Giemsa in a violet-red color;
- δ-granules - dense granules containing a large amount of serotonin, K + ions, Ca 2+, Mg 2+, etc.
The α-granules contain strictly specific proteins of platelets, such as the 4th plate factor and β-thromboglobulin, which are markers of platelet activation; their determination in blood plasma can help in the diagnosis of current thrombosis.
In addition, in the structure of platelets there is a system of dense tubules, which is, as it were, a depot for Ca 2+ ions, as well as a large number of mitochondria. When platelets are activated, a number of biochemical reactions occur, which, with the participation of cyclooxygenase and thromboxane synthetase, lead to the formation of thromboxane A2 (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 receptor for glycoprotein Ia binds to collagen, the receptor for glycoprotein Ib interacts with von Willebrand factor, glycoproteins IIb-IIIa - 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. - a third plate factor (membrane phospholipid) appears on their outer membrane, activating the blood coagulation rate, increasing it by 500-700 thousand times.
Plasma coagulation factors
Blood plasma contains several specific systems that are involved in the blood coagulation cascade. These are the systems:
- adhesive molecules,
- clotting factors,
- fibrinolysis factors,
- factors of physiological primary and secondary anticoagulants-antiproteases,
- factors of physiological primary repair-healers.
Plasma adhesive molecule system
The system of adhesive plasma molecules is a complex of glycoproteins responsible for intercellular, cell-substrate and cell-protein interactions. It includes:
- von Willebrand factor,
- fibrinogen,
- fibronectin,
- thrombospondin,
- 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 has many functions, but the main ones are two:
- interaction with factor VIII, due to which antihemophilic globulin is protected from proteolysis, which increases its lifespan;
- ensuring the processes of adhesion and aggregation of platelets in the circulatory bed, especially at high blood flow rates in the vessels of the arterial system.
A decrease in the von Willebrand factor level below 50%, observed with illness or von Willebrand syndrome, leads to severe petechial bleeding, usually of the microcirculatory type, manifested by bruising with minor injuries. However, in severe von Willebrand disease, a hematoma type of bleeding similar to hemophilia may occur ().
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 peripheral vein thrombosis, 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 fibrin thrombus (thrombus reinforcement) and the implementation of the process of platelet aggregation (attachment of some platelets to others) due to specific platelet receptors of glycoproteins IIb-IIIa.
Plasma fibronectin
Plasma fibronectin is an adhesive glycoprotein that interacts with various factors of blood coagulation. Also one of the functions of plasma fibronectin is to repair defects in blood vessels and tissues. It has been shown that the application of fibronectin to areas of tissue defects (trophic ulcers of the cornea of the eye, erosion and ulcers of the skin) promotes the stimulation of reparative processes and faster healing.
The normal concentration of plasma fibronectin in the blood is about 300 μg / ml. In severe injuries, massive blood loss, burns, prolonged abdominal surgeries, sepsis, acute disseminated intravascular coagulation as a result of consumption, the level of fibronectin decreases, which reduces the phagocytic activity of the macrophage system. This can explain the high incidence of infectious complications in persons who have suffered massive blood loss, and the advisability of prescribing a transfusion of cryoprecipitate or fresh frozen plasma containing a large amount of fibronectin to patients.
Thrombospondin
The main functions of thrombospondin are to ensure complete aggregation of platelets and their binding to monocytes.
Vitronectin
Vitronectin, or a protein that binds to glass, is involved in several processes. In particular, it binds the AT III-thrombin complex and further removes it from circulation through the macrophage system. In addition, vitronectin blocks the cell-lytic activity of the final cascade of factors of the complement system (complex C 5 -C 9), 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 types of damage to the integrity of the vascular wall.
Fibrinolysis system
The fibrinolysis system is the most important system that prevents uncontrolled blood clotting. The fibrinolysis system is activated 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 is converted into plasmin, which cleaves fibrin molecules into small fragments (X, Y, D, E), which are opsonized by plasma fibronectm.
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 fibrinolysis activation is often used in clinical practice for the lysis of acute thrombosis of various localization (with pulmonary embolism, acute myocardial infarction, etc.).
System of primary and secondary anticoagulants-antiproteases
The 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.
The primary anticoagulants include a system that includes 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 external pathway of blood coagulation activation, namely the TF-VII factor complex. In this system, heparin 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 main antiprotease that inactivates tissue plasminogen activator activity.
The physiological secondary anticoagulants-antiproteases include components, the concentration of which increases during blood coagulation. One of the main secondary anticoagulants is fibrin (antithrombin I). It actively adsorbs on its surface and inactivates free thrombin molecules circulating in the bloodstream. Derivatives of factors Va and VIIIa can also inactivate thrombin. In addition, in the blood, thrombin inactivates circulating molecules of soluble glycocalicin, which are residues of the platelet receptor for glycoprotein Ib. In the composition of glycocalicin there is a certain sequence - a "trap" for thrombin. The participation of soluble glycocalicin in the inactivation of circulating thrombin molecules makes it possible to achieve self-limitation of thrombus formation.
System of primary repair-healers
In the blood plasma there are certain factors that contribute to the healing and repair of vascular and tissue defects - the so-called physiological system of primary repair-healers. This system includes:
- plasma fibronectin,
- fibrinogen and its derivative fibrin,
- transglutaminase or factor XIII of the blood coagulation system,
- thrombin,
- platelet growth factor - thrombopoietin.
The role and significance of each of these factors separately has already been discussed.
The mechanism of blood coagulation
The internal and external mechanisms of blood coagulation are distinguished.
Internal blood clotting pathway
The internal mechanism of blood clotting involves factors that are 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 is converted into factor XIIa (activated), which activates factor XI (the precursor of plasma thromboplastin), converting it to 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. The activation of factor IX involves Ca 2+ ions and the 3rd platelet factor.
The complex of factors IXa and VIIIa with Ca 2+ ions and the 3rd platelet factor activates X factor (Stewart factor), converting it into factor Xa. Factor Va (proaccelerin) is also involved in the activation of factor X.
The complex of factors Xa, Va, Ca ions (IV factor) and the 3rd platelet factor is called prothrombinase; it activates prothrombin (or factor II), converting it to 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) turns into insoluble fibrin, which directly reinforces (strengthens) the platelet thrombus.
External blood coagulation pathway
The external mechanism of blood coagulation is carried out when tissue thromboplastin (or III, tissue factor) enters the circulatory bed from the tissues.
Tissue thromboplastin binds to factor VII (proconvertin), converting it to factor VIIa.
The latter activates the X factor, transforming it into factor Xa.
Further transformations of the coagulation cascade are the same as when plasma coagulation factors are activated by an internal mechanism.
The mechanism of blood coagulation in brief
In general, the blood coagulation mechanism can be briefly represented as a series of sequential stages:
- as a result of disruption of normal blood flow and damage to the integrity of the vascular wall, an endothelial defect develops;
- von Willebrand factor and plasma fibronectin adhere to the exposed basement membrane of the endothelium (to collagen, laminin);
- circulating platelets also adhere to collagen and laminin of the basement membrane, and then to von Willebrand factor and fibronectin;
- adhesion of platelets and their aggregation lead to the appearance of the third plate factor on their outer surface membrane;
- with the direct participation of the 3rd plate factor, plasma coagulation factors are activated, which leads to the formation of fibrin in the platelet thrombus - the thrombus is reinforced;
- the fibrinolysis system is activated both by internal (through factor XII, high molecular weight kininogen and kallikrein-kinin system) and by external (under the influence of TAP) mechanisms, stopping further thrombus formation; in this case, not only the lysis of blood clots occurs, but also the formation of a large number of fibrin degradation products (FDP), which in turn block pathological thrombus formation, having fibrinolytic activity;
- reparation and healing of a 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 hemostasis system, namely between the mechanisms of thrombus formation and fibrinolysis, is rapidly disturbed, 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.
Blood coagulation is an extremely complex and in many ways still mysterious biochemical process that starts when the circulatory system is damaged and leads to the transformation of blood plasma into a gelatinous clot that plugs the wound and stops bleeding. Violations of this system are extremely dangerous and can lead to bleeding, thrombosis or other pathologies, which together are responsible for the lion's share of death and disability in the modern world. Here we will consider the structure of this system and talk about the most recent advances in its study.
Anyone who at least once in his life received a scratch or wound, thereby acquired a wonderful opportunity to observe the transformation of blood from a liquid into a viscous, non-flowing mass, leading to a stop of bleeding. This process is called blood clotting and is controlled by a complex system of biochemical reactions.
To have some kind of system for stopping bleeding is absolutely necessary for any multicellular organism with a liquid internal environment. Blood coagulation is also vital for us: mutations in the genes of the main coagulation proteins are usually lethal. Alas, among the many systems of our body, disturbances in the work of which pose a danger to health, blood clotting also occupies the absolute first place as the main immediate cause of death: people suffer from various diseases, but almost always die from blood clotting disorders... Cancer, sepsis, trauma, atherosclerosis, heart attack, stroke - for a wide range of diseases, the immediate cause of death is the inability of the coagulation system to maintain a balance between the liquid and solid states of the blood in the body.
If the cause is known, why can't it be dealt with? Of course, it is possible and necessary to fight: scientists are constantly developing new methods for diagnosing and treating coagulation disorders. But the problem is that the folding system is very complex. And the science of the regulation of complex systems teaches that such systems need to be controlled in a special way. Their response to external influences is non-linear and unpredictable, and in order to achieve the desired result, you need to know where to put the effort. The simplest analogy: to launch a paper airplane into the air, it is enough to throw it in the right direction; at the same time, to take off an airliner, you will need to press the right buttons in the cockpit at the right time and in the right sequence. And if you try to launch an airliner with a throw like a paper airplane, it will end badly. So it is with the coagulation system: in order to successfully treat, you need to know the "control points".
Until very recently, blood coagulation has successfully resisted attempts by researchers to understand its work, and only in recent years has there been a qualitative leap. In this article we will tell you about this wonderful system: how it works, why it is so difficult to study, and - most importantly - we will tell you about the latest discoveries in understanding how it works.
How does blood clotting work?
Stopping bleeding is based on the same idea that housewives use to prepare jellied meat - the transformation of liquid into a gel (a colloidal system where a network of molecules is formed that can hold a liquid that is a thousand times its weight in its cells due to hydrogen bonds with water molecules). By the way, the same idea is used in disposable diapers for babies, in which material that swells when wet is placed. From a physical point of view, there you need to solve the same problem as in coagulation - combating leaks with minimal effort.
Blood clotting is central hemostasis(stopping bleeding). The second link of hemostasis is special cells - platelets, - capable of attaching to each other and to the site of injury to create a blood-stopping plug.
A general idea of the biochemistry of coagulation can be obtained from Figure 1, at the bottom of which the conversion reaction of soluble protein is shown fibrinogen v fibrin which is then polymerized into a mesh. This reaction is the only part of the cascade that has a direct physical meaning and solves a clear physical problem. The role of the rest of the reactions is exclusively regulatory: to ensure the conversion of fibrinogen to fibrin only in the right place and at the right time.
Figure 1. Main reactions of blood coagulation. The coagulation system is a cascade - a sequence of reactions, where the product of each reaction acts as a catalyst for the next. The main "entrance" to this cascade is in its middle part, at the level of factors IX and X: protein tissue factor(designated in the scheme as TF) binds factor VIIa, and the resulting enzymatic complex activates factors IX and X. The result of the cascade is the fibrin protein, which can polymerize and form a clot (gel). The overwhelming majority of activation reactions are proteolysis reactions, i.e. partial breakdown of the protein, increasing its activity. Almost every coagulation factor is necessarily inhibited in one way or another: feedback is necessary for the stable operation of the system.
Legend: Reactions of converting clotting factors into active forms are shown one-way thin black arrows... Wherein curly red arrows show under the action of which enzymes activation occurs. Activity loss reactions due to inhibition are shown thin green arrows(For simplicity, the arrows are depicted as simply "leaving", ie, it is not shown with which inhibitors the binding occurs). Reversible reactions of complex formation are shown double-sided thin black arrows... Coagulation proteins are designated either by names, or by Roman numerals, or by abbreviations ( TF- tissue factor, PC- protein C, APC- activated protein C). To avoid congestion, the diagram does not show: binding of thrombin to thrombomodulin, activation and secretion of platelets, contact activation of coagulation.
Fibrinogen resembles a rod 50 nm long and 5 nm thick (Fig. 2 a). Activation allows its molecules to stick together into a fibrin thread (Fig. 2 b), and then into a fiber capable of branching and forming a three-dimensional network (Fig. 2 v).
Figure 2. Fibrin gel. a - Schematic structure of the fibrinogen molecule. Its basis is composed of three pairs of mirrored polypeptide chains α, β, γ. In the center of the molecule, one can see the binding regions that become accessible when fibrinopeptides A and B are cut off by thrombin (FPA and FPB in the figure). b - Fibrinous fiber assembly mechanism: molecules are attached to each other "overlapping" according to the principle of head-to-middle, forming a double-stranded fiber. v - Electron micrograph of the gel: fibrin fibers can stick together and split, forming a complex three-dimensional structure.
Figure 3. Three-dimensional structure of the thrombin molecule. The diagram shows the active site and the parts of the molecule responsible for the binding of thrombin to substrates and cofactors. (An active site is a part of the molecule that directly recognizes the cleavage site and performs enzymatic catalysis.) The protruding parts of the molecule (exosites) allow the "switch" of the thrombin molecule, making it a multifunctional protein capable of working in different modes. For example, the binding of thrombomodulin to exosite I physically blocks access to thrombin for procoagulant substrates (fibrinogen, factor V) and allosterically stimulates activity towards protein C.
The fibrinogen activator thrombin (Fig. 3) belongs to the family of serine proteinases - enzymes capable of cleaving peptide bonds in proteins. It is a relative of the digestive enzymes trypsin and chymotrypsin. Proteinases are synthesized in an inactive form called zymogen... To activate them, it is necessary to cleave the peptide bond that holds the part of the protein that closes the active site. Thus, thrombin is synthesized in the form of prothrombin, which can be activated. As seen from Fig. 1 (where prothrombin is designated factor II), this is catalyzed by factor Xa.
In general, coagulation proteins are called factors and are numbered in Roman numerals in the order of official discovery. Index "a" means an active form, and its absence means an inactive predecessor. Proper names are also used for long-discovered proteins such as fibrin and thrombin. Some numbers (III, IV, VI) are not used for historical reasons.
The coagulation activator is a protein called tissue factor present in the cell membranes of all tissues, with the exception of endothelium and blood. Thus, the blood remains liquid only due to the fact that it is normally protected by a thin protective sheath of the endothelium. In case of any violation of the integrity of the vessel, the tissue factor binds factor VIIa from the plasma, and their complex is called external tenase(tenase, or Xase, from the word ten- ten, i.e. number of activated factor) - activates factor X.
Thrombin also activates factors V, VIII, XI, which leads to an acceleration of its own production: factor XIa activates factor IX, and factors VIIIa and Va bind factors IXa and Xa, respectively, increasing their activity by orders of magnitude (the complex of factors IXa and VIIIa is called internal tenase). A deficiency of these proteins leads to serious disorders: for example, the absence of factors VIII, IX or XI causes a serious illness hemophilia(the famous "tsarist disease", which was sick of Tsarevich Alexei Romanov); and deficiency of factors X, VII, V or prothrombin is incompatible with life.
Such a system device is called positive feedback: Thrombin activates proteins that accelerate its own production. And here an interesting question arises, why are they needed? Why is it impossible to immediately make the reaction fast, why does nature make it initially slow, and then comes up with a way to further accelerate it? Why is there duplication in the collapsing system? For example, factor X can be activated by both complex VIIa-TF (external tenase) and complex IXa-VIIIa (internal tenase); it looks completely pointless.
Coagulation proteinase inhibitors are also present in the blood. The main ones are antithrombin III and a tissue factor pathway inhibitor. In addition, thrombin is able to activate serine proteinase protein C, which breaks down coagulation factors Va and VIIIa, causing them to completely lose their activity.
Protein C is a precursor of serine proteinase, very similar to factors IX, X, VII and prothrombin. It is activated by thrombin like factor XI. However, upon activation, the resulting serine proteinase uses its enzymatic activity not to activate other proteins, but to inactivate them. Activated protein C produces several proteolytic cleavages in coagulation factors Va and VIIIa, causing them to completely lose their cofactor activity. Thus, thrombin, a product of the coagulation cascade, inhibits its own production: this is called negative feedback. And again we have a regulatory question: why does thrombin both accelerate and slow down its own activation?
Evolutionary origins of clotting
The formation of protective blood systems began in multicellular organisms over a billion years ago - in fact, just in connection with the appearance of blood. The coagulation system itself is the result of overcoming another historical milestone - the emergence of vertebrates about five hundred million years ago. Most likely, this system arose from immunity. The emergence of another immune response system that fought bacteria by enveloping them with fibrin gel, led to an accidental side effect: the bleeding began to stop faster. This made it possible to increase the pressure and strength of flows in the circulatory system, and the improvement of the vascular system, that is, the improvement of the transport of all substances, opened up new horizons for development. Who knows if the appearance of coagulation was not an advantage that allowed vertebrates to take their current place in the Earth's biosphere?
In a number of arthropods (such as the horseshoe crab), coagulation also exists, but it arose independently and remained in immunological roles. Insects, like other invertebrates, usually get by with a weaker type of bleeding control system based on platelet aggregation (more precisely, amoebocytes - distant relatives of platelets). This mechanism is quite functional, but it imposes fundamental restrictions on the efficiency of the vascular system, just as the tracheal form of respiration limits the maximum possible size of an insect.
Unfortunately, creatures with intermediate forms of the coagulation system are almost all extinct. The only exception is jawless fish: genomic analysis of the lamprey coagulation system showed that it contains much fewer components (that is, it has a much simpler structure). From jaw fish to mammals, the coagulation systems are very similar. Cellular hemostasis systems also operate on similar principles, despite the fact that small, nuclear-free platelets are characteristic only of mammals. In other vertebrates, platelets are large cells with a nucleus.
To summarize, the coagulation system has been studied very well. No new proteins or reactions have been discovered in it for fifteen years, which is an eternity for modern biochemistry. Of course, the likelihood of such a discovery cannot be completely ruled out, but so far there is not a single phenomenon that we could not explain with the help of available information. Rather, on the contrary, the system looks much more complicated than it needs to be: we recall that of all this (rather cumbersome!) Cascade, only one reaction is actually engaged in gelling, and all the rest are needed for some incomprehensible regulation.
That is why now coagulology researchers working in various fields - from clinical hemostasiology to mathematical biophysics - are actively moving from the question "How does folding work?" to questions "Why is folding done this way?", "How does it work?" and finally "How do we need to influence clotting to achieve the desired effect?"... The first thing that needs to be done to answer is to learn how to investigate coagulation as a whole, and not just individual reactions.
How to investigate clotting?
Various models - experimental and mathematical - are created to study coagulation. What exactly do they allow you to get?
On the one hand, it seems that the best approximation for studying an object is the object itself. In this case, a person or an animal. This allows all factors to be taken into account, including blood flow through the vessels, interactions with the vessel walls, and much more. However, in this case, the complexity of the problem exceeds reasonable limits. The folding models allow to simplify the research object without missing its essential features.
Let's try to get an idea of what requirements these models should meet in order to correctly reflect the folding process. in vivo.
In the experimental model, the same biochemical reactions must be present as in the body. Not only proteins of the coagulation system should be present, but also other participants in the coagulation process - blood cells, endothelium and subendothelium. The system should take into account the spatial heterogeneity of coagulation in vivo: activation from the damaged area of the endothelium, the spread of active factors, the presence of blood flow.
It is natural to start considering coagulation models with coagulation research methods. in vivo... The basis of almost all approaches of this kind is to inflict controlled damage on the experimental animal in order to induce a hemostatic or thrombotic reaction. This reaction is investigated by various methods:
- monitoring the time of bleeding;
- analysis of plasma taken from an animal;
- autopsy of a sacrificed animal and histological examination;
- monitoring the thrombus in real time using microscopy or nuclear magnetic resonance (Fig. 4).
Figure 4. Thrombus formation in vivo in a model of laser-induced thrombosis. This picture is reproduced from a historical work, where scientists for the first time were able to observe the development of a blood clot "live". To do this, a concentrate of fluorescently labeled antibodies to coagulation proteins and platelets was injected into the blood of the mouse, and, placing the animal under the lens of a confocal microscope (allowing three-dimensional scanning), they chose an arteriole accessible for optical observation under the skin and damaged the endothelium with a laser. The antibodies began to attach to the growing blood clot, making it possible to observe it.
The classic formulation of a coagulation experiment in vitro consists in the fact that blood plasma (or whole blood) is mixed in a container with an activator, after which the clotting process is monitored. According to the observation method, experimental techniques can be divided into the following types:
- monitoring the coagulation process itself;
- monitoring the change in the concentration of coagulation factors from time to time.
The second approach provides incomparably more information. Theoretically, knowing the concentration of all factors at an arbitrary moment in time, one can obtain complete information about the system. In practice, the study of even two proteins at the same time is expensive and involves great technical difficulties.
Finally, coagulation in the body is not uniform. Clot formation starts on the damaged wall, spreads with the participation of activated platelets in the plasma volume, and stops with the help of the vascular endothelium. It is impossible to adequately study these processes using classical methods. The second important factor is the presence of blood flow in the vessels.
Awareness of these problems led to the emergence, starting in the 1970s, of a variety of flow-through experimental systems. in vitro... It took a little more time to understand the spatial aspects of the problem. Only in the 1990s, methods began to appear that take into account the spatial heterogeneity and diffusion of coagulation factors, and only in the last decade they began to be actively used in scientific laboratories (Fig. 5).
Figure 5. Spatial growth of fibrin clot in health and disease. Coagulation in a thin layer of blood plasma was activated by tissue factor immobilized on the wall. In the photos, the activator is located left. Gray flared stripe- growing fibrin clot.
Along with experimental approaches for the study of hemostasis and thrombosis, mathematical models are also used (this research method is often called in silico). Mathematical modeling in biology allows deep and complex relationships between biological theory and experience to be established. The experiment has certain boundaries and is fraught with a number of difficulties. In addition, some theoretically possible experiments are impracticable or prohibitively expensive due to the limitations of the experimental technique. Simulation simplifies the conduct of experiments, as you can pre-select the necessary conditions for the experiments in vitro and in vivo at which the effect of interest will be observed.
Regulation of the coagulation system
Figure 6. Contribution of external and internal tenase to the formation of a fibrin clot in space. We used a mathematical model to investigate how far the influence of a coagulation activator (tissue factor) can extend in space. For this, we calculated the distribution of factor Xa (which determines the distribution of thrombin, which determines the distribution of fibrin). The animation shows the distributions of the factor Xa, produced by external tenase(complex VIIa-TF) or internal tenase(complex IXa – VIIIa), as well as the total amount of factor Xa (shaded area). (The inset shows the same on a larger scale of concentration.) It can be seen that the factor Xa produced on the activator cannot penetrate far from the activator due to the high rate of inhibition in plasma. On the contrary, complex IXa – VIIIa works away from the activator (because factor IXa is inhibited more slowly and therefore has a greater distance of effective diffusion from the activator), and ensures the spread of factor Xa in space.
Let's take the next logical step and try to answer the question - how does the system described above work?
Cascading coagulation system
Let's start with a cascade - a chain of enzymes that activate each other. A single enzyme operating at a constant rate gives a linear dependence of product concentration over time. At the cascade of N enzymes, this dependence will have the form t N, where t- time. For the effective operation of the system, it is important that the response is of just such an “explosive” nature, since this minimizes the period when the fibrin clot is still fragile.
Triggering Clotting and the Role of Positive Feedbacks
As mentioned in the first part of this article, many clotting reactions are slow. Thus, factors IXa and Xa are in themselves very poor enzymes and require cofactors (factors VIIIa and Va, respectively) to function effectively. These cofactors are activated by thrombin: this device, when an enzyme activates its own production, is called a positive feedback loop.
As we have shown experimentally and theoretically, the positive feedback of the activation of factor V by thrombin forms a threshold for activation - the property of the system not to respond to a small activation, but to quickly respond when a large one appears. This ability to switch seems to be very valuable for folding: it helps to prevent "false positives" of the system.
Role of the intrinsic pathway in the spatial dynamics of folding
One of the intriguing mysteries that haunted biochemists for many years after the discovery of the major coagulation proteins was the role of factor XII in hemostasis. Its deficiency was found in the simplest clotting tests, increasing the time required for clot formation, but, unlike factor XI deficiency, it was not accompanied by clotting disorders.
One of the most plausible options for solving the role of the internal pathway was proposed by us using spatially inhomogeneous experimental systems. It was found that positive feedbacks are of great importance precisely for the spread of clotting. Effective activation of factor X by an external tenase on the activator will not help to form a clot away from the activator, since factor Xa is rapidly inhibited in plasma and cannot move far from the activator. But factor IXa, which is inhibited an order of magnitude slower, is quite capable of this (and it is helped by factor VIIIa, which is activated by thrombin). And where it is difficult for him to reach, factor XI, also activated by thrombin, begins to work. Thus, the presence of positive feedback loops helps to create the three-dimensional structure of the clot.
Protein C pathway as a possible mechanism for localizing thrombus formation
The activation of protein C by thrombin is slow in itself, but it is sharply accelerated when thrombin binds to the transmembrane protein thrombomodulin, which is synthesized by endothelial cells. Activated protein C is capable of destroying factors Va and VIIIa, slowing down the clotting system by orders of magnitude. Spatially heterogeneous experimental approaches have become the key to understanding the role of this reaction. Our experiments suggested that it stops the spatial growth of the thrombus, limiting its size.
Summarizing
In recent years, the complexity of the coagulation system has gradually become less mysterious. The discovery of all the essential components of the system, the development of mathematical models and the use of new experimental approaches have opened the veil of secrecy. The structure of the coagulation cascade is deciphered, and now, as we saw above, for almost every essential part of the system, a role has been identified or proposed that it plays in the regulation of the entire process.
Figure 7 shows the most recent attempt to revise the structure of the coagulation system. This is the same circuit as in fig. 1, where the parts of the system that are responsible for different tasks are highlighted with multi-colored shading, as discussed above. Not everything in this scheme is well established. For example, our theoretical prediction that activation of factor VII by factor Xa allows clotting to respond in a threshold manner to flow rate remains untested experimentally.
Blood clotting
Blood coagulation is the most important stage in the hemostasis system, which is responsible for stopping bleeding in case of damage to the vascular system of the body. Blood coagulation is preceded by the stage of primary vascular-platelet hemostasis. This primary hemostasis is almost entirely due to vasoconstriction and mechanical blockage by platelet aggregates of 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 the formation of fibrin protein filaments in the blood, which polymerizes and forms blood clots, as a result of which the blood loses fluidity, acquiring a curdled consistency. Blood coagulation in a healthy person occurs locally, at the site of the formation of the primary platelet plug. The characteristic time for the formation of a fibrin clot is about 10 minutes.
Physiology
A fibrin clot obtained by adding thrombin to whole blood. Scanning Electron Microscopy.
The process of hemostasis is reduced to the formation of a platelet-fibrin clot. It is conventionally divided into three stages:
- Temporary (primary) vasospasm;
- Platelet plug formation due to platelet adhesion and aggregation;
- Retraction (contraction and hardening) of the platelet plug.
Vascular damage is followed by immediate platelet activation. The adhesion (adhesion) of platelets to the fibers of the connective tissue along the edges of the wound is due to the von Willebrand factor glycoprotein. Along with adhesion, platelet aggregation occurs: activated platelets attach to damaged tissues and to each other, forming aggregates that block the path of blood loss. A platelet plug appears
Various biologically active substances (ADP, adrenaline, norepinephrine, etc.) are intensively secreted from platelets that have undergone adhesion and aggregation, which lead to secondary, irreversible aggregation. Simultaneously with the release of platelet factors, thrombin is formed, which affects fibrinogen with the formation of a fibrin network, in which individual erythrocytes and leukocytes get stuck - a so-called platelet-fibrin clot (platelet plug) is formed. Thanks to the contractile protein thrombostenin, platelets are pulled towards each other, the platelet plug contracts and becomes denser, and its retraction occurs.
Blood clotting process
The classic scheme of blood coagulation according to Moravitz (1905)
The process of blood coagulation is mainly an enzyme-enzyme cascade, in which enzymes, passing into an active state, acquire the ability to activate other factors of blood coagulation. In its simplest form, the blood clotting process can be divided into three phases:
- the activation phase includes a complex of sequential reactions leading to the formation of prothrombinase and the transition of prothrombin to thrombin;
- coagulation phase - the formation of fibrin from fibrinogen;
- retraction phase - the formation of a dense fibrin clot.
This scheme was described back in 1905 by Moravitz and has not lost its relevance to this day.
In the field of a detailed understanding of the process of blood coagulation, significant progress has been made since 1905. Dozens of new proteins and reactions have been discovered that are involved in the blood coagulation process, which has a cascading nature. 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, phospholipoproteins are released, which, together with plasma factors X a and V a, as well as Ca 2+ ions, form an enzyme complex that activates prothrombin. If the clotting process begins under the action of phospholipoproteins secreted from the cells of damaged vessels or connective tissue, we are talking about external blood coagulation system(external 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 external tenase complex.
If initiation occurs under the influence of clotting factors present in the plasma, use the term internal coagulation system... The complex of factors IXa and VIIIa, which forms on the surface of activated platelets, is called internal tenase. Thus, factor X can be activated by both complex VIIa-TF (external tenase) and complex IXa-VIIIa (internal tenase). The external and internal blood coagulation systems complement each other.
In the process of adhesion, the shape of platelets changes - they become round cells with spine-like 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 the damaged vessels narrows, functional ischemia occurs. Ultimately, the vessels are blocked by a mass of platelets adhering to the edges of collagen fibers along the edges of the wound.
At this stage of hemostasis, thrombin is formed under the action of tissue thromboplastin. It is he who initiates irreversible platelet aggregation. 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 action of thrombin, polymerization of soluble fibrinogen (see fibrin) occurs and the formation of a structureless network of insoluble fibrin fibers. From this moment on, blood cells begin to filter in these threads, creating additional rigidity for the entire system, and after a while 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. Many conditions affect blood clotting. For example, cations speed up the process, and anions slow it down. In addition, there are substances both completely blocking blood coagulation (heparin, hirudin, etc.) and activating it (gyurza poison, feracryl).
Congenital disorders of the blood coagulation system are called hemophilia.
Methods for diagnosing blood coagulation
All the 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 taking into account all the incidental factors of influence. Global methods play a key role at the first stage of diagnosis: they provide an integral picture of the ongoing changes in the coagulation system and allow predicting a tendency towards hyper- or hypocoagulation in general. "Local" tests characterize the result of the work of individual links of the blood coagulation cascade, as well as individual coagulation factors. They are indispensable for the possible clarification of the localization of the pathology with an accuracy of the coagulation factor. To get a complete picture of how hemostasis works in a patient, the doctor should be able to choose which test he needs.
Global tests:
- Determination of the clotting time of whole blood (Mas-Magro method or Moravitz 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 detecting changes in the concentration of individual factors
All methods that measure the time interval from the moment of adding a reagent (activator that triggers the clotting process) to the formation of a fibrin clot in the studied plasma are referred to clotting methods (from the English "slot" - clot).
see also
Notes (edit)
Links
Wikimedia Foundation. 2010.
- Baseball at the 1996 Summer Olympics
BLOOD COLLECTION- transformation of liquid blood into an elastic clot as a result of the transition of fibrinogen dissolved in blood plasma into insoluble fibrin; protective reaction of animals and humans, preventing blood loss in case of violation of the integrity of blood vessels ... Biological encyclopedic dictionary
blood clotting- - Topics of biotechnology EN blood clotting ... Technical translator's guide
blood clotting encyclopedic Dictionary
BLOOD COLLECTION- blood coagulation, the transition of blood from a liquid state to a gelatinous clot. This property of blood (clotting) is a defensive reaction that prevents the body from losing blood. S. to. Proceeds as a sequence of biochemical reactions, ... ... Veterinary encyclopedic dictionary
BLOOD COLLECTION- 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 during the outflow of blood from the damaged vessel. Fibrin, polymerizing, forms thin threads that hold ... ... Natural science. encyclopedic Dictionary
Clotting factors- Scheme of the interaction of coagulation factors in the activation of hemocoagulation Blood coagulation factors are a group of substances contained in blood plasma and platelets and provide ... 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 curdled consistency. In normal condition ... ... Wikipedia
One of the most important processes in our body is blood clotting. Its scheme will be described below (images are also provided for clarity). And since this is a complex process, it is worth examining it in detail.
How is it going?
So, the designated process is responsible for stopping bleeding that occurs due to damage to one or another component of the vascular system of the body.
In simple terms, there are three phases. The first is activation. After damage to the vessel, sequential reactions begin to occur, which ultimately lead to the formation of the so-called prothrombinase. It is a complex complex consisting of V and X. It is formed on the phospholipid surface of platelet membranes.
The second phase is coagulation. At this stage, fibrin is formed from fibrinogen - a high molecular weight protein, which is the basis of blood clots, the occurrence of which implies blood coagulation. The diagram below demonstrates this phase.
And finally, the third stage. It involves the formation of a fibrin clot, characterized by a dense structure. By the way, it is by washing and drying it that it is possible to obtain a "material", which is then used to prepare sterile films and sponges to stop bleeding caused by rupture of small vessels during surgical operations.
About reactions
Above, the Scheme was briefly described, by the way, it was developed back in 1905 by a coagulologist named Paul Oscar Moravitz. And it does not lose its relevance to this day.
But since 1905, a lot has changed in the field of understanding blood clotting as a complex process. Thanks to progress, of course. Scientists were able to discover dozens of new reactions and proteins that are involved in this process. And now the blood coagulation cascade is more common. Thanks to her, the perception and understanding of such a complex process becomes a little more understandable.
As you can see in the image below, what is happening is literally "disassembled into bricks." The internal and external system is taken into account - blood and tissue. Each is characterized by a certain deformation resulting from damage. In the blood system, damage is done to the vascular walls, collagen, proteases (degrading enzymes) and catecholamines (mediator molecules). In the tissue, cell damage is observed, as a result of which thromboplastin comes out of them. Which is the most important stimulator of the coagulation process (otherwise called coagulation). It goes directly into the bloodstream. This is his "path", but it has a protective character. After all, it is thromboplastin that triggers the clotting process. After its release into the blood, the implementation of the above three phases begins.
Time
So, what roughly constitutes blood coagulation, the diagram helped to understand. Now I would like to talk a little about time.
The whole process takes at most 7 minutes. The first phase lasts from five to seven. During this time, prothrombin is formed. This substance is a complex type of protein structure responsible for the course of the coagulation process and the ability of the blood to thicken. Which is used by our body to form a blood clot. It clogs the damaged area, thereby stopping the bleeding. All this takes 5-7 minutes. The second and third stages are much faster. In 2-5 seconds. Because these phases of blood clotting (diagram provided above) affect processes that occur everywhere. This means that at the place of damage directly.
Prothrombin, in turn, is produced in the liver. And it takes time to synthesize it. How quickly a sufficient amount of prothrombin is produced depends on the amount of vitamin K in the body. If it is not enough, the bleeding will be difficult to stop. And this is a serious problem. Since a lack of vitamin K indicates a violation of the synthesis of prothrombin. And this is an ailment that must be treated.
Synthesis stabilization
Well, the general scheme of blood clotting is clear - now we should pay a little attention to the topic of what needs to be done to restore the required amount of vitamin K in the body.
For starters - eat right. The largest amount of vitamin K is found in green tea - 959 mcg per 100 g! Three times more, by the way, than in black. Therefore, it is worth drinking it actively. You should not neglect vegetables - spinach, white cabbage, tomatoes, green peas, onions.
Meat also contains vitamin K, but not in everything - only in veal, beef liver, lamb. But least of all it is found in garlic, raisins, milk, apples and grapes.
However, if the situation is serious, then it will be difficult to help with a variety of menus. Usually, doctors strongly recommend combining your diet with the drugs they are prescribed. Do not delay with treatment. It is necessary to start it as soon as possible in order to normalize the blood coagulation mechanism. The treatment regimen is prescribed directly by the doctor, and he is also obliged to warn what can happen if the recommendations are neglected. And the consequences can be liver dysfunction, thrombohemorrhagic syndrome, tumor diseases and damage to bone marrow stem cells.
Schmidt's scheme
At the end of the 19th century, there lived a famous physiologist and doctor of medical sciences. His name was Alexander Alexandrovich Schmidt. He lived for 63 years and devoted most of his time to researching the problems of hematology. But he studied the topic of blood coagulation especially carefully. He managed to establish the enzymatic nature of this process, as a result of which the scientist offered a theoretical explanation for it. Which graphically depicts the blood coagulation diagram below.
First of all, there is a reduction in the damaged vessel. Then a loose, primary platelet plug forms at the site of the defect. Then it gets stronger. As a result, a red blood clot forms (otherwise called a blood clot). After which it partially or completely dissolves.
During this process, certain factors of blood coagulation are manifested. The diagram, in its expanded version, also displays them. They are designated by Arabic numerals. And there are 13 of them in total. And each must be told.
Factors
A complete blood coagulation scheme is impossible without listing them. Well, it's worth starting with the first.
Factor I is a colorless protein called fibrinogen. Synthesized in the liver, dissolved in plasma. Factor II - prothrombin, which was already mentioned above. Its unique ability is to bind calcium ions. And it is precisely after the breakdown of this substance that the coagulation enzyme is formed.
Factor III is lipoprotein, tissue thromboplastin. It is usually called the transport of phospholipids, cholesterol, and also triacylglycerides.
The next factor, IV, is Ca2 + ions. The ones that bind under the influence of a colorless protein. They are involved in many complex processes, in addition to coagulation, in the secretion of neurotransmitters, for example.
Factor V is globulin. Which is also formed in the liver. It is necessary for the binding of corticosteroids (hormonal substances) and their transport. Factor VI existed for a certain time, but then it was decided to remove it from the classification. Since scientists have found out - it includes factor V.
But they did not change the classification. Therefore, after V comes factor VII. Includes proconvertin, with the participation of which tissue prothrombinase is formed (first phase).
Factor VIII is a single chain protein. It is known as antihemophilic globulin A. It is because of its lack that such a rare hereditary disease as hemophilia develops. Factor IX is "related" to the one previously mentioned. Since it is antihemophilic globulin B. Factor X is directly globulin synthesized in the liver.
And finally, the last three points. This is the Rosenthal factor, Hageman factor and fibrin stabilization. Together, they affect the formation of intermolecular bonds and the normal functioning of a process such as blood clotting.
Schmidt's scheme includes all of these factors. And it is enough to get acquainted with them quickly enough to understand how the described process is complex and multifaceted.
Anticoagulant system
This concept also needs to be noted attention. The blood coagulation system was described above - the diagram also clearly demonstrates the course of this process. But the so-called "anti-coagulation" also takes place.
To begin with, I would like to note that in the course of evolution, scientists have solved two completely opposite problems. They tried to find out - how does the body manage to prevent blood from flowing out of damaged vessels, and at the same time keep it intact in a liquid state? Well, the solution to the second problem was the detection of the anticoagulant system.
It is a specific set of plasma proteins that can reduce the rate of chemical reactions. That is, inhibit.
And antithrombin III is involved in this process. Its main function is to control the work of several factors, which include the scheme of the blood coagulation process. It is important to clarify: it does not regulate the formation of a blood clot, but eliminates unnecessary enzymes that have entered the bloodstream from the place where it is formed. What is it for? To prevent the spread of coagulation to areas of the bloodstream that are damaged.
Obstructing element
Talking about what the blood coagulation system is (the scheme of which is presented above), one cannot fail to note the attention of such a substance as heparin. It is a sulfur-containing acidic glycosaminoglycan (a type of polysaccharide).
It is a direct anticoagulant. A substance that helps to inhibit the activity of the coagulation system. It is heparin that prevents the formation of blood clots. How does this happen? Heparin simply reduces the activity of thrombin in the blood. However, it is a natural substance. And it is beneficial. If you introduce this anticoagulant into the body, then you can promote the activation of antithrombin III and lipoprotein lipase (enzymes that break down triglycerides - the main sources of energy for cells).
So, heparin is often used to treat thrombotic conditions. Only one of its molecules can activate a large amount of antithrombin III. Accordingly, heparin can be considered a catalyst - since the action in this case is really similar to the effect caused by them.
There are other substances with the same effect contained in Take, for example, α2-macroglobulin. It promotes the cleavage of the thrombus, influences the process of fibrinolysis, performs the function of transport for 2-valent ions and some proteins. It also inhibits the substances involved in the coagulation process.
Observed changes
There is one more nuance that the traditional blood coagulation scheme does not demonstrate. The physiology of our body is such that many processes involve not only chemical changes. But also physical. If we could observe coagulation with the naked eye, we would see that the shape of platelets changes in the process. They turn into rounded cells with characteristic spine-like processes, which are necessary for the intensive implementation of aggregation - the combination of elements into a single whole.
But that is not all. In the process of clotting, various substances are released from platelets - catecholamines, serotonin, etc. Because of this, the lumen of the vessels, which have been damaged, narrows. Due to what happens functional ischemia. The blood supply to the damaged area is reduced. And, accordingly, the outpouring is also gradually reduced to a minimum. This gives the platelets the ability to seal off the damaged areas. They, due to their spine-like processes, seem to be "attached" to the edges of collagen fibers, which are located at the edges of the wound. This concludes the first and longest activation phase. It ends with the formation of thrombin. This is followed by a few more seconds of the coagulation and retraction phase. And the last stage is the restoration of normal blood circulation. And it matters a lot. Since full wound healing is impossible without a good blood supply.
Good to know
Well, something like this, in words, looks like a simplified blood coagulation scheme. However, there are a few more nuances that I would like to note with attention.
Hemophilia. It has already been mentioned above. This is a very dangerous disease. Any hemorrhage by a person suffering from it is difficult to experience. The disease is hereditary, develops due to defects in proteins involved in the coagulation process. It can be detected quite simply - at the slightest cut, a person will lose a lot of blood. And it will spend a lot of time stopping it. And in especially severe forms, hemorrhage can begin for no reason. People with hemophilia can become disabled early. Since frequent hemorrhages in muscle tissue (common hematomas) and in joints are not uncommon. Is it curable? With difficulties. A person should in the literal sense of the word treat his body as a fragile vessel, and always be neat. If bleeding occurs, an urgent need to enter donor fresh blood, which contains factor XVIII.
Usually men suffer from this disease. And women act as carriers of the hemophilia gene. Interestingly, the British Queen Victoria was such. One of her sons passed on the disease. The other two are unknown. Since then, hemophilia, by the way, is often called the royal disease.
But there are also the opposite cases. Means If it is observed, then the person also needs to be no less careful. Increased clotting indicates a high risk of intravascular blood clots. That clog up whole blood vessels. Often the consequence can be thrombophlebitis, accompanied by inflammation of the venous walls. But this defect is easier to treat. Often, by the way, it is acquired.
It's amazing how much of everything happens in the human body when it is elementary cut with a piece of paper. You can talk for a long time about the features of blood, its coagulation and the processes that accompany it. But all the most interesting information, as well as the schemes that clearly demonstrate it, are provided above. The rest, if desired, can be found on an individual basis.
In the future, under the influence of platelet factors, reduction of fibrin filaments (retraction), as a result of which the clot thickens and serum is released.
Consequently, blood serum differs in its composition from plasma by the absence of fibrinogen and some other substances involved in the process of blood coagulation.
The blood from which fibrin has been removed is called defibrinated. It consists of corpuscles and serum.
Hemocoagulation inhibitors prevent or slow down intravascular coagulation. The most potent blood clotting inhibitor is heparin.
Heparin- a natural broad-spectrum anticoagulant, formed in mast cells (mast cells) and basophilic leukocytes. Heparin inhibits all phases of the blood clotting process.
Blood, leaving the vascular bed, coagulates and thereby limits blood loss. In the vascular bed, the blood is liquid, and therefore it performs all its functions. There are three main reasons for this:
· factors of the blood coagulation system in the vascular bed are in an inactive state;
The presence of anticoagulants (inhibitors) in the blood, blood cells and tissues that prevent the formation of thrombin;
· the presence of intact (intact) vascular endothelium.
The antipode of the hemocoagulation system is the fibrinolytic system, the main function of which is the splitting of fibrin filaments into soluble components. It contains the enzyme plasmin (fibrinolysin), which is inactive in the blood, in the form of plasminogen (profibrinolysin), activators and inhibitors of fibrinolysis. Activators stimulate the conversion of plasminogen to plasmin, inhibitors inhibit this process.
The process of fibrinolysis must be considered in conjunction with the process of blood coagulation. A change in the functional state of one of them is accompanied by compensatory shifts in the activity of the other. Violation of functional relationships between the systems of hemocoagulation and fibrinolysis can lead to severe pathological conditions of the body, or to increased bleeding, or to intravascular thrombus formation.
Factors that accelerate the blood clotting process include: 1) warmth, since blood clotting is an enzymatic process; 2) calcium ions, since they are involved in all phases of hemocoagulation; 3) contact of blood with a rough surface (vascular damage by atherosclerosis, vascular sutures in surgery); 4) mechanical influences (pressure, fragmentation of tissues, shaking of containers with blood, as this leads to the destruction of blood cells and the release of factors involved in blood coagulation).
The factors that slow down and prevent hemocoagulation include: 1) lowering the temperature; 2) sodium citrate and oxalate (bind calcium ions); 3) heparin (suppresses all phases of hemocoagulation); 4) smooth surface (smooth sutures when suturing vessels in surgery, silicone coating or waxing of cannulas and containers for donor blood).
Loading ...