Chapter 2. Physiology

Physiology in numbers Newton managed to express the movement of celestial bodies in mathematical equations. Mathematical thought has the power to transform biology, pathology and medicine. In its most basic application it can facilitate the discovery of new possibilities for

Muscle Physiology There are three types of muscles: striated skeletal muscle, striated cardiac muscle and smooth muscle. Muscles have the following physiological properties: 1. excitability, i.e. the ability to be excited by the action of stimuli; 2.

Physiology of synapses The term “synapse” was introduced by C. Sherrington. A synapse is a functional connection between nerve cell and other cells. Synapses are those areas where nerve impulses can influence the activity of a postsynaptic cell, exciting or

Physiology of the heart

Physiology of sleep Sleep is a physiological state that is characterized by the loss of active mental connections of the subject with the world around him. Sleep is vital for higher animals and humans. Long time believed that sleep represents rest,

Fibrinolysis system- an enzymatic system that breaks down fibrin strands that are formed during blood clotting into soluble complexes. The fibrinolysis system is completely opposite to the blood coagulation system. Fibrinolysis limits the spread of blood coagulation through the vessels, regulates the permeability of blood vessels, restores their patency and ensures the liquid state of the blood in the vascular bed. The fibrinolysis system includes the following components:

1) fibrinolysin (plasmin). It is found inactive in the blood in the form of profibrinolysin (plasminogen). It breaks down fibrin, fibrinogen, some plasma coagulation factors;

2) plasminogen activators (profibrinolysin). They belong to the globulin fraction of proteins. There are two groups of activators: direct action and indirect action. Direct-acting activators directly convert plasminogen into its active form - plasmin. Direct-acting activators - trypsin, urokinase, acid and alkaline phosphatase. Indirect-acting activators are in the blood plasma in an inactive state in the form of a proactivator. To activate it, tissue and plasma lysokinase is required. Some bacteria have lysokinase properties. There are tissue activators in the tissues, especially a lot of them are found in the uterus, lungs, thyroid gland, prostate;

3) fibrinolysis inhibitors (antiplasmins) - albumins. Antiplasmins inhibit the action of the enzyme fibrinolysin and the conversion of profibrinolysin to fibrinolysin.

The fibrinolysis process occurs in three phases.

During phase I, lysokinase, entering the blood, brings the plasminogen proactivator into an active state. This reaction occurs as a result of the cleavage of a number of amino acids from the proactivator.

Phase II – conversion of plasminogen to plasmin due to the cleavage of the lipid inhibitor under the influence of the activator.

During phase III, under the influence of plasmin, fibrin is broken down into polypeptides and amino acids. These enzymes are called fibrinogen/fibrin degradation products and have a pronounced anticoagulant effect. They inhibit thrombin and inhibit the formation of prothrombinase, suppress the process of fibrin polymerization, platelet adhesion and aggregation, enhance the effect of bradykinin, histamine, angeotensin on the vascular wall, which promotes the release of fibrinolysis activators from the vascular endothelium.

Distinguish two types of fibrinolysis– enzymatic and non-enzymatic.

Enzymatic fibrinolysis carried out with the participation of the proteolytic enzyme plasmin. Fibrin is broken down into degradation products.

Non-enzymatic fibrinolysis carried out by complex compounds of heparin with thrombogenic proteins, biogenic amines, hormones, conformational changes occur in the fibrin-S molecule.

The process of fibrinolysis occurs through two mechanisms - external and internal.

Along the external pathway, activation of fibrinolysis occurs due to tissue lysokinases and tissue plasminogen activators.

Proactivators and activators of fibrinolysis take part in the internal activation pathway, capable of converting proactivators into plasminogen activators or acting directly on the proenzyme and converting it into plasmin.

Leukocytes play a significant role in the process of fibrin clot dissolution due to their phagocytic activity. Leukocytes capture fibrin, lyse it and release its degradation products into the environment.

The process of fibrinolysis is considered in close connection with the process of blood coagulation. Their relationships occur at the level of common pathways of activation in the reaction of the enzyme cascade, as well as through neurohumoral regulatory mechanisms.

The intravascular conversion of fibrinogen to fibrin, which is normally very limited, can increase significantly during shock. Fibrinolysis is the main mechanism that ensures, under these conditions, the maintenance of the liquid state of the blood and the patency of blood vessels, primarily the microvasculature.

The fibrinolytic system includes plasmin and its precursor plasminogen, plasminogen activators, and inhibitors of plasmin and activators (Fig. 12.3). Fibrinolytic activity of blood increases with various physiological conditions body ( physical activity, psycho-emotional stress etc.), which is explained by the entry of tissue plasminogen activators (tPA) into the blood. It can now be considered established that the main source of plasminogen activator found in the blood is cells vascular wall, mainly endothelium.

Despite the fact that in vitro experiments have shown the release of tPA from the endothelium, it remains open question whether such secretion is a physiological phenomenon or is it simply a consequence of “leakage”. IN physiological conditions, apparently, the release of tPA from the endothelium is very small. With vessel occlusion and stress, this process intensifies. Biologically play a role in its regulation active substances: catecholamines, vasopressin, histamine; kinins increase, and IL-1, TNF and others decrease the production of tPA.

In the endothelium, along with tPA, its inhibitor, PAI-1 (plasminogen activator inhibitor-1), is also formed and secreted. PAI-1 is found in cells in more than TAP. In blood

									-FHP
		PAI-I- -
	PAI-II-

alpha2 Macroglobulin ------ *~Plasmin -

Fibrinogen

(D-fragment)

Rice. 12.3. Fibrinolytic system:

TPA - tissue plasminogen activator; PAI-I - tPA inhibitor; PAI-II - urokinase inhibitor; a Gir C - activated protein C; HMK - high molecular weight kininogen; FDF - degradation products of fibrin (fibrinogen); _ _ -

inhibition;----------- - activation

and subcellular matrix, PAI-1 is associated with the adhesive glycoprotein vitronectin. In this complex, the biological half-life of PAI-1 increases 2-4 times. Due to this, the concentration of PAI-1 in a certain region and local inhibition of fibrinolysis is possible. Some cytokines (IL-1, TNF) and endothelium suppress fibrinolytic activity mainly by increasing the synthesis and secretion of PAI-1. At septic shock the content of PAI-1 in the blood is increased. Disruption of the participation of the endothelium in the regulation of fibrinolysis is an important link in the pathogenesis of shock. The detection of a large amount of tPA in the blood is not yet evidence of fibrinolysis occurring. Tissue plasminogen activator, like plasminogen itself, has a strong affinity for fibrin. When it is released into the blood, plasmin is not generated in the absence of fibrin. Plasminogen and tPA can coexist in the blood but do not interact. Plasminogen activation occurs on the surface of fibrin.

The activity of tPA present in human plasma disappears rapidly both in vivo and in vitro. Biological half-life of tPA released after administration healthy people nicotinic acid, is 13 min in vivo and 78 min in vitro. The liver plays the main role in the elimination of tPA from the blood; functional failure there is a significant delay in elimination. Inactivation of tPA in the blood also occurs under the influence of physiological inhibitors.

The formation of plasmin from plasminogen under the influence of tissue activators is considered as an external mechanism of activation.

plasminogen mutations. The internal mechanism is associated with the direct or indirect action of f. CN and kallikrein (see Fig. 12.3) and demonstrates the close relationship between the processes of blood coagulation and fibrinolysis.

An increase in blood fibrinolytic activity detected in vitro does not necessarily indicate activation of fibrinolysis in the body. Primary fibrinolysis, which develops with a massive intake of plasminogen activator into the blood, is characterized by hyperplasminemia, hypofibrinogenemia, the appearance of fibrinogen breakdown products, a decrease in plasminogen, plasmin inhibitors, and a decrease in blood f. Y and f. Yiii. Markers of fibrinolysis activation are peptides that are detected on early stage action of plasmin on fibrinogen. With secondary fibrinolysis, which develops against the background of hypocoagulation, the content of plasminogen and plasmin in the blood is reduced, hypofibrinogenemia is pronounced, and a large number of fibrin degradation products (FDP).

A change in fibrinolytic activity is observed in all types of shock and has a phase character: a short-term period of increase in fibrinolytic activity and its subsequent decrease. In some cases, usually with severe shock, secondary fibrinolysis develops against the background of DIC.

The most pronounced primary fibrinolysis is observed with shock from electrical trauma, used with therapeutic purpose V psychiatric clinic and develops mainly when current passes through the brain. At the same time, the time of lysis of plasma euglobulins sharply decreases, which indicates the activation of fibrinolysis. At the same time, the shock that occurs when current passes through chest, is not accompanied by activation of fibrinolysis. It has been shown that these differences are explained not by different levels of plasminogen activator in the brain and heart, but by activation of fibrinolysis if the electric shock is accompanied by muscle cramps. Perhaps this causes compression of the veins by contracted muscles and release of plasminogen activator from the endothelium (Tyminski W. et al., 1970).

IN experimental studies It has been shown that during electric shock, plasminogen activators are released not only from the vascular endothelium, but from the heart, the renal cortex and, to a lesser extent, the lungs and the liver (Andreenko G.V., Podorolskaya L.V., 1987). In the mechanism of release of plasminogen activator during electric shock, neurohumoral stimulation is of primary importance. In traumatic shock, primary fibrinolysis is also often observed. Yes, already in early dates after injury (1-3 hours), victims experience an increase in fibrinolytic activity (Pleshakov V.

L., Tsybulyak G.N., 1971; Suvalskaya L.A. et al., 1980). A certain role here may be played not only by the release of vascular and tissue plasminogen activators, but also by the activation of f. XII. One of the mechanisms for activation of fibrinolysis during traumatic shock is a decrease in the activity of the CI esterase inhibitor, which activates f. HPa and kallikrein. As a result, the duration of circulation of activators of internal fibrinolysis increases. The degree of activation of fibrinolysis may also depend on the location of the injury, since the content of plasminogen activator in different tissues is not the same.

The biological half-life of plasmin is about 0.1 s; it is very quickly inactivated by a2-antiplasmin, which forms a stable complex with the enzyme. This, apparently, can explain that in some cases primary fibrinolysis in the initial period traumatic shock is not detected and, moreover, inhibition of fibrinolysis is observed. So, in case of organ injury abdominal cavity(II--III stages of shock) against the background of hypercoagulation, the presence of soluble fibrin-monomer complexes in the blood, fibrinolytic activity was reduced (Trushkina T.V. et al., 1987). This may be due to a sharp increase in the production of plasmin inhibitors as a response to the initial short-term hyperplasminemia. Total antiplasmin activity increases primarily due to α2-antiplasmin, as well as plasminogen activator inhibitor and histidine-rich glycoprotein. This reaction was described in detail by I. A. Paramo et al. (1985) in patients in the postoperative period.

After the primary activation of fibrinolysis in trauma complicated by shock, a stage of decreased fibrinolytic activity and/or secondary fibrinolysis develops. With the rapid development of shock DIC syndrome and secondary fibrinolysis develop very quickly (Deryabin I.I. et al., 1984).

In the mechanism of inhibition of fibrinolysis in shock, what is important is primarily an increase in general antiplasmin activity (mainly a2-antiplasmin), as well as a glycoprotein rich in histidine, which interferes with the binding of plasminogen to fibrin. Against the background of a decrease in fibrinolytic activity in the systemic circulation, local fibrinolysis in the damaged area appears to be enhanced. This is evidenced by the amount of PDF in the blood after injury.

Data on fibrinolytic activity of blood during hemorrhagic shock very contradictory, which is explained by differences in the volume of blood loss, associated complications etc. (Shuteu Yu. et al., 1981; Bratus V.D., 1991). Experimental data also did not bring complete clarity to this issue. Thus, I. B. Kalmykova (1979) observed in dogs after blood loss (40-45% of the blood volume, blood pressure = 40 mm Hg) an increase in fibrinolysis against the background of hypercoagulation, and in the hypocoagulation phase fibrinolysis decreased. In similar experiments, within 3 hours after blood loss, R. Garsia-Barreno et al. (1978) found that the time of lysis of plasma euglobulins and fibrinogen concentration did not change, and after 6 hours some inhibition of fibrinolysis was observed.

It is fundamentally important that changes in fibrinolysis during hemorrhagic shock are secondary, i.e., they arise against the background of circulatory hypoxia, metabolic acidosis etc. With other types of shock, activation of fibrinolysis can occur regardless of hemodynamic disturbances (for example, with electric shock).

In septic shock, fibrinolytic activity changes very quickly and, as with other types of shock, has a phase character: increased fibrinolysis, inhibition, secondary fibrinolysis (does not develop in all cases). R. Garcia-Barreno et al. (1978) tracked changes in the fibrinolytic activity of the blood in dogs with endotoxin shock, starting from the 30th minute and up to 6 hours after the release of Escherichia coli lipopolysaccharide. Fibrinolytic activity in experimental animals increased sharply, fibrinogen concentration decreased, and PDF was detected in 100% of animals after 1 hour. Consequently, coagulopathic changes, including fibrinolysis, developed independently of hemodynamic disorders, hypoxia, etc.

In the mechanism of activation of fibrinolysis during septic shock, primary importance is attached to inner path activation of plasminogen with the participation of f. XII and kallikrein (see Fig. 12.3). Primary hyperfibrinolysis in endotoxin shock develops due to the interaction of endotoxin with the serum complement system through activation of the properdin system. Component C3 and the last components of complement (C5-C9) activate both fibrinolysis and hemocoagulation.

Given that septic shock causes rapid and severe damage to the endothelium, it is safe to assume the involvement of an extrinsic plasminogen activation mechanism. Finally, in patients with septic shock, a decrease in Cl-esterase inhibitor, which is an inhibitor of fibrinolysis, was detected - it inactivates f. CPA and kallikrein (Colucci M. et al.,

1985). At the same time, under the influence of endotoxin, the formation of a fast-acting inhibitor of plasminogen activator increases (Blauhut B. et al., 1985). The significance of this regulatory mechanism remains to be studied.

If during traumatic, septic, hemorrhagic shock and electric shock, most researchers identify the initial period of activation of fibrinolysis, then in the early phase of cardiogenic shock fibrinolytic activity is reduced, and in the late phase it is increased (Lyusov V. A. et al., 1976; Gritsyuk V. I. and al., 1987). This is probably due to the fact that acute heart attack myocardium, complicated by cardiogenic shock, develops against the background of significant changes in the hemostatic system - hypercoagulation, tension of the fibrinolytic system, etc. This leads to depletion of the reserves of the vascular plasminogen activator, therefore, in cardiogenic shock, primary hyperfibrinolysis does not develop, despite severe hyperadrenalineemia. In the later stage of shock, hypofibrinogenelia, thrombocytopenia, and a decrease in f. activity are recorded. And, Y, YII, positive paracoagulation tests, i.e. signs of intravascular coagulation, and against this background secondary hyperfibrinolysis develops.

Changes in fibrinolytic activity during shock not only demonstrate a violation functional state hemostasis system, but also has pathogenetic significance. Increased fibrinolysis in initial stage shock undoubtedly has positive value, since the dissolution of fibrin helps maintain suspension stability of the blood and microcirculation. On the other hand, increased fibrinolysis against the background of a deficiency of procoagulants disrupts the coagulation mechanism of hemostasis. The breakdown products of fibrinogen and fibrin (FDP) have antithrombin, antipolymerase activity, inhibit platelet adhesion and aggregation, which reduces the effectiveness of platelet-vascular hemostasis. Thus, the pathogenetic significance of increased fibrinolysis during shock (especially secondary fibrinolysis) is that this increases the likelihood of hemorrhages.

Color index (CPU), or farb index (Fi), is a relative value that gives an idea of ​​the hemoglobin (Hb) content in an individual red blood cell (E) compared to the standard.

The standard is calculated as follows. The hemoglobin content in one red blood cell is equal to the quotient of the amount of Hb divided by the number of red blood cells. CP = Hb g/l*3 / 2 first digits of red blood cell count*10. Fine color index fluctuates between 0.75-1.0 and very rarely can reach 1.1. In this case, the red blood cells are called normochromic.

The color index is used in clinical practice to differential diagnosis anemia. Most anemias are accompanied hypochromia (a decrease in the amount of Hb in an erythrocyte), the color index will be less than 0.75. Hypochromia occurs as a result of a decrease in either the size of erythrocytes or the amount of hemoglobin (with anemia caused by blood loss, infection, etc.) Hyperchromia observed when pernicious anemia, severe anemia in children, the CP in these cases will be more than 1.1. Hyperchromia depends solely on an increase in the size of red blood cells.

4. The first phase of blood coagulation, external and inner loops(the main factors involved in the formation of prothrombinase).Blood clotting process is predominantly a proenzyme-enzyme cascade in which proenzymes, passing into an active state, acquire the ability to activate other blood coagulation factors. Such activation can be sequential and retrograde.

The process of blood coagulation can be divided into three phases: the first includes a set of sequential reactions leading to the formation of prothrombinase, in the second phase the transition of prothrombin (factor II) to thrombin (factor IIa) occurs, and in the third phase fibrin is formed from fibrinogen.

First phase - the formation of prothrombinase can occur by external and internal mechanisms. The external mechanism requires the presence of thromboplastin (factor III), while the internal mechanism is associated with the participation of platelets (factor P3) or destroyed red blood cells. At the same time, the internal and external pathways of prothrombinase formation have much in common, since they are activated by the same factors (factor XIIa, kallikrein, VMC, etc.), and also ultimately lead to the appearance of the same active enzyme - factor Xa , performing the functions of prothrombinase. In this case, both complete and partial thromboplastin serve as matrices on which enzymatic reactions unfold in the presence of Ca2+ ions.

The formation of prothrombinase along the external pathway begins with the activation of factor VII during its interaction with thromboplastin and factor XIIa. Besides, factor VII can enter an active state under the influence of factors XIa, IXa, Xa, IIa and kallikrein. In turn, factor VIIa not only converts factor X to Xa (leading to the appearance of prothrombinase), but also activates factor IX, which is involved in the formation of prothrombinase by an internal mechanism.

The formation of prothrombinase along the external pathway occurs extremely quickly (in 20-30 s), leading to the appearance of small portions of thrombin (IIa), which promotes irreversible platelet aggregation, activation factors VIII and V and significantly accelerates the formation of prothrombinase by an internal mechanism. The initiator of the internal mechanism of prothrombinase formation is factor XII, which is activated by the injured surface of the vessel wall, skin, collagen, adrenaline, in laboratory conditions - upon contact with glass, after which it converts factor XI to XIa. Kallikrein (activated by factor XIIa) and BMC (activated by kallikrein) may participate in this reaction. Factor XIa has a direct effect on factor IX, converting it to factor IXa. The specific activity of the latter is aimed at proteolysis of factor X and occurs with the obligatory participation of factor VIII (or VIIIa).

It should be noted that the activation of factor X under the influence of a complex of factors VIII and IXa is called the tenase reaction.

Ticket 5 1. Agglutigation reaction, conditions for its development. ABO blood groups. Agglutination - the process of gluing red blood cells, and it occurs only with certain combinations of serum and red blood cells.

Specific proteins in the red blood cell membrane - agglutinogens A and B, and in the blood plasma - specific proteins - agglutinins α and β. For each group according to the AB0 system, there is a certain combination of these proteins, two out of four:

Erythrocyte antigen system ABO. It is known that there are four blood groups. On what basis can the blood of all people on the planet be divided into only four blood groups? It turns out that based on the presence or absence of only two antigens in the erythrocyte membrane, A and B, four options the presence of these antigens on the erythrocyte membrane: option 1 - the erythrocyte membrane contains neither antigen A nor antigen B, such blood is classified as group I and is designated O(I). Option 2 - red blood cells contain only antigen A - the second group A (II). Option 3 - red blood cells contain only antigen B - the third group B (III). Option 4 - red blood cells contain both antigens - A and B - blood group AB (IV).

And blood clots, an integral part of the hemostasis system, always accompanying the process of blood coagulation and cultivated by factors involved in this process. Is important defensive reaction body and prevents blockage of blood vessels by fibrin clots. Fibrinolysis also promotes recanalization of blood vessels after bleeding has stopped.

Involves the breakdown of fibrin under the influence of plasmin, which is present in the blood plasma in the form of an inactive precursor - plasminogen. The latter is activated simultaneously with the beginning of the blood clotting process.

Internal and external pathway of activation

Fibrinolysis scheme. Blue arrows - stimulation; red arrows - suppression

Fibrinolysis, like the process of blood coagulation, occurs via an external or internal mechanism. The external activation pathway is carried out with the integral participation of tissue activators, synthesized mainly in the vascular endothelium. These activators include tissue plasminogen activator (tPA) and urokinase.

The internal activation mechanism is carried out thanks to plasma activators and activators of blood cells - leukocytes, platelets and erythrocytes. The internal activation mechanism is divided into Hageman-dependent and Hageman-independent. Hageman-dependent fibrinolysis occurs under the influence of blood coagulation factor XIIa, kallikrein, which causes the conversion of plasminogen to plasmin. Hageman-dependent fibrinolysis occurs most quickly and is urgent. Its main purpose is to cleanse the vascular bed of unstabilized fibrin, which is formed during the process of intravascular coagulation.

Hageman-independent - carried out under the influence of proteins C and S

Fibrinolysis inhibition

The fibrinolytic activity of the blood is largely determined by the ratio of inhibitors and activators of the fibrinolysis process.

In the blood plasma there are also fibrinolysis inhibitors that suppress it. One of the most important such inhibitors is α2-antiplasmin, which causes the binding of plasmin, trypsin, kallikrein, urokinase, tissue plasminogen activator. Thus, interfering with the process of fibrinolysis in its early and late stages. The α1-protease inhibitor is also a potent inhibitor of plasmin. Fibrinolysis is also inhibited by alpha2-macroglobulin, a C1-protease inhibitor, and a number of plasminogen activator inhibitors produced in the endothelium, as well as fibroblasts, macrophages and monocytes.

Regulation of fibrinolysis

A balance is maintained between the processes of blood coagulation and fibrinolysis in the body.

Increased fibrinolysis is due to increased tone of the sympathetic nervous system and entry into the blood