Thrombosis

Thrombosis (from Greek thrombsis - coagulation), lifelong formation of blood clots (thrombi)
in the lumen of the vessels or in the cavities of the heart. It is the most important cause of local
circulatory disorders: ischemia and venous hyperemia. In addition, 99% of the embolism is caused
by thrombi or parts thereof, the so-called thromboembolism.
Analyzing this definition, it is necessary to pay attention to the following two points. First,
thrombosis is an intravital phenomenon, differing from the postmortem blood clotting. The
thrombus is fixed on the vascular wall, and the postmortem clot of blood lies in the lumen of the
vessel freely and can be easily removed from it. This circumstance is important in forensic
medicine, when it is necessary to establish the cause of death and the time of its onset. Secondly,
thrombosis is not only the clotting of blood, but a complex process that involves a number of stages
and leads to the formation of a dense mass consisting of blood elements in the lumen of the vessel.
Blood coagulation is only one of the components of thrombosis.

Causes of thrombosis
1. Physical factors - the effect of electric current.
2. Chemical factors - adrenaline releases inhibit the synthesis of prostaglandin (prostaglandin slows
blood clotting), thereby promoting thrombosis; Taking hormonal preparations (for example,
contraceptives); Smoking contributes to the formation of nicotine thromboxane - a powerful
regulator of blood coagulability.
3. Mechanical factors - mechanical damage to the vessel wall.
4. Biological factors - the effect of endotoxins of microorganisms; Childbirth; Atherosclerosis,
diabetes mellitus, hypertension, allergies; the process of the appearance of tumors (development of
benign and malignant tumors) promotes thrombus formation.
5. Social factors - sedentary lifestyle contributes to inadequate blood circulation and can cause
pulmonary embolism or venous thrombosis.

Conditions for thrombus:

1. The strength of the stimulus.
2. Place of action.
3. Time of action.
4. The initial state of the body at the time of the action of the stimulus.

The main conditions contributing to intravascular coagulation (and, hence, thrombosis) were
formulated by Rudolf Virkhov in the middle of the last century and were called the triad of Virchow
or a cause-and-effect relationship in the mechanisms of thrombus formation:
1. Damage of the vascular wall;
In a normal blood vessel with an intact wall, laminar blood flow is observed when layers of
blood slide relative to each other linearly. If the integrity of the vessel wall is disturbed at the site of
this damage, the laminar flow is replaced by turbulent flow, that is, turbulence develops, which
contributes to the retention of the formed blood elements near the vascular wall and forms the basis
for the formation of a thrombus.
If the vascular wall is damaged, this part of it becomes wettable, that is, drops of liquid begin
to adhere to the wall of the vessel. This also contributes to fixing on it the uniform elements of
blood.
Normally, the blood cells and vascular wall have the same electrical charge, which leads to
their mutual repulsion. At the site of damage, the vascular wall loses its charge, due to which the
formed elements of blood settle on this place.
When the vessel wall is damaged from it, tissue thromboplastin is released into the
bloodstream, which, reacting with other coagulation factors, gives a push of blood coagulation, and
is also necessary for the formation of a thrombus.
 2. Violation of the activity of coagulating and anticoagulating blood systems. Changes in the
physico-chemical properties of blood, leading to an increase in its coagulability. For example, with
a disease such as erythremia, which significantly increases the number of all blood cells, including
blood platelets - platelets, and increases the viscosity of the blood, very often there is a generalized
thrombosis of the vessels, from which the patient dies.
3. Slowing of blood flow. The faster the blood flow in the vessel, the harder it is to hold the
shaped elements near the vascular wall, even despite its damage. For example, with severe
atherosclerosis, the wall of the ascending aorta is most severely damaged. However, in this part of
the aorta, thrombi are very rare, since the blood flow velocity is so high that the beginning clot
forms all the time from the wall and is carried away by the blood flow. The most common thrombi
form in the veins, where the blood flow is sharply slowed. Therefore, any factor that causes a
slowing of blood flow in the vessels, will promote thrombogenesis.
However, both of these factors remain only conditions conducive to thrombosis, but no more.
If there is no damage to the vascular wall, a thrombus is not formed, even if the blood flow in the
vessel is slowed and the physicochemical properties of the blood have changed. And only damage
to the vessel wall is the initiating moment of thrombus formation.

There are three types of thrombi:

1. White (agglutinative) thrombus. In its formation, the main role is played by the processes of
agglutination (gluing) of the blood elements, mainly platelets, leukocytes and fibrin. This thrombus
is formed slowly with a rapid flow of blood (more often in the arteries).
2. Red (coagulative) thrombus. In its formation, the main role is played by the processes of
coagulation (coagulation) of blood. In the loops of fibrin, in the formation of this thrombus,
erythrocytes are retained in large quantities, so this thrombus is red, formed rapidly with a slow
blood flow (usually in the veins).
Since the coagulation process proceeds faster than the agglutination process, the red blood clot
forms more rapidly than the white clot. Therefore, in emergency situations, when rapid formation of
a thrombus is required (for example, with bleeding), red blood clots are predominantly formed.
3. Mixed thrombus. It occurs most often. In the formation of this type of thrombus, processes
of agglutination and coagulation alternately take part. On a cut, this thrombus has a layered
character. The head of the mixed thrombus, that is, its part attached to the vascular wall, is usually
white, the body is layered, and the tail is red.
4. Hyaline thrombus.
Hyaline thrombus usually consists of destroyed erythrocytes, platelets, precipitating plasma
proteins, rarely contain fibrin. Thrombotic masses resemble hyaline. Such thrombi are found in the
vessels of the microcirculatory bed.

Depending on the size of the lumen in the vessel, distinguish:

1. The parietal thrombus is often found:
- in the heart on the valve or parietal endocardium with its inflammation
(thromboendocarditis);
- in the ears and between the trabeculae in chronic heart failure (heart disease, chronic
ischemic heart disease);
- in large arteries with atherosclerosis;
- in the veins with their inflammation (thrombophlebitis), in aneurysms of the heart and blood
vessels.
2. Clogging (occlusive) thrombus is formed more often:
- in the veins and small arteries with the growth of the parietal thrombus,
- less often - in large arteries and aorta.

Mechanisms of hemostasis, underlying the thrombosis.

In the process of thrombosis, four stages are distinguished:
 Stage 1 - cell (adhesion, aggregation and agglutination of platelets);
Stage 2 - coagulation (plasma coagulation phase (thrombin formation, fibrin formation));
Stage 3 - retractions (compaction).
4 stage - the outcome.

The degree of impaired function of the organs in thrombosis depends on its outcome, which
can be as follows:
1. Organization of thrombus, ingrowth into thrombus and replacement with its connective
tissue; Leads to a decrease in lumen or complete occlusion of the vessel, a violation of blood flow
and the development of ischemia or venous hyperemia (depending on where the thrombus was
located - in the artery or vein).
2. Closure of the thrombus and its transformation into embolus. In this case, the severed
thrombus is transferred by a current of blood to other regions of the body and clogs the vessel
through which it can not pass, and causes disturbances in the local circulation in this area.
3. Organization - recanalization - can develop in the process of organizing a thrombus due to
incomplete replacement of thrombus with connective tissue, which leads to inferior restoration of
blood flow in the vessel and pathological changes in the vascular wall; In the veins, there is often a
violation of the structure of the valves, their insufficiency, which is the cause of further
development of venous hyperemia (for example, with thrombophlebitis of the veins of the lower
extremities and the development of postthrombophlebitic syndrome).
4. Septic, purulent melting of the thrombus. When a thrombus is infected in the area where it
is located, purulent inflammation can begin. From a clot will begin to come off pieces and turn into
emboli. In addition to hemodynamic disorders, which these emboli cause, by clogging small
vessels, they will promote the dissemination of microorganisms to various organs and tissues.
5. Aseptic melting. Thrombotic resorption leading to restoration of blood flow in the vessel. In
this case, the degree of disruption of tissue function will depend on the duration of the ischemia
process until the complete resolution of the thrombus.

Evaluation of thrombosis for the body should be carried out from two positions. First of all,
thrombosis is a physiological process aimed at stopping bleeding from a damaged vessel. However,
with a pathological change in the walls of blood vessels, thrombosis from a protective-adaptive
reaction turns into pathological, leads to the development of often very severe disorders of local
circulation, which can result in disability or even death of the patient.
Positive and negative value of thrombosis for the body. It should be noted that thrombosis,
like many other processes in the body (inflammation, pain, etc.), from the standpoint of biological
expediency should be considered dialectically. On the one hand, thrombosis is a protective-adaptive
reaction, since it performs a biologically expedient role for the organism, especially in cases when it
is triggered by local, more exogenous, damage to the vascular wall, without which the existence of
the organism would be absolutely impossible, since any bleeding Would be fatal.
On the other hand, in pathological conditions in which thrombosis is triggered by the action of
endogenous (for example, alteration of the vascular wall in atherosclerosis,
hyperkatecholamineemia, release of proteolytic enzymes as a result of activation of the complement
system in an allergic reaction, etc.) or exogenous factors of extreme strength (multiple trauma ,
Severe stress), it becomes the cause of severe and even fatal complications (myocardial infarction,
pulmonary thrombosis, ischemic gangrene of the extremity, etc.), which allows Consider
thrombosis as a pathological process. The consequences of such thrombosis are extremely
unfavorable for the body, although the initial phase of pathological thrombus formation develops as
a result of the same causes as the process of normal blood clotting.
The consequences of thrombosis: thromboembolism, ischemia, venous hyperemia, ischemic
or venous infarction, gangrene.

Mechanisms of hemostasis
 Hemostasis is the stopping of bleeding with damage to blood vessels. Mechanisms that
provide hemostasis are realized not only with bleeding, but also with any damage to the
endothelium of the vascular wall caused by physical (for example, catheterization), hemodynamic,
chemical factors, inflammation, immune complexes, metabolic disorders (atherosclerosis, collagen
diseases) E. Hemostasis is achieved mainly due to the formation of thrombus as a result of the
interaction of plasma components, platelets and the vascular wall.
In this case, both parietal and intramural thrombosis can develop. Functional inferiority of the
hemostatic system can lead to local or generalized bleeding.
There are two mechanisms of hemostasis: platelet-vascular (primary) and coagulation
(secondary).
The predominance of this or that mechanism depends mainly on the caliber of the damaged
vessel and the rate of blood flow. However, effective hemostasis is possible only with the normal
functioning of both mechanisms.
Thrombolytic-vascular hemostasis. The stop of bleeding with damage to the vessels of the
microcirculatory bed is due to spasm of blood vessels and the formation of a platelet thrombus. The
totality of these processes is the essence of thrombolytic-vascular hemostasis.
To damage microvessels respond with a short-term spasm, resulting in bleeding from them in
the first 20-30 s. Does not arise. This vasoconstriction is caused by reflex spasm of blood vessels
due to contraction of smooth muscle cells of the vascular wall and is maintained by vasospastic
agents secreted by endothelium and platelets - serotonin, noradrenaline, adrenaline.
Normally, the number of platelets ranges from 150 x 109 / L to 400 x 109 / L, the normal life
span of the platelet after ligation from the megakaryocyte is 6-10 days, in addition, 15-25% of the
platelets are absorbed daily by the vascular endothelium, which provides angiotrophic and
endotheliocyte support Function of thrombocytes. They promote endothelialization at the site of
damage involving the secretion of growth factors.
In the formation of a thrombocytic thrombus, several consecutive stages are isolated:
- activation of platelets and adhesion of platelets to the vascular wall;
- aggregation of platelets;
- Release reaction;
- Compaction of platelet thrombus.
Activation and adhesion of platelets. When the vessels are damaged, there is a buildup of
platelets in this zone and their interaction with subendothelium elements - collagen and microfibrils.
After 1-2 seconds after injury, platelets adhere to the vascular wall. This represents the initial period
of platelet thrombus formation.
The most pronounced adhesive properties are collagen I and III types and von Willebrand
vascular wall factor, to which there are receptors on the surface of still unactivated platelets. In the
process of adhesion, the shape of platelets changes, from disc-shaped they become transformed into
prolate process cells-activated platelets. Adhesion of platelets to the subendothelium is facilitated by
a slowing of the blood flow, aggregation of erythrocytes, an increase in the viscosity of the blood,
an increase in the plasma content of large-dispersed proteins and lipids.
Aggregation of platelets. Along with adhesion, aggregation of platelets occurs, ie, their
connection with each other and the formation of conglomerates (aggregates) of different sizes and
densities. The aggregation inductors are arachidonic acid, thrombin, thromboxane A2, collagen,
adenosine diphosphate (ADP), serotonin, adrenaline, noradrenaline. Thrombin, arachidonic acid,
collagen stimulate the secretion of the contents of granules of platelets - the "release" reaction and
the synthesis of cyclic endoperoxides in platelets, including thromboxane A2. Serotonin and
thromboxane A2 also have vasoconstrictor properties.
In the platelets there are granules of four types - dense (type 1), a-granules (type 2),
peroxisomes (type 3), lysosomes (type 4). During the release reaction, the α-granules release the
following: (i-thromboglobulin, platelet factor 4, von Willebrand factor, platelet growth factor,
antiheparin factor, adrenaline, serotonin and ADP causing dense platelet aggregation from dense
granules, from peroxisomes and lysosomes - such Enzymes, such as arabinosidases, acid
hydrolases, proteases.
In the process of platelet aggregation, two phases are distinguished: reversible and
irreversible.
The first phase - the formation of loose platelet aggregates of 10-15 platelets with
pseudopodia. Such platelet aggregates are easily destroyed and carried away by a current of blood.
These aggregates do not provide complete hemostasis. At this stage, spontaneous disaggregation
under the influence of ATP, AMP, adenosine, fibrinogen degradation products and fibrin is possible.
The most pronounced disaggregating effect is prostacyclin (PG 12), which is formed
predominantly in the endothelium of vessels from cyclic endoperoxides, including platelets, under
the influence of prostacyclininsyntase. Prostacyclin stimulates platelet adenylate cyclase, which is
accompanied by the accumulation of cAMP and inhibition of aggregation. The half-life of
prostacyclin is about 2 minutes. Prostacyclin also has vasodilatory properties. Unlike other
prostaglandins, prostacyclin is not inactivated in the lungs. The concentration of prostacyclin in the
blood is low, but this is quite enough to prevent the formation of platelet aggregates in the
bloodstream and disaggregation of platelets at the site of vascular injury.
The second phase of irreversible aggregation - the formation of persistent platelet aggregates
occurs at a high concentration of substances that cause aggregation, and also at the action of low
concentrations of such aggregates, which have a pronounced stimulating effect and activate the
release of platelet granules (thrombin, arachidonic acid, thromboxane A2, collagen). In the
mechanism of platelet aggregation, an extremely important role is played by cyclic endoperoxides
and thromboxanes. Under the influence of inducers of aggregation of collagen and thrombin,
phospholipase A2 of the platelet membrane activates, which ensures the activation of the process of
lipid peroxidation, leading to the cleavage of membrane phospholipids. As a result, the arachidonic
cascade is activated and cyclic endoperoxides - prostaglandins (nFG2 and PGH2) and
thromboxanes A2 and B2 are formed. These prostaglandins and thromboxanes, especially
thromboxane A2, are powerful inducers of aphasia. Under the influence of thromboxane A2,
adenylate cyclase of platelets is inhibited, cAMP formation decreases, intracellular concentration of
Ca2 + ions increases, phosphotidylinositide pathway of hydrolysis of phospholipids of membranes
is activated, and platelet aggregation occurs.
Under normal conditions, the formation of platelet cyclic endoperoxides and thromboxanes is
insignificant. In the mechanism of limiting the biosynthesis of these thrombogenic substances,
cAMP plays the leading role, which regulates the concentration of intracellular Ca2 + through the
protein kinase system and inhibits the phospholipase A2. When the cAMP content in platelets
increases, their aggregation is inhibited, and when it decreases, it increases. Active influence on
lipid peroxidation and platelet cAMP exchange is one of the ways of pharmacological correction of
platelet aggregation.
Under conditions of aggregation, a decisive role is played by thrombin, which is secreted from
platelets and formed during coagulation hemostasis. Thrombin quickly activates irreversible platelet
aggregation, which ends with a viscous metamorphosis, a complex of morphological and
biochemical changes in platelets, including the formation of strong bridges between them, an
increase in membrane permeability, degranulation, and cell destruction.
During the aggregation, the contractile protein of platelets, thrombostenin, is activated. With
his participation there is a change in the form of platelets and their maximum approximation to each
other in aggregates that become dense and impermeable to the blood. The formation of a stable
platelet thrombus is facilitated by the filaments of insoluble fibrin formed in the zone of damage to
the vascular wall. Tissue thromboplastin (factor III) of the vascular wall interacts with plasma
clotting factors and as a result, thrombin is formed, which converts fibrinogen to fibrin, which fills
the space between platelets. Condensation of thrombus is facilitated by retraction of fibrin.
Thus, platelets determine the mechanisms of platelet-vascular hemostasis. In the process of
coagulation, platelet membranes are a kind of matrix on which the formation of enzyme-substrate
complexes occurs and the cascade process of serine protease activation. Isolation of thromboplastin
by platelets contributes to the activation of the external way of blood clotting.
Coagulation hemostasis. With damage to the arteries and veins, hemostasis occurs not only
with the participation of platelets, but also due to clotting of blood and the formation of a
coagulation thrombus. A prerequisite for the formation of a thrombus is the interaction of plasma,
platelet and tissue factors. Phospholipids of platelet membranes are the place where fixation of
procoagulants occurs and their activation.
Blood coagulation is a complex autocatalytic process, in which sequential activation of
inactive factors and the formation of serine proteases occur. There are three consecutive stages of
coagulation hemostasis: the formation of prothrombinase; Thrombin formation; Formation of fibrin.
Formation of prothrombinase. The formation of prothrombinase takes place along the
internal and external pathways.
The internal pathway for the formation of prothrombinase begins with contact activation of
factor XII in damage to the vascular wall. This is facilitated by naked collagen filaments and the
action of proteases of the damaged endothelium. The phase of contact activation is completed by
the formation of active factor XI (factor X1a). Fletcher factors (plasma precalicyrein) and Fitzgerald
(high molecular weight kininogen) participate in this process, which accelerate the activation of
factor XI and additionally provide the activation of factor XII, as well as zinc ions. Factor X1a on
the platelet membrane converts factor IX into factor IXa. Further, an enzyme-substrate complex is
formed with the inclusion of factors 1Xa and X, coenzyme of factor VIII and participation of Ca2 +
ions. The result of this process is the formation of factor Xa.
Factor VIII is a complex protein consisting of several subunits. The transport factor VIII
subunit is the von Willebrand factor (factor W), which provides stability in the circulatory bed of
factor VIII and the necessary concentration in the damage zone. Therefore, with a pronounced
deficit of factor W, there is a deficiency in the activity of factor VIII.
External pathway of protrombinase formation is realized when the vascular wall is damaged
and the interaction of tissue, platelet and plasma factors of hemostasis. When tissue (for example,
the vascular wall) is damaged, tissue thromboplastin (factor III), which is a lipoprotein containing
phospholipids and possessing protease activity, enters the bloodstream. Cytokines (IL-1, IL-8, FIO),
which activate the formation and isolation of factor III from endothelial cells and monocytes, can
play a large role in the mechanisms of tissue factor release. Tissue thromboplastin forms a complex
with factor VII and Ca2 + ions. This complex activates factor X. The external mechanism provides
faster formation of prothrombinase. However, effective hemostasis is possible only with the normal
functioning of both mechanisms of protrombinase formation.
There is an additional possibility of activation of factors IX and XI by the complex "factor III-
factor VII" (Josso loop), which promotes the formation of thrombin in the internal pathway.
Formation of thrombin. A complex of factors Xa, V, platelet phospholipids (factor III),
calcium ions and is a prothrombinase, which splits prothrombin to thrombin. The factor Xa, which
is part of the prothrombinase, cleaves a large fragment from the prothrombin molecule and creates
an inactive intermediate product, prothrombin 2, which is further cleaved by factor Xa to thrombin
that cleaves fibrinogen to fibrin. The resulting thrombin regulates thrombinogenesis, splitting the
prothrombin molecule to inactive prothrombin I and thereby preventing the formation of new
portions of thrombin. The main function of thrombin is the cleavage of fibrinogen. It also promotes
aggregation and platelet release, the biosynthesis of thromboxane A2 activation of factor XIII, etc.
In the clinical picture, the multifactorial effect of thrombin on hemostasis is of decisive importance
in patients with disseminated intravascular coagulation (thrombinemia).
Formation of fibrin. In the third stage of blood coagulation under the influence of thrombin,
fibrinogen is cleaved and converted into soluble and insoluble fibrin. The transformation of
fibrinogen into fibrin occurs in three stages.
Stage I - proteolysis of fibrinogen by thrombin; Peptides A and B are cleaved from the amino
acid portion of the a and β chains, forming a fibrin monomer.
 II stage - polymerization of fibrin monomer and formation of a soluble fibrin polymer
sensitive to plasmin.
Stage III - stabilization of soluble fibrin under the influence of factor XIII and the formation
of insoluble fibrin, resistant to plasmin.
Factor XIII (transamidase) is synthesized in the liver, circulates in the plasma, and is also
contained in platelets, erythrocytes, the vascular wall. In plasma, factor XIII is in the form of an
inactive precursor, which is activated by thrombin in the presence of Ca2 + ions. The XI factor
stabilizes fibrin by forming covalent cross-links in the fibrin-polymer molecule. After stabilization
of fibrin, a red blood clot is formed, consisting of insoluble fibrin and formed elements of blood.
Further consolidation of the thrombus occurs due to retraction under the influence of thrombostenin
of platelets.
Anticoagulant system of blood. The rate of thrombus formation, its size, the possibility of
spontaneous lysis, depends not only on the activity of coagulation factors, but also on the content of
natural anticoagulants in the blood and the activity of the fibrinolytic system.
Natural anticoagulants are divided into primary and secondary.
Primary anticoagulants. They are constantly formed in the body and enter the blood, where
they interact with the active form of procoagulants and inhibit them. The primary anticoagulants
include antithrombin III (AT III), heparin, cofactor II heparin, a2-macroglobulin, protein C,
thrombomodulin, protein S, etc.
Antithrombin III (AT III) - α2-globulin with a molecular weight of 58,000, is formed in the
liver and endothelial cells. Heparin-sulfated glycosaminoglycan-mucopolysaccharide, with a
molecular weight of 4000 to 40,000, is synthesized in mast cells and basophils of blood. A lot of it
is contained in the liver and lungs.
AT III inactivates factors IIa, IXa, Xa, XIa, Xa, XIIIa, stimulating the formation of an
enzyme-inhibitory complex with the inclusion of heparin from them. The kinetics of this process
depends on the sequence of inclusion in the complex of AT III, heparin and enzyme-coagulant. In
sum, heparin increases the activity of AT III approximately 2000 to 3000 times, i.e. Is included as
an immediate blood coagulation inhibitor. Heparin, connecting with AT III, changes its
conformational structure, with the active center of the latter becoming "more accessible" for
thrombin.
The proportion of AT III and heparin is approximately 80% of the total anticoagulant activity
of the blood. The complex «AT III - heparin» can be fixed on membranes of endothelial cells,
providing thrombore resistance of the vascular wall.
α2-macroglobulin is a glycoprotein that has a nonspecific antiprotease activity. It reversibly
binds and transports factors IIa, XIa, XIIa, kallikrein, plasmin, trypsin, chemotripsin and proteases
of the acute phase of inflammation. This glycoprotein interacts with thrombin much more slowly
than AT III.
Protein C is a vitamin K-dependent protein formed in the liver. Anticoagulant properties show
only the active form of protein C (A-PrC). The natural activator of PrS is thrombin. In the body,
activation of PP is carried out on the surface of membranes of endotheliocytes with the participation
of membrane protein of endothelial cells - thrombomodulin. The proteolytic activity of the
"thrombomodulin-PrC" complex is significantly enhanced in the presence of another vitamin K-
dependent protein-protein S, phospholipids of the cell membrane of platelets. The active form of
protein C inhibits non-enzymatic coagulation factors - Va and VIIIa, by subjecting them to
proteolysis.
Thrombomodulin is a protein integrated into the cell membrane of the epithelium. It is found
in the endothelium of macro - and microvessels of all organs, except for microvessels of the brain.
Thrombomodulin has a great affinity for thrombin and reversibly binds to it, while Ca2 + ions are
not required. After the connection with thrombomodulin, the conformational changes take place in
the thrombin molecule and the newly formed complex shows the activation properties of PrC in the
presence of Ca2 + ions. The rate of this process is induced by thrombin in 20,000 times.
Thrombomodulin promotes the release of tissue plasminogen activator, reduces the activity of the
tissue thromboplastin inhibitor (antithromboplastin).
Protein S - glycoprotein, is formed in the liver and endothelium, is contained in granules of
platelets. It significantly enhances the anticoagulant effect of A-PrS.
The main function of npS is the optimization of the binding of the active PRC to the surface of
the membranes, which catalyzes the proteolytic inactivation of the factors Va and VIIIa. Protein S
with the active form of protein C blocks the platelet receptors to the factor Xa. The interaction of Pr,
thrombin, thrombomodulin and npS occurs with the participation of the endothelial cell membrane
(Figure 18.5). Thus, the thrombin-activated system of PrC-npS, on the one hand, inhibits
haemocoagulation, and the other increases the fibrinolytic activity of the blood. Activation of this
system is considered as a primary anticoagulant mechanism.
The natural anticoagulants of the external pathway are the lipoprotein-associated coagulation
inhibitor (polypeptide), the inhibitor of the external clotting pathway, the apolipoprotein A and
protease inhibitor (antithromboplastins), which decrease the activity of factors II and VIIa, the lipid
inhibitor is a competitive inhibitor of platelet factor III, the mechanisms of their action are under
study.
Secondary anticoagulants. These anticoagulants are formed in the process of blood
coagulation and fibrinolysis. These include:
- antithrombin I (fibrin) - sorbs thrombin and factor Xa and turns them into inactive forms;
- antithrombin IV - the product of thrombin prothrombin cleavage, disrupts prothrombin
activation by prothrombinase;
- antithrombin VI - degradation products of fibrin, disrupt the polymerization of fibrin
monomer, inhibit platelet aggregation, factor Xa, thrombin.
Fibrinolytic system of blood.
Fibrin, formed in the process of blood clotting, undergoes cleavage - fibrinolysis. Central to
the system of enzymatic fibrinolysis is the activation of plasminogen with the formation of active
plasmin, the main enzyme of the fibrinolytic system. Substances that cause this reaction are called
plasminogen activators, they are found in many tissues and body fluids. There are two types of
tissue activators of plasminogen (TAP) - tissue (TAP 1) and urokinase (TAP 2). They are a series of
new proteases that are synthesized mainly in endothelial cells, and are also formed in the process of
microsomal and lysosomal oxidation in all organs, with the exception of the liver. The greatest
amount of activator is formed in the uterus, thyroid gland, adrenal glands, lungs, prostate gland.
TAP 1 is synthesized in monocytes, macrophages and secreted into the blood in small amounts. In
the epithelial cells of the renal tubules, urokinase is formed, which causes the activation of
circulating plasminogen and determines 15% of external fibrinolytic activity. Protease of leukocytes
possess independent fibrinolytic activity.
Under stress, physical activity, the introduction of some pharmacological drugs (ADH,
catecholamines, drugs containing nicotinic acid), the activity of the plasminogen activator in the
circulating blood is rapidly increasing. Powerful stimulants of TAP release are vasoactive
substances, especially adrenaline, histamine. When TAP 1 is released from tissue damage, it causes
local fibrinolysis that does not actually affect the total fibrinolytic activity of the blood.
Fibrinolysis is a protective mechanism that prevents excessive deposition of fibrin and thus
maintains normal conditions for microcirculation. Fibrinolytic activity of blood depends not only on
the content of plasminogen and its activators, but also on fibrinolysis inhibitors. Inhibitors of
fibrinolysis are divided into two groups: anti-activators and antiplasms.
Inhibitors of the activator of plasminogen of the first type are produced by endotheliocytes,
hepatocytes and bind TAP. Their production is increased in patients with myocardial infarction, with
inflammatory processes. The inhibitor of the plasminogen activator of the second type, formed in
endotheliocytes and monocytes and macrophages (including the placenta), inhibits urokinase
activity. Large amounts of inhibitor of the activator of plasminogen of the second type are produced
by cells of malignant tumors. Anti-activators inhibit the activation of plasminogen, with
predominantly local action. In recent years, a certain value has been attached to the inhibitor of
fibrinolysis activated by thrombin (TAFI - thrombin activator fibrinolys inhibitor). It is a protein
that, after activation by thrombin, acquires antifibrinolytic activity.
Antiplasms inactivate plasmin and are in abundance in the plasma. These include: a2-
macroglobulin, a-1-antitrypsin, complex "AT III-heparin", etc. The most important as a
physiological inhibitor of plasmin is the antiplasmin-a-2-glycoprotein, formed in the liver.
Antiplasmin for 0.1 sec irreversibly neutralizes the circulating plasmin, and also prevents the
binding of plasmin to fibrin and, thus, has an additional antifibrinolytic effect. Α2-Macroglobulin
inactivates plasmin, which interacts with fibrin.
In addition to fibrinolysis associated with the action of plasmin, formed from plasminogen
under the influence of the above activators, the factor XII-kallikrein-dependent fibrinolysis and
complement-mediated fibrinolysis are isolated.
Heparin-dependent fibrinolysis. This type of fibrinolysis develops after the formation of
complexes, which can include AT III-heparin, thrombin, plasminogen, plasmin, fibrinogen,
catecholamines, serotonin, factor XIII, thyroxine. These complexes have a lytic effect on unstable
fibrin, inhibit the polymerization of fibrin monomer and stabilize it with factor XIII. It is believed
that ε-aminocaproic acid inhibits precisely heparin-dependent fibrinolysis. Proteases released from
granules of activated leukocytes, especially neutrophils, proteases of microorganisms and fungi
(streptokinase, brynza, ochrase), pancreatic proteases (trypsin, chymotrypsin) have independent
fibrinolytic activity. Activation of fibrinolysis is observed with the action of tumor necrosis factor
(TNF), as well as under the influence of IL-1.
Complement-mediated fibrinolysis. When the C8 fragment is activated, plasminogen
converts to plasmin, the C3a component participates in the lysis of the fibrin clot.
A significant increase in fibrinolytic blood activity is normally compensated by neutralization
of plasmin and increased elimination of plasminogen activators. In pathological processes, primary
and secondary activation of fibrinolysis is possible.
Mechanisms of thrombophilia. Thrombophilia is a condition characterized by a
predisposition to thrombosis. For the development of thrombophilia, vascular damage to the
vascular wall (alteration of thrombogenic activity and thrombus resistance of blood vessels),
platelet (increased platelet function and thrombocytosis) and plasma mechanisms (increase in active
coagulants in blood - hypercoagulation, decrease in anticoagulant blood activity, inhibition of
fibrinolysis).
Changes in thrombogenic and thrombo-resistant activity of the vascular wall. In the
cellular elements of the vascular wall, substances such as tissue thromboplastin (factor III),
fibronectin, von Willebrand factor, thromboxane A2, platelet activating factor and others that form a
thrombogenic potential are formed. Some of them initiate thrombinogenesis and fibrin formation,
others - adhesion and aggregation of platelets. In physiological conditions, the formation and
release of thrombogenic factors in the vascular wall is limited, and when it is damaged or activated
by the active substances (adrenaline, histamine, serotonin, bradykinin, interleukin-1, thrombin, etc.),
the endothelium significantly increases.
In the mechanism of increasing the thrombogenicity of blood vessels, intramural thrombosis,
which develops with microdamages of the endothelium, is of great importance. Various factors are
released from the platelets, including the growth factor (factor 4), which causes the proliferation of
smooth muscle cells and fibroblasts, their migration to the endothelium, and the enhancement of the
secretion of collagen and other connective tissue components that have thrombogenic properties.
This mechanism of damaging the vascular wall is most pronounced in diabetes mellitus and
atherosclerosis.
Endothelial cells are both producers and effectors of IL-1, IL-6, IL-8, FIO, the growth of their
production is noted in sepsis, tumors, inflammation and serves as a nonspecific response to damage
to the endothelium. This leads to an increase in the adhesive properties of endothelial cells,
inhibition of thrombomodulin activity on the endothelium, and also to an increase in the production
of factor III, which leads to the formation of thromboses. In recent years, the importance of the
syndrome of antiphospholipid antibodies in the pathogenesis of thromboses and hypercoagulability
is widely discussed. For the first time they were found in patients with systemic lupus
erythematosus, who had thrombosis of veins and arteries. At present, anti-phospholipid antibodies
in the pathogenesis of IHD have a definite value.
A certain role in damage to the endothelium can also be played by smoking. In a complex
mechanism, damage is attributed to a decrease in the production of nitric oxide, an increase in the
sensitivity and release of endothelial vasoconstrictors, and a decrease in the angioprotective role of
high density lipoproteins due to a decrease in their synthesis in the liver.
Recently, in the damage to the vascular wall, great importance is attached to the disruption of
the amino acid exchange of homocysteine - hyperhomocysteinemia, which is often (10-15%)
observed in the European population, with the initiation of oxidative stress and associated
endothelial damage, and the proliferation of smooth muscle cells of the vessels , Which contributes
to the development of atherosclerosis. The risk of damage to the vascular wall during
hyperhomocysteinemia is comparable to that of hypercholesterolemia, hypertension, and tobacco
smoking.
Along with the thrombogenic properties of the vessels have antithrombogenic properties, or
thrombore resistance. In the endothelium and to a lesser degree in other cells of the vascular wall, a
number of factors are formed that inhibit blood clotting, activate fibrinolysis, inhibit aggregation
and adhesion of platelets. Factors that have anticoagulant activity and are formed mainly in the
endothelium include proteins C and S, thrombomodulin, heparin sulfates, etc. It is the
glycosaminoglycans that make up a pronounced negative charge of the endothelial wall, which
prevents the adhesion of blood cells on the vascular wall. Activation of fibrinolysis occurs with the
participation of the vascular activator of plasminogen and protein C, and the inhibition of platelet
aggregation - under the influence of prostacyclin, the endothelium relaxation factor, N0. Some
proteoglycans also inhibit the aggregation of platelets and their adhesion to endothelium and
subendothelium. Increased thrombogenic activity of the vascular wall and a decrease in thrombore
resistance provide conditions for thrombosis even with a slight damage to the vessel.
Increase in the functional activity of platelets and thrombocytosis. Increased propensity of
platelets to adhesion and aggregation is observed in atherosclerosis, diabetes, hypertension and
other diseases. The enhancement of platelet aggregation can be primary, i.e. Associated, for
example, with hyperproduction of thromboxane A2, which is observed with insulin-dependent
diabetes mellitus, late gestosis of pregnant women, development of malignant tumors, etc.
Hyperglycemia, hyperlipidemia (especially low-density lipoproteins) contribute to an increase
in platelet aggregation activity and their sensitivity to aggregation inducers. In insulin-dependent
diabetes mellitus, this is due to the presence of glycosylated platelet receptors, which ensures their
greater reactivity, including active adhesion to the collagen of the vascular wall. An increase in the
blood levels of adrenaline, β-lipoproteins, free fatty acids, factor W is accompanied by a significant
increase in aggregation activity of platelets. Deficiency of prostacyclin as the main antiplatelet
agent is also characterized by hyperaggregation of platelets.
The increase in the number of platelets above 600 x 10 9 / L, as a rule, causes thrombophilia,
thrombocytosis, observed in certain myeloproliferative diseases (Vakeza disease, myelofibrosis),
and as a reaction to splenectomy, iron deficiency.
For thrombogenic situations, as a rule, a decrease in the threshold of platelet sensitivity to
aggregation inducers, increased spontaneous aggregation of platelets in the bloodstream, a decrease
in the lifetime of circulating platelets is characteristic. Plasma increases the level of intra-platelet
factors β-thromboglobulin, anti-heparin factor, etc.), indicating the activation of the "release
reaction". The use of medicinal inhibitors of platelet receptors for fibrinogen IIb / IIIa is of great
importance in situations in which thromboses of arterioles lead to critical conditions, myocardial
infarction, etc.
Increase in the content of procoagulants in the blood. In some cases, for example after
acute blood loss, an increase in blood clotting is a compensatory reaction. Long and pronounced
hypercoagulation creates conditions for thrombosis.
 An increase in the activity of plasma procoagulants and coagulation potential alone does not
lead to thrombogenesis, but if the vascular wall is damaged, it accelerates and spreads thrombosis.
In the mechanism of hypercoagulability in conditions of pathology, the receipt of tissue
thromboplastin from the vascular wall into the blood is of great importance. This leads to the
formation of prothrombinase and thrombin in amounts exceeding the antithrombin activity of the
blood, resulting in increased coagulation potential. In mobilizing activators of blood coagulation
from the vascular wall under stress, adrenaline plays a big role. Activation of the sympathetic-
adrenal system stimulates the synthesis of fibrinogen, and glucocorticoids - the synthesis of
prothrombin, fibrinogen, proaccelerin.
An increase in the activity of procoagulants may be due to the direct action of certain plasma
components from them. Hyperlipidemia creates conditions for spontaneous activation of factor XII
and acceleration of prothrombinase formation. Hyperlipidemia and thromboplastinemia are noted
after intense emotional and physical exertion, so professional athletes are likely to have acute
coronary artery thrombosis with a decrease in the thrombore-resistant properties of the vascular
wall. In patients with clinical manifestations of atherosclerosis and hypertensive disease, a
significant increase in the blood of fibrinogen, prothrombin, factors VIII, XII, etc. occurs. Massive
entry into the blood of tissue thromboplastin as a result of extensive tissue damage, hemolysis,
intravascular activation of factor XII in septicemia can lead to intravascular coagulation Blood and
hemodynamic disorders. Pregnant women from the end of the II - beginning of the III trimester
have progressive growth in the plasma of coagulation factors I, II, VII, VIII, IX, XI, XII. By the end
of a physiologically occurring pregnancy, their level rises on average to 150-300%; The
concentration of fibrinogen is 4-5 g / l.
For dysfibrinogenemia, inherited autosomally recessively, an abnormal synthesis of fibrinogen
molecules is characteristic.
Reduction of anticoagulant activity of blood. One of the causes of thrombophilia is a
deficiency of natural anticoagulants and, above all, AT III. Disturbance of AT III metabolism can be
congenital and acquired. The congenital deficiency is inherited by the autosomal dominant type and
manifests itself both in a decrease in the production of AT III and in its affinity for heparin and
thrombin. The acquired deficiency of AT III develops in patients with hepatic insufficiency and a
predominant decrease in the synthetic function of hepatocytes, including those caused by vitamin A
deficiency. The variant of acquired deficiency of AT III is depletion of its depot in patients with
chronic renal failure, with nephrotic syndrome, acute venous thrombosis, Syndrome, against a
background of intensive heparin therapy. It is possible to bind AT III antibodies.
In atherosclerosis, diabetes, late stages of hypertension, the heparin content in the blood
decreases, this is due to the depletion of endogenous resources of heparin as a result of its constant
consumption as a coenzyme of lipoprotein lipase. One of the reasons for heparin-resistance may
also be a disruption of the interaction of AT III with heparin in patients with systemic lupus
erythematosus, Shenlene-Henoch disease. Congenital deficits of PrS and npS are inherited by an
autosomal dominant pathway, the incidence in the population is 1: 300. Reduction of the content of
FIpS in the blood is described in normal pregnancy, the intake of hormonal contraceptives,
thrombosis of the splanchnic veins and is a risk factor for thrombosis and hypercoagulability.
Oppression of fibrinolysis. Factors contributing to thrombosis include oppression of
fibrinolysis. Most often, the cause of oppression of fibrinolysis is a metabolic disorder in the
vascular wall and a decrease in the secretion of tissue activators of plasminogen (atherosclerosis,
hypertension, rheumatoid arthritis). The amount of TAP decreased in patients with myocardial
infarction. Fibrinolytic activity decreases with inflammation due to increased endothelium
production of the inhibitor of the first type of plasminogen activator. Large amounts of inhibitor of
TAP 2 (urokinase) are produced by malignant tumor cells. In pregnancy, as a rule, the production of
TAP under the influence of progesterone and placental lactogen decreases.
Excess antiplasms can also lead to a thrombophilic condition. Severe cases of thrombotic
disease associated with a genetically determined increase in the production of antiplasms are
described. An increase in the number of circulating inhibitors of plasmin and a decrease in
fibrinolytic activity is observed in kidney diseases.
A sharp decrease in the fibrinolytic activity of the blood is observed with a deficiency of
factor XII, pre-kalikrein, high-molecular kininogen. Factor XII dependent fibrinolysis is disrupted
in vasculitis, disseminated by intravascular coagulation, intensive treatment with streptokinase, etc.
Mechanisms of hypocoagulation and bleeding. Hypocoagulation and bleeding are
symptoms and complications of many diseases. The most common causes of hemostasis are:
thrombocytopenia and thrombocytopathy; Deficiency of plasma procoagulants; Increased
anticoagulant blood activity; Hyperfibrinolysis.
Thrombocytopenia and impaired functional activity of platelets. With pronounced
thrombocytopenia (less than 40 109 / l), the formation of prothrombinase (deficiency of factors III,
II) decreases and slows down the stages I and II of blood coagulation. With a decrease in the
number of platelets below 20 x 109 / l, retraction of the clot, which is carried out with the
participation of the platelet factor - thrombostenin, is also disturbed. Disorders of platelet formation
in the bone marrow occur in diseases such as B12 and folic deficiency anemia, radiation sickness,
tuberculosis, leukemia, and metastasis of tumors in the bone marrow. Congenital thrombocytopenia
may accompany chromosomal abnormalities such as trisomy over the 13th, 18th, 21st pairs of
chromosomes. Some medications (trimethoprim, methoxazole, cytostatics, estrogens, thiazide
diuretics), alcohol cause a decrease in platelet production.
Thrombocytopenia can also develop as a result of increased destruction of platelets during
transfusion of old canned blood (with a shelf life of more than 5 days), in a centrifugal pump of the
pulmonary circulation apparatus and platelet damage by prosthetic heart valves ("active" surface).
Lysis of platelets during the cytotoxic reaction is associated with the effect of antiplatelet
antibodies, primarily IgG (90% of cases). This is observed with immune thrombocytopenic purpura
(Verlhof disease), with systemic lupus erythematosus. Antithrombocyte antibodies of a pregnant
woman, bypassing the hematoplacental barrier, cause thrombocytopenia in the fetus.
Thrombocytopenia due to heteroimmune changes can occur in children during convalescence after
acute respiratory viral infections (influenza, adenovirus), cytomegalovirus infection, rubella,
measles, chicken pox, sepsis, and after vaccination. Immune mechanisms of thrombocytopenia have
definite value in patients receiving sulfonamides, rifampicin, quinidine, and gold preparations.
Thrombocytopenia is often found in people with HIV infection. Probably, the combined
mechanisms of thrombocytopoiesis disorder caused by IL-2 deficiency and changes in IL-3 activity,
immune platelet damage, and the action of medications are likely to be included.
Thrombocytopenia is characteristic of the Shenllein-Genoch syndrome, hemolytic-curum
syndrome, and the Moszkowitz disease (thrombotic thrombocytopenic purpura). In these situations,
the decrease in the number of circulating platelets is caused by their intensive consumption in the
process of microthrombogenesis.
When thrombocytopenia is marked sluggish healing of wounds in the oral cavity, as platelet
growth factors are necessary for normal repair of mucosal cells.
Primary thrombocytopathy is due to genetic disorders of the platelet receptor apparatus or
deficiencies in the storage pools of granules. In these cases, the intensity of adhesion and
aggregation of platelets decreases.
Thrombocytopathy associated with a deficiency of platelet factors (the number of factors III
and IV) is manifested by a violation of the release reaction and a decrease in their adhesive and
aggregation activity. In this case, even against a normal number of platelets, the time of bleeding
from the vessels of the microcirculatory bed increases.
Secondary thrombocytopathy occurs with the use of non-steroidal anti-inflammatory drugs
(salicylates, brufen, butazolidine), antidepressants (MAO inhibitors), cardiac glycosides,
adrenoblockers, antibiotics (levomycetin, carbenicillin, large doses of penicillin), thiazide diuretics,
antihistamines.
The mechanism of action of the listed drugs is reduced to a decrease in the formation and
depletion of storage pools of certain platelet factors.
 The rapid depletion of storage pools occurs in platelets of canned blood already within the
first 24 hours after its preparation.
Clinical signs of thrombocytopathy are manifested by subcutaneous hemorrhage, gingival
(extraction of teeth, use of a rigid toothbrush), nasal, menstrual bleeding.
Deficiency of plasma procoagulants. Deficiency of plasma procoagulants is manifested by
the violation of the coagulation unit of blood coagulation and hypocoagulation. Deficiency of
plasma procoagulants is observed with hereditary or acquired violations of their biosynthesis,
increased consumption (excessive use during the coagulation process, the action of antibodies), and
also an increase in the rate of their decay.
Hereditary hypocoagulation occurs in patients with a deficiency of almost all coagulation
factors. Hereditary deficiency of plasma procoagulants is quite rare and does not always manifest
clinically. This is because in the blood of a healthy person there is a significant excess of each
factor. So, for normal hemostasis, only about 30-40% of the prothrombin present in the blood, 5-
10% of proconvertin, 25-50% of fibrinogen, etc. are required.
Hereditary deficiency of factors XII, IX, VIII, VII leads mainly to a slowing down of the first
stage of blood clotting and a decrease in the formation of prothrombinase, a deficiency of factor II
to a slowing down of the second stage of blood coagulation and a decrease in the formation of
thrombin.
Hereditary coagulopathies in 90% of cases are associated with deficiency of factors VIII and
IX (haemophilia A and B) and von Willebrand disease.
Haemophilia A is noted in the population of one for 10 - 100 thousand men. Some members of
families of patients with hemophilia A have now succeeded in detecting an abnormal allele when
inheriting fragments of RFLP S associated with the factor VIII gene in the 10th chromosome. This
gene often mutates, which explains the appearance of new "sick families". The locus responsible for
the synthesis of factor VIII adjoins the loci of color blindness and the enzyme glucose-6-phosphate
dehydrogenase. The development of delayed hemorrhage in patients with hemophilia A is only
observed with factor VIII deficiency in more than 75% of cases. Transport factor VIII is carried out
by the plasma part of factor W. Therefore, in patients with hemophilia A there is a compensatory
increase in the level of factor W in plasma, which facilitates the delivery of factor VIII to the matrix
of the prothrombinase complex. In patients with haemophilia A (mild and moderate severity - the
concentration of factor VIII above 5%) in response to damage to the vascular wall, the release of
factors VIII and W from the endothelium is significantly increased, especially after the
administration of vasopressin drugs. During surgery, a significant release of factor III in these
patients, combined with preoperative preparation (transfusion of cryoprecipitate, blood plasma) to
some extent prevent severe blood loss.
In women - conductors of hemophilia A, the deficit of factor VIII is approximately 50% of its
normal level in the plasma of healthy individuals. Clinically, such a deficit of the factor can
manifest only in operations with severe blood loss and during childbirth.
Hemophilia B (Christmass disease) is a disease caused by factor IX deficiency, the path of
inheritance is recessive, linked to the X chromosome. Frequency of occurrence is 1 / (100 - 700
thousand). The hemophilia clinic B is indistinguishable from hemophilia A, and the diagnosis is
established using laboratory diagnostics. Approximately 1% of hemophilia B patients also have
antibodies inhibiting factor IX in the plasma.
One of the manifestations of hereditary disruption of the synthesis of plasma procoagulants is
the formation of abnormal clotting factors, such as factor VIII (hemophilia A), factor IX
(hemophilia B), factors I, II, IX, XIII. By their immune properties, they are similar to normal
factors, but functionally inactive.
Factor XIII deficiency refers to rare diseases with an incomplete-rooted type of inheritance,
manifested by a violation of the formation of cross-links of fibrin. Rapid lysis of inferior fibrin
lining in patients is manifested by slow healing of wounds. Due to the violation of embryo
implantation, women experience habitual miscarriages. In newborns from the first days of life, there
is a so-called umbilical syndrome, characterized by high bleeding from the umbilical cord and poor
healing of the umbilical wound. Factor XIII, apparently, participates in the mechanisms of
spermatogenesis, since men with this deficiency suffer infertility.
Von Willebrand disease is a disease that occurs in persons with a deficiency of factor W, the
path of inheritance is autosomal dominant, less often autosomal recessive. Frequency of occurrence
1 / (10 -20 thousand). The latent course of von Willebrand disease is observed in 1% of the
population.
The factor W consists of two components - plasma and vascular (antigenic). Plasma factor W
is a transport coarse-molecular component of factor VIII, vascular factor W provides adhesion of
platelets. Therefore, the value of factor W is reduced to its participation in the mechanisms of
platelet-vascular and coagulation hemostasis.
Several types of Willebrand disease are described: type I and type III are caused by a
quantitative deficit of unchanged factor W, and IIa and IIb types are associated with the synthesis of
abnormal W factor molecules. Clinically, the disease is characterized by the appearance of bleeding
immediately after injury, bleeding from the vessels of the microcirculatory bed, the appearance of
petechial hemorrhages , Vesicles with hemorrhagic contents in the oral cavity, in women - with
hyperspolymenorei.
Acquired hypocoagulation is observed much more often. The reason for the disruption of the
coagulation mechanism of hemostasis is a lack of biosynthesis of procoagulants or an increase in
their elimination due to disintegration, consumption, and binding. With liver diseases (hepatitis,
cirrhosis, toxic lesions), biosynthesis of factors 1, II, V, VII, IX, X, XIII in hepatocytes decreases.
Most often, there is a decrease in the activity of factors VII and II. This is one of the reasons for
reducing the coagulation potential of blood in patients with liver disease.
In the synthesis of factors II, VII, IX, X, vitamin K is required at the final stage of their
formation, when glutamic acid is included in the γ-carboxylation reaction. Therefore, these factors
are called vitamin K-dependent and procoagulants. Vitamin K enters the body with food, in the
small intestine it is emulsified and absorbed. The source of endogenous provitamin K is the
saprophytic bacterial flora of the intestine, it is transported to the liver where it is converted into
active vitamin K (epoxide) in the hepatocyte microsome with the participation of epoxidase.
Deposited vitamin K in the liver, its reserves are sufficient for the synthesis of vitamin K-dependent
procoagulants for 20 to 30 days. Absolute deficiency of vitamin K develops when its intake is
insufficient with food, impaired absorption in the intestine in the syndrome of malabsorption (hypo
and achiolia, enteropathy), its insufficient formation of intestinal microflora in dysbacteriosis. The
relative deficiency of vitamin K occurs when the body's need exceeds its intake.
Physiological deficit of vitamin K is observed in newborns due to insufficient colonization of
the intestine with microflora. Under physiological conditions, the biosynthesis and decomposition
of clotting factors are in a state of dynamic equilibrium. In many pathological processes, this
equilibrium is disrupted and, in particular, the decay prevails over the synthesis, which leads to a
decrease in the activity of procoagulants and hypocoagulation. Blood clotting is reduced,
hemorrhagic complications are often observed.
In canned blood, the number of factors V and VII is sharply reduced, since they are the
shortest-lived (the half-life of factor VII fluctuates from 2 to 6 hours).
To the majority of plasma procoagulants, antibodies can be produced, in their structure it is
usually IgG, which inhibit clotting factors.
Deficiency of factor V is observed in patients with chronic myelogenous leukemia in the
presence of the Philadelphia chromosome, as well as in patients with lymphoblastic leukemia.
There are patients with acquired forms of Willebrand disease, usually of an autoimmune
nature.
Increase in anticoagulant activity of blood. This condition arises not only because of
deficiency of procoagulants, but also in excess of anticoagulants - antithrombin III, heparin.
An increase in the blood of endogenous heparin is observed with collagenoses, leukemias,
anaphylactic shock, with thrombin formation inhibited and blood clot formation slowing down.
 Exogenous hypergeparinemia is associated with an overdose of heparin in the treatment of
thromboembolic complications, operations with prolonged extracorporeal circulation. In this case,
all stages of blood coagulation are inhibited and hemorrhagic syndrome develops.
Increased activity of AT III is observed in patients with cholestasis (vitamin A deficiency)
receiving anticoagulants of indirect action (imbalance between the synthesis of vitamin K-
dependent procoagulants and AT III), in women suffering from menorrhagia.
There are primary and secondary hyperfibrinolysis.
Primary hyperfibrinolysis is observed with a massive intake of tissue activators of
plasminogen into the bloodstream and a sharp decrease in the formation of antiplasms. The increase
in the formation of TAP is noted in cases of progression of the tumor process and severe hepatic
insufficiency. In the period of menstrual blood loss, with burns, stress, prescription of drugs of
nicotinic acid, the release of TAP also increases. Enzymes of bacterial origin have the ability to
activate fibrinolysis. Reduction of the formation of antiplasms and increased fibrinolytic activity
often occur in patients with liver damage. They have a pronounced tendency to bleeding, and this is
also noted in the genetic defect of production (x2-antiplasmin (Miasato disease).) Enhanced lysis of
fibrin can be noted with factor XIII deficiency due to a disruption in the formation of fibrin
polymer.
Secondary hyperfibrinolysis is an increase in fibrinolytic activity of blood in response to an
increase in fibrin formation, develops against the background of DIC syndrome. The violation of
hemostasis in hyperfibrinolysis is due to the dissolution of fibrin and the inability to form a
coagulation thrombus. In addition, PDF have an inhibitory effect on platelet aggregation and all
stages of blood clotting.

Syndrome of disseminated intravascular coagulation (DIC-syndrome).

DIC-syndrome is characterized by a generalized activation of the system of hemostasis and
fibrinolysis, in which there is a mismatch in the regulation of the aggressive state of the blood.
The most common DIC syndrome is a complication of the following diseases:
- shocks of any genesis (in 90 - 100% of cases);
- septic states (in 70% of cases);
- bacteremia and viremia (in 30% of cases);
- tumors, primarily leukemia;
- thromboembolism of the pulmonary artery;
- burns;
- Long crush syndrome;
- obstetric pathology (premature detachment and placenta previa, severe late gestosis of
pregnant women, manual removal of the placenta, cesarean section, bleeding);
- Acute intravascular hemolysis and cytolysis (hemorrhagic fevers, malaria, transfusion of
incompatible blood, action of snake and fungal poisons);
- operations on the parenchymal organs (liver, spleen, prostate, lung), accompanied by severe
blood loss;
- Vascular endoprosthetics, operations on the valvular heart apparatus;
- use of the device of artificial circulation;
- transplantation of organs and tissues.
Mechanisms of DIC-syndrome. At the heart of the DIC syndrome lie: marked activation of
the coagulation and thrombocyte links of hemostasis with the addition of a secondary massive
endothelial damage. The parallel launch of these mechanisms, each of which is capable of
enhancing the other, determines the rapid formation in the vascular bed of active forms of
coagulants. The main ways of implementing these mechanisms are as follows:
External activation mechanism is carried out with a massive intake of factor III in patients
with extensive burns, decay of tumors, embolism with amniotic fluid, premature placental
abruption, with a dead fetus syndrome. Expressed amounts of factor III are released in massive
cytolysis, which is caused by death of leukocytes (sepsis, cytostatic therapy), or erythrocytes (crises
of hemolytic anemia). The central role in the activation of coagulation in sepsis, inflammation,
autoimmune processes is given to the action of cytokines IL-1 and IL-6.
The internal mechanism of activation is observed in the primary diffuse lesion of the vascular
wall and the activation of factor XII under the influence of endotoxins. This is observed in sepsis,
rickettsial, viral, bacterial infections, damage to the endothelium by immune complexes. The
pronounced activation of factor XII leads to simultaneous stimulation of the coagulation and
fibrinolysis system, and, consequently, to a multidirectional effect on hemostasis in general. The
cytokines (IL-1) have a significant effect on the mechanism of activation of the internal pathway.
Direct activation of factors by proteolytic enzymes, including trypsin in acute pancreatitis
(activates factor X and thrombin) by the products of cell death, by toxins of microorganisms.
The primary activation of platelets occurs with tropical malaria, the impact on platelets of
soluble complexes of AG-AT in the case of the Shenlein-Genoch syndrome. With pronounced
damage to the endothelium, initiation of intravascular aggregation of platelets (contact with
collagen and other aggregation activators) is noted, which is observed, for example, in
meningococcal sepsis.
In the process of aggregation, a large amount of factor III is released from the perishing
platelets, which supports haemocoagulation along the external pathway.
Damage to the endothelium is initiated by immune complexes that activate the cascade of the
complement system. The components of СЗа and especially С5а increase the formation of free
oxygen radicals by activating neutrophils and isolating IL-1, FIO (tumor necrosis factor) from
monocytes. Activated neutrophils release serineelastase, which directly damages the endothelium.
The most demonstrative are these lesions in sepsis. Damage to the endothelium is possible due to
"osmotic impact" in hyperglycemia.
In the clinical picture of ICE, these mechanisms, as a rule, are combined with each other.
According to the nature of the flow, acute and chronic DVS-syndrome are isolated. Mortality
with the development of acute DIC syndrome is 30 - 50%.
The process is of a phasic character and always begins with hypercoagulation, which activates
the processes of fibrinolysis.
Stage I - hypercoagulable - lasting an average of 15 - 20 minutes. With a rapid flow of DIC-
syndrome, it can dramatically decrease. Intravascular coagulation is accompanied by the
consumption of coagulation factors and anticoagulants. The resulting thrombi loose, circulating
microthrombi represent emboli and, consequently, clog small vessels, disrupting microcirculation in
organs and tissues. The leading symptoms in the clinical picture are: cold extremities, severe pallor
of the skin, dyspnea with an inspiratory component, which determines the development of severe
tissue hypoxia and metabolic acidosis.
It should be noted that the microthrombi formed in the DIC syndrome have a loose gel-like
consistency and are very different in structure from classical blood clots formed in large vessels.
II stage - consumption coagulopathy. Isolate stage IIa, characterized by depletion of clotting
factors due to their consumption without excessive activation of fibrinolysis. Stage IIb is
characterized by progressive activation of fibrinolysis in combination with increasing
hypocoagulation. Activation of fibrinolysis has an adaptive value, since it promotes the partial
release of microcirculation from microthrombi and the elimination of tissue ischemia. The plasma
reduces the number of platelets, gradually reducing the concentration of fibrinogen. Clinically, this
stage is characterized by the appearance of bleeding in the areas of damage (surgical wound, uterine
cavity, injection site).
Stage III - hypocoagulation - is characterized by the depletion of all coagulation factors and
anticoagulants, expressed by hypofibrinogenemia, thrombocytopenia, as well as abnormal
fibrinolytic activity (secondary hyperfibrinolysis). At the same time there is fibrinolysis and
fibrinogenolysis, which leads to an increase in the tens and hundreds of times the CDEF in the
blood.
Activation of the kallikrein-kinin system of plasma, caused by the presence of activated forms
of the factor of HNa, leads to an increase in the permeability of the vascular wall and a decrease in
its tone. Clinical signs of the stage are progressive bleeding in the areas of damage and previously
intact tissues (mucous membranes of the eyes, gastrointestinal tract, genitourinary system,
respiratory tract).
IV stage is a stage of outcomes or a stage of residual manifestations of vascular blockade by
microthrombi.
When pharmacological correction of disorders in the system of hemostasis in patients with
DIC syndrome should take into account the phase nature of its development and the transition from
intravascular coagulation to bleeding.
DIC-syndrome can be one of the reasons for the development of increasing multi-organ
insolvency, characterized by the development of acute renal failure, hemolytic-uremic syndrome,
respiratory distress syndrome, acute adrenal insufficiency
Chronic DIC-syndrome is often found in patients with a tumor process at stages I-IV of its
development, chroniosepsis, at the initial stage of renal failure, in pneumonia, influenza and other
acute respiratory viral infections.
The process is characterized by prolonged local hypercoagulability and phlebotrombosis in the
veins of the lower extremities, less often in the veins of the pelvis and upper extremities (Tussaud's
syndrome). The metastasis of dense tumors in 75% of cases is accompanied by migrating
phlebothrombosis. Chronic DVS-syndrome can develop in patients with malignant lung tumors,
ovaries, mammary carcinoma, prostate carcinoma, disseminated neuroblastoma, metastatic gastric
adenocarcinoma, and colon carcinoma. For a clinician, the appearance of signs of persistent
phlebotrombosis against the background of normal somatic status and consistency of the venous
bed should always serve as a basis for examining the patient and excluding oncological pathology.
With chronic hepatic insufficiency, there is an internal combustion engine with severe
hypocoagulation. Development of chronic DVS-syndrome is possible with microthromboskulitis
(hemolytic syndrome, thrombotic thrombocytopenic purpura).
Hemolytic-uremic syndrome (Gasser's syndrome) is noted in viral, bacterial infections in
children and women who gave birth. Thrombotic thrombocytopenic purpura (Moshkovitsa's
disease) actually repeats the pattern of hemolytic-uremic syndrome: fever, hemorrhagic syndrome,
acute renal failure, microangiopathic hemolytic anemia. Intravascular coagulation is noted in all
organs.
With Shenlen-Henoch disease, the development of DIC syndrome is due to the formation of
generalized microthrombovasculitis, which is based on the damage of microvessels by circulating
immune complexes and activated components of the complement system. The factor that induces
DIC syndrome in hypertensive disease is most likely damage to endotheliocyte membranes in case
of hemodynamic stress.
Micro- or macroangiopathy in diabetic patients is a condition for the development of chronic
DIC syndrome. This is promoted by hypercoagulation in combination with hypophybrinolysis and
high reactivity of platelets.
A definite value in the pathogenesis of DIC syndrome has a long-term localized intravascular
coagulation of blood in various organs, which, as a rule, are damaged by the inflammatory process.
This is especially true for glomerulonephritis, acute pneumonia, some diffuse lesions of the liver
parenchyma, metroendometritis, salpingo-oophoritis. In the pathogenesis of these conditions, the
stage of hypercoagulability of different duration and severity is noted, which is determined by the
degree of tissue damage and subsequent chronic release of tissue thromboplastin, as well as chronic
damage to the endothelium by immune complexes. The vessels of the microcirculatory bed of these
organs are gradually filled with microthrombi, which contributes to depletion of the coagulation
potential and activation of fibrinolysis with the development of hypocoagulation in the future. The
possibility of developing the DIC syndrome when circulating a significant amount of streptococci in
the bloodstream that can enter the systemic circulation from the microvessels of the dentoalveolar
system during dental interventions (treatment of caries, etc.) has been noted. Streptococci cause
intravascular aggregation of platelets, contribute to the formation and "dispatch" of microthrombi,
including microvessels of the myocardium. In patients, there were cases of myocardial infarction
and even development of septic shock.
The examination of patients with changes in the hemostasis system begins with the
determination of the number of platelets as direct participants in the process of thrombus formation.
For a more detailed evaluation of the hemostasis system, coagulation tests (clotting time, bleeding
time, recalcification time, kaolin time, prothrombin index, thrombin time, plasma tolerance to
heparin, free heparin, AT III, plasma fibrinogen, fibrinolytic activity, paracoagulation tests) and
coagulation tests are used. The study of adhesive and aggregation activity of platelets.

Embolism
Embolism is a typical pathological process caused by the presence and circulation in the blood
or lymph of particles not found there under normal conditions, often causing occlusion (blockage)
of the vessel with subsequent violation of local blood supply.
As emboli, 99% of all embolisms are clots of blood coagulated inside the blood vessels, that
is, clots. Embolism, as well as thrombosis, is an important reason for reducing the cross-sectional
area of the vessel, and consequently, the volume velocity of blood flow and perfusion of the blood
vessel. Typically, embolism occurs in the arteries as a result of the transfer of emboli along the
course of the blood flow. However, embolism of the veins is also possible - if a large embolus gets
stuck in the valve area or, moving against the blood flow under the influence of gravity, falls into a
narrow section of the vein (retrograde embolism).
Classification of embolism
1. By origin of the embolus:
- exogenous - air, gas, medicamentous embolism, foreign bodies;
- endogenous - thromboembolism (detached part of thrombus), fatty (with trauma, fractures of
tubular bones), tumor masses, amniotic fluid, bacterial, solid particles (tissues, microbes, parasites,
foreign bodies);
2. Localization:
- a small circle of blood circulation,
- a large circle of blood circulation,
- portal vein.
3. On the mechanism of development:
- orthograde - according to blood flow;
- retrograde - against current under the influence of gravity, develops in large venous trunks
with a slowing of blood flow and a decrease in the sucking action of the chest;
- Paradoxical - due to the presence of defects of the interatrial or interventricular septum and
other heart defects with the right-left shunt, emboli are able to pass the branches of the pulmonary
artery and find themselves in a large circle without getting stuck in the small capillaries;
Air embolism arises from the ingress of air into the vascular system from the environment.
Causes of air embolism can be damage to large veins of the neck, chest, sinuses of the dura mater,
neurosurgical operations with opening of venous sinuses, artificial circulation, medical and
diagnostic puncture of the lungs, laparoscopic operations, improperly conducted intravenous
injections, etc.
Air can get into the vessel (most often in a vein or venous sinus) under two indispensable
conditions: if there is a message of the vessel with an air source and excess air pressure over
intravascular pressure. The development of air embolism is facilitated by a number of concomitant
circumstances. So, this embolism often develops in conditions of hypovolemia. When hypovolemia
in the venous section of the vascular bed, a negative pressure is created in relation to the
surrounding atmosphere, because with a lack of venous return the right atrium sucks blood from the
venous vessels. The second circumstance, facilitating the emergence of air embolism, is the deep
breaths that makes the patient. A sharp discharge, created at this moment inside the chest, sucks air
into the gaping venous vessels, wherever they are.
 Gas embolism is associated with the release in the blood of bubbles of gases (nitrogen and
helium) soluble in it with a rapid transition from high atmospheric pressure to normal or from
normal to low. Such a situation can arise when sudden decompression, for example, with the rapid
rise of a diver from a considerable depth. One of the variants of gas embolism is the formation of
gas bubbles during blood transfusion using methods of rapid heating of blood to body temperature.
The solubility of gas in the blood with increasing its temperature by more than 30 ° decreases, and
gas bubbles can enter the bloodstream, the bubbles seem to boil in the bloodstream and clog the
blood vessels of the microcirculation. Gas embolism is also dangerous because nitrogen bubbles
activate the fibrin system and thrombocytes, provoking thrombosis.
A rare variety is the embolism of putrefactive gases in gangrene.
Microbial embolism occurs when septicopyemia, when the blood flow is a large number of
microorganisms. Microbial embolism can be the cause of the development of metastatic abscesses.
Parasitic embolism occurs in helminthiases. So with ascariasis, embolism of the vessels of the
lungs is possible. In countries with a hot climate, embolism of lymphatic vessels with filaria occurs,
which leads to a violation of lymphatic drainage in the limbs and the development of "elephant
disease".
Fat embolism occurs when the vessels are clogged with endogenous lipoprotein particles,
chylomicron aggregation products or exogenous fat emulsions and liposomes. Endogenous true fat
embolism is observed in type 1 hyperlipoproteinemia, when, due to a defect in lipoprotein lipase,
chylomicrons are not cleaved by the lungs and persist in the plasma. The most severe form - the fat-
embolic syndrome has a complex pathogenesis and occurs not only from the dissemination of fat
tissue elements after injuries of bones and subcutaneous fat, but also from the fusion of
chylomicrons. With a true fat embolism, there is a high level of free fatty acids in the blood that
have an arrhythmogenic effect, and disturbances in the heart rhythm promote intracardiac
thrombosis.
Fat embolism can be accompanied by a unique combination of pulmonary embolism and focal
cerebral ischemia due to the passage of chylomicrons and small fat emboli through capillaries:
Tissue embolism is divided into amniotic, tumor and adipocytic embolism.
Embolism with amniotic fluid leads to clogging of pulmonary vessels by conglomerates of
cells suspended in the amniotic fluid and thromboembols formed by the procoagulants contained in
it.
Tumor embolism is a complex process of hematogenous and lymphogenic metastasis of
malignant neoplasms. Tumor cells form in the bloodstream conglomerates with platelets due to the
production of mucins and adhesive surface proteins. Activated platelets release growth factors that
help the proliferation of tumor cells. Tumor emboli are spread according to laws different from the
classical rules of embolism. Due to specific cytoadhesive receptor interactions, tumor emboli can be
fixed in the vessels of certain organs and tissues. So, tumors practically never metastasize into
skeletal muscles, spleen. Metastases of many tumors have specific addresses, that is, metastasize
only to certain organs.
Tissue (in particular adipocytic) embolism can be the result of injuries, when the particles of
the crushed tissues fall and the lumen of the damaged vessels.
Embolism of foreign bodies is quite rare and occurs when injuries or medical invasive
procedures.
A variety of endogenous emboli - thromboembolism - arises from the clogging of blood
vessels with torn clots or their particles. Thromboembolism is a consequence of thrombosis or
thrombophlebitis of various parts of the venous system of the body. One of the most severe is PE,
which occurs with phlebotrombosis of central and peripheral vessels, it is promoted by obesity and
hypokinesia, varicose veins, prolonged immobilization, cancer, septic lesions, trauma.

Embolism of the great circle of blood circulation.

Embolii BKK. The source of emboli are pathological processes (thromboendocarditis,
myocardial infarction, ulceration of atherosclerotic plaques) in pulmonary veins, left cavities of the
heart, aorta, and arteries of a large circle. These embolisms are accompanied by serious circulatory
disorders, up to the development of foci of necrosis in the organ, whose vessel is clogged.

Embolism of the small circle of blood circulation

Embolism of the ICC is the result of skidding of emboli from the right side of the heart and
veins of a large circle. This type of embolism is characterized by the suddenness of the onset, the
rapidity of the growth of extremely severe clinical manifestations.
A piece of blood clot, detached from the wall of a large circle of venous vessel, comes with a
blood flow through the hollow veins into the right atrium, the ventricle and from there into the
pulmonary artery. In the pulmonary artery, the detached pieces of the parietal thrombi of the right
heart also fall. Embolus may linger either in the trunk of the pulmonary artery, or in its branches, or
in the pulmonary capillaries. In the right lung there was a heart attack.

Embolism of the portal vein system.

Embolism of the portal vein is formed during pathological processes in the intestinal veins
(HES, OCN and HCN, etc.). Embolism of the portal vein is a relatively rare but life-threatening
phenomenon that leads to the development of congestive bowel congestion, resulting in up to 90%
of the blood accumulating in the abdominal cavity. This leads to a disorder of hemodynamics and
death.

Effects of embolism.
Depending on the site of localization, embolism can lead to ischemia (see below) in arterial
vessels or to venous hyperemia (see above) - with venous embolism.

Outcomes of embolism.
Systemic thromboembolism of blood vessels of the great circle of blood circulation is
accompanied by the development of infarctions of internal organs, ischemic strokes, limb ischemia
and violation of the function of the corresponding organs and systems.
The most formidable and dangerous consequence of PE that is a threatened condition for the
life of the patient.