Violation of the system of hemostasis and miscarriage of pregnancy

The state of the hemostatic system determines the course and outcome of pregnancy for the mother and fetus. In recent years, there has been a significant number of publications pointing to the great role of thrombophilic complications in habitual miscarriage, fetal death, placental abruption, eclampsia development, intrauterine growth retardation.

The basic mechanisms of hemostasis

The system of hemostasis or the system of regulation of the aggregate state of the blood (PACK) is a biological system that ensures regulation of the aggregation state of the blood and maintenance of the necessary hemostatic potential for the organism. The PACK system is mosaic, i.e. The haemostatic potential in different parts of the blood flow is not the same. This state is normal for the functional system. The system of regulation of the aggregate state of the blood includes:

• central organs of the system - bone marrow, liver, spleen;
• peripheral formations - mast cells, endometrium and other layers of the vascular wall, blood cells;
• local regulatory systems - autonomic nervous system, subcortical structures.

The hemostasis system is regulated by complex neurohumoral mechanisms. These mechanisms create conditions under which the locally begun coagulation process, necessary for stopping bleeding, does not pass during the normal functioning of the system in the process of general intravascular coagulation.

There are four main links in the hemostasis system:

1. Vascular-platelet link;
2. Procoagulants;
3. Fibrinolytic link;
4. Link of inhibitors of blood clotting.

Vascular-platelet link

The vascular-platelet link of the hemostatic system is often referred to as primary hemostasis. Endothelium of blood vessels plays an important role in maintaining the aggregate state of circulating blood. This is due to the following features:

1. the ability to form and release into the blood a potent platelet aggregation inhibitor - prostacyclin (arachidonic acid metabolite);
2. the production of tissue activator fibrinolysis;
3. inability to contact activation of the blood coagulation system;
4. the creation of an anticoagulant potential at the blood / tissue boundary by fixing the heparin-antithrombin III complex on the endothelium;
5. the ability to remove activated clotting factors from the bloodstream.

The participation of platelets in the hemostasis is determined by their ability to adhere at the site of endothelial damage, the process of their aggregation and the formation of the primary platelet plug, and their ability to maintain vasospasm by secretion of vasoactive substances - epinephrine, noradrenaline, serotonin, ADP, etc., accumulate and secrete substances that promote adhesion and aggregation.

Thus, numerous studies have concluded that primary hemostasis is mainly carried out by platelets, rather than by blood clotting. The leading role in the realization of primary hemostasis belongs to the adhesive-aggregation function of platelets.

Adhesion - adhesion of platelets to the site of damage to the vascular wall, kokallagenovym fibers of the vascular wall, to microfibrin and elastin. The most important plasma cofactors of this process are calcium ions and the von Willebrand protein synthesized in the endothelium and the platelet membrane glycoproteins. The physiological purpose of adhesion is to close the defect of the vascular wall. Simultaneously with adhesion, platelet aggregation proceeds. In this case, the platelets not only stick together, but also adhere to the adherent platelets, thereby forming a hemostatic plug. From the platelets in the process of adhesion and aggregation, granules containing substances that enhance the aggregation process and form its second wave are actively secreted. The release of platelet factors - ADP, adrenaline, noradrenaline, serotonin, anti-heparin factor, beta-thromboglobulin, etc. Later granules containing lysosomal enzymes (release reaction II) are secreted. The release of adrenaline, noradrenaline and serotonin not only enhances aggregation, but also contributes to secondary spasm of blood vessels, which is accompanied by reliable fixation of platelet plug at the site of vessel damage. As a result of the interaction of platelet and plasma factors in the zone of hemostasis, thrombin is formed which not only enhances platelet aggregation, but at the same time it is a stimulator of blood coagulation. The fibrin formed thereby forms a thrombus that becomes dense and impermeable to plasma and serum, and retraction occurs.

To a large extent, the mechanism of platelet aggregation became clear after the discovery of prostaglandins in platelets and the vascular wall. Various aggregating agents activate phospholipase Al, which causes cleavage from the phospholipids of arachidonic acid, a potent aggregating agent. Under the influence of prostaglandin synthetase, cyclic endoperoxides of prostaglandins are formed, which stimulate platelet fibrillation and have a powerful aggregating effect. Under the influence of thromboxane synthetase in thrombocytes, thromboxane A1 is synthesized. The latter promotes the transport of Ca ²⁺ in the platelet, which leads to the formation of ADP - the main endogenous aggregation stimulator. The level of cAMP-universal biological transporter is regulated by adenylate cyclase, which catalyzes the reaction of ATP-cAMP.

A similar process occurs in the vascular endothelium - under the influence of prostaglandin synthetase from arachidonic acid, prostaglandin endoperoxides are formed. Further, under the influence of prostacyclin synthase, prostacyclin (prostaglandin L) is formed, which has a powerful disaggregating effect and activates adenylate cyclase.

Thus, the so-called. Thromboxane - prostacyclin balance is one of the main regulators of the state of vascular wall tone and platelet aggregation.

Procoagulant hemostasis

In the process of blood clotting, the compounds contained in the plasma (procoagulants) take part. This is a complex multi-stage enzyme process, which can be conditionally divided into 3 stages.

• Stage I - a complex of reactions leading to the formation of prothrombin of the active complex or prothrombinase. The composition of the complex includes factor X, the third factor of platelets (phospholipid), V factor and ions of Ca ²⁺. This is the most difficult and long phase.
• II stage - under the influence of prothrombinase prothrombin passes into thrombin.
• III stage - under the influence of thrombin fibrinogen passes into fibrin.

The key point in the formation of prothrombinase is the activation of the X factor of blood coagulation, which can be accomplished by two main mechanisms of triggering the process of clotting, external and internal.

With an external mechanism, clotting is stimulated by the ingestion of tissue thromboplasmin (III or phospholipid-apoprotein III complex) into the plasma. This mechanism is determined by a prothrombin time (PT) test.

With the internal mechanism, coagulation is carried out without the involvement of tissue thromboplastin. The triggering factor in this way of coagulation is the activation of factor X. Activation of factor X can occur due to contact with collagen in damage to the vascular wall or enzymatically by kallikrein, plasmin or other proteases.

Both with external and internal coagulation pathways, interaction and activation of factors is carried out on phospholipid membranes, on which protein coagulation factors are fixed with the help of Ca ions.

Nomenclature of plasma clotting factors:

• I - fibrinogen;
• II - prothrombin;
• III - tissue thromboplastin;
• IV - calcium;
• V - accelerating factor;
• VI - factor V activator;
• VII - proconvertin;
• VIII - anti-hemophilic globulin A;
• IX - anti-hemophilic factor B (factor of Christmas);
• X - prothrombinase;
• XI - plasma precursor of thromboplastin;
• XII - Hageman factor;
• XIII - fibrinase.

The external and internal mechanism of activation of the blood coagulation system is not isolated from each other. The inclusion of "bridges" between them serves as a diagnostic sign when recognizing the intravascular activation of the clotting system. When analyzing the results of the main coagulation tests, the following should be considered:

1. Of plasma factors of coagulation, only factor VII participates in the external mechanism of coagulation, and with its deficiency, only prothrombin time lengthens.
2. Factors XII, IX, XI, VIII and prekallikrein participate only in the internal mechanism of activation, in connection with which, when their deficiency is violated, APTT and autocoagulation test, while prothrombin time remains normal.
3. With a deficiency of factors X, V, II, I on which both clotting mechanisms are closed, the pathology is revealed in all the tests listed.

In addition to external and internal mechanisms of hemocoagulation, there are additional redundant activation routes in the body, which are included in the "requirement". The most important way is macrophagal - a monocytic mechanism of hemocoagulation. When activated by endotoxins or other infectious antigens, these cells begin to secrete more tissue thromboplastin.

Endogenous coagulation inhibitors

To maintain blood in the liquid state and to limit the process of thrombosis, physiological anticoagulants are necessary. It is now known that natural anticoagulants represent a large group of compounds acting on different phases of the hemostasis process. Moreover, many anticoagulants simultaneously affect fibrinogenesis, generation of kallikrein-kinin system, complement system.

Natural anticoagulants are divided into primary, constantly present in the plasma and formed elements of blood and acting regardless of the formation or dissolution of the blood clot, and secondary, which arise in the process of blood clotting and fibrinolysis, due to the proteolytic action of the enzyme on the substrate. Up to 75% of the natural anticoagulant potential is attributed to antithrombin III (AT III). Antithrombin III is able to block prothrombinase both by external and internal mechanisms, because, as an inhibitor of factors XIIa, XIa, IXa, VIIIa, kallikrein, A III binds plasmin. The activity of antithrombin III increases more than 100 times when complexes with heparin are formed. Heparin is not associated with antithrombin III anticoagulant. With a decrease in the level of antithrombin III there is a severe thrombophilic condition, which is characterized by recurrent thrombosis, pulmonary embolism, infarcts. With a decrease in antithrombin III below 30%, patients die from thromboembolism, and heparin does not have an anticoagulant effect on their blood. Deficiency of antithrombin III forms heparin-resistance.

The natural anticoagulants include protein C, protein S, alpha2-macroglobulin.

Protein C is a proenzyme, activated by thrombin and factor Xa. Activation proceeds in combination with phospholipid and calcium. The process is intensified by the influence of thrombomodulin and protein S, which weakens the ability of thrombin to activate factors VIII and V. Protein C deficiency shows a tendency to thrombosis, which is observed with acute DIC syndrome, respiratory distress syndrome, etc.

In the process of blood coagulation and fibrinolysis, secondary, natural anticoagulants are formed as a result of further enzymatic degradation of clotting factors.

Pathological anticoagulants are absent in the blood under normal conditions, but appear with various immune disorders, including antibodies to blood coagulation factors, most often to factors VIII and V (often occurring after delivery and massive blood transfusions and immune complexes - lupus anticoagulant, antithrombin V) .

Fibrinolytic system

The fibrinolytic system consists of plasminogen and its activators and inhibitors.

Plasminogen activators are a group of factors that convert plasminogen to plasmin. These include such substances as kakurokinase, bacterial enzymes. Active plasmin is quickly blocked by antiplasmin and is eliminated from the bloodstream. Activation of fibrinolysis, as well as activation of blood coagulation, is carried out both along the external and internal pathways.

The internal way of fibrinolysis activation is due to the same factors as blood clotting, i.e. Factors XIIa or XIII with kallikrein and kininogen. The external pathway of activation is carried out by tissue-type activators synthesized in the endothelium. Tissue-type activators are found in many tissues and body fluids, blood cells. Inhibits fibrinolysis with anti-plasminins alpha2-globulin, alpha2-macroglobulin, antitrypsin, etc. The plasmic system is adapted to lysis of fibrin in clots (thrombi) and soluble fibrin-monomer complexes (RFMC). And only with its excessive activation there is a lysis of fibrin, fibrinogen and other proteins. Active plasmin causes sequential cleavage of fibrinogen / fibrin with the formation of products of their degradation (PDF), the presence of which indicates the activation of fibrinolysis.

As a rule, in the majority of clinical cases, the activation of fibrinolysis is secondary and is associated with disseminated intravascular coagulation.

In the process of clotting and fibrinolysis, the emerging secondary, natural anticoagulants - PDD and other worked out clotting factors - are biologically active, which act as antiplatelet agents and anticoagulants.

At present, immune thrombophilic complications and hereditary hemostasis defects are distinguished.

System of hemostasis in pregnancy

The point of view according to which in an organism of the pregnant woman certain conditions for development of a syndrome of a disseminated intravascular coagulation dominates. This is expressed in an increase in the total coagulant potential (total activity of clotting factors), increased functional activity of platelets with a certain decrease in their number, a decrease in fibrinolytic activity with increasing PDF, a decrease in the activity of antithrombin III, while some decrease in its content. These features are compensatory and adaptive in nature and are necessary both for the normal formation of the fetoplacental complex and for limiting blood loss in labor. In the activation of the hemostasis system, an important role is played by changes in the general hemodynamics in the body of a pregnant woman. For the normal functioning of the fetoplacental system in conditions of high blood coagulation potential, compensatory-adaptive mechanisms come into play: an increase in the number of terminal villi of small caliber with hyperplasia and peripheral arrangement of capillaries, a decrease in the thickness of the placental barrier with thinning of syncytium, the formation of syncytocapillary membranes, syncytial nodules.

Features of the functioning of the hemostatic system are associated with certain changes in the system of the spiral arteries of the uterus. This - the invasion of trophoblast cells into the wall of spiral arteries, replacement of the internal elastic membrane and internal media with a thick layer of fibrin, disruption of endothelial integrity and exposure of collagen subendothelial structures. In this process, the development of the intervillian space with its inherent morphological and hemodynamic features also matters.

Features of the system of hemostasis in a physiologically occurring pregnancy are determined by the formation of the uterine-placental circulatory system.

The level of platelets in uncomplicated pregnancy remains virtually unchanged, although there are studies where there is a decrease in platelet count. With a decrease in platelet count below 150,000 / ml, studies are needed to identify the causes of thrombocytopenia.

In pregnancy, there is an increase in coagulant potential, the body is preparing for possible bleeding during childbirth. An increase in all clotting factors was noted with the exception of factor XI and XIII.

The increase in the level of fibrinogen begins from the 3rd month of pregnancy and despite the increase in the volume of circulating plasma, the level of fibrinogen at the end of pregnancy increases at least twice as compared to the non-pregnant state.

The activity of factor VIII (vWF) also increases, not only in healthy women, but also in patients who are hemophilia conductors and those with Willebrand disease. It should be borne in mind that with a mild and moderate degree of this disease, the level of this factor can be almost normal. In contrast to the overall increase in clotting factors, a slight decrease in the XI factor at the end of pregnancy and a more marked decrease in the XIII factor (fibrin-stabilizing factor) were noted in pregnancy. The physiological role of these changes is not yet clear.

The coagulation potential of the blood increases even as the level of antithrombin III decreases, protein C rises mainly in the puerperium, and protein S is lowered during pregnancy and significantly reduced after delivery.

In pregnancy, decreased fibrinolysis at the end of pregnancy and during childbirth. In the early postpartum period, fibrinolysis activity returns to normal. Concerning the presence of PDF in the bloodstream, there are conflicting data in the literature. According to the results of the study, there was a slight increase in PDP in the last months of pregnancy. According to research data, with uncomplicated pregnancy, an increase in the content of degradation products is not detected until the onset of labor. According to J. Rand et al. (1991), the level of some fragments of degradation products of fibrin increases from 16 weeks of pregnancy and reaches a plateau at 36-40 weeks. However, a significant increase in PDP during pregnancy is most likely a reflection of the fibrinolytic process due to the activation of intravascular coagulation.

Change in hemostasis system in pregnant women with antiphospholipid syndrome

The parameters of the hemostatic system in pregnant women with antiphospholipid syndrome differ significantly from those in women with a physiological pregnancy. Since the onset of pregnancy, most patients have had changes in the platelet count of hemostasis. Aggregation of platelets with stimulation of ADP is 55-33% higher than in the physiological course of pregnancy. The tendency to increase aggregation is maintained against the background of antiplatelet therapy.

Aggregation of platelets under the action of collagen is 1.8 times higher than in the physiological course of pregnancy. Aggregation of thrombocytes under the influence of adrenaline is 39% higher than in the control group. If under the influence of current therapy it is not possible to reduce these indicators, then such persistent hyperactivity of platelets is the basis for increasing the dose of antiplatelet agents or the appointment of additional antiplatelet agents. The parameters of ristomycin - aggregation in the middle of the first trimester remain within the norm. Studies have shown that, from early pregnancy in patients with APS, there is an increased platelet response to the effects of biological inducers, mainly found in platelet functional assays, such as ADP aggregation of 1x10 ³ M and 1x10 ⁵ M, arachidonic acid.

When assessing the qualitative characteristics by aggregategram types, no disaggregation (reversible aggregation) was observed in the case of even weak ADP stimuli 1 x ^{10 7} M. This is evidenced by a change in the profile of the curves toward the so-called "atypical" hyperfunctional aggregationgrams.

The parameters of the hemostasis plasma in the first trimester of pregnancy have also been changed in comparison with the control: a significant acceleration of ABP was noted, the r + k factor was shortened on the thromboelastogram, the indicator of the structural properties of the fibrin clot-ITP was significantly higher.

Thus, in pregnant women with APS in the first trimester, moderate hypercoagulation in the plasma hemostasis is observed, which develops earlier than hypercoagulation associated with the adaptation of hemostasis in a physiologically occurring pregnancy. These changes, which determine the hyperactivity of hemostasis as a whole in the first trimester of pregnancy, are not considered as pathological activation of intravascular thrombus formation. Extremely rare in this period of pregnancy, we observed the appearance of markers of DIC - degradation products of fibrin and fibrinogen (PDF). The content of PDF in the first trimester did not exceed 2x10 g / l. This was the basis for evaluating the hyperactivity of the platelet and plasma links of hemostasis, as the hypercoagulation and the background for the development of ICE are not appropriate for the period of pregnancy.

In the II trimester of pregnancy, despite therapy, changes in the plasma link of hemostasis were noted. It was revealed that APTTV is 10% and ABD is 5% shorter than in physiological pregnancy. These data indicate an increasing hypercoagulation. The same trend is noted in the thrombotic-elastogram: the indicators of chronometric coagulation r + k, the parameters of Ma and the value of ITP are higher than in physiological pregnancy.

In the thrombocyte hemostasis, a statistically significant increase in aggregation and an increase in hyperfunctional types of curves are observed when exposed to weak stimulants, which indicates stable platelet hyperactivity in pregnant women with APS, resistant to ongoing therapy.

In the third trimester of pregnancy, the same tendency toward an increase in the phenomena of hypercoagulability was noted, despite the ongoing therapy. The indices of fibrinogen concentration, ABP and APTT, indicate the development of hypercoagulation. Although in connection with the large control of hemostasiograms, therapeutic measures manage to keep hypercoagulation within the limits close to physiological parameters.

Given that the main, natural inhibitors of blood coagulation are synthesized by the vascular wall, including the vessels of the placenta, it is of great interest to estimate the total activity of the plasminogen activator inhibitor (IAP) as pregnancy progresses in women with antiphospholipid syndrome. Conducted in the dynamics of pregnancy, the definitions of the content of IAP showed that in pregnant women with antiphospholipid syndrome there is no increase in the blocking effect of IAP 1 and placental IAP 2.

The maximum increase in inhibitor of the plasminogen activator in individual observations was 9.2-9.7 units / ml (normally 0.3-3.5 U / ml) against a background of sufficiently high activity and content of plasminogen, the main fibrinolytic substrate (112 -115% and 15.3-16.3 g / l, with a norm of 75-150% and 8 g / l respectively). The early signs of the pathological activity of the hemostasis system (thrombinemia) in the I trimester for the level of the inactive complex of antithrombin III (TAT) are noted only in single observations, which confirms the actual intravascular generation of procoagulant activity.

Investigations of the components of the anticoagulant mechanisms of the hemostasis system have made it possible to establish a large variability in the content of protein C (PRC), in most cases the decrease in its level does not depend on the gestational age. The maximum activity of PRC did not exceed 97%, in most cases it was 53-78% (norm 70-140%).

Individual analysis of the content of the plasminogen activator inhibitor in the second trimester of pregnancy made it possible to detect a sharp increase in the inhibitor of the plasminogen activator to 75 U / ml in only 1 case, with a combination of an increase in the plasminogen activator inhibitor with pronounced pathology of AT III, activity 45.5%, concentration 0.423 g / l. In all other observations, the content of the inhibitor of plasminogen activator ranged from 0.6-12.7 U / ml, on the average 4.7 ± 0.08 U / ml. Further, in the III trimester, the content of the plasminogen activator inhibitor also remained low, the oscillations were 0.8 to 10.7 U / ml, 3.2 ± 0.04 U / ml on average, only 16.6 U / ml. Considering that usually a sharp increase in the content of the plasminogen activator inhibitor reduces the fibrinolytic activity and local thrombus formation (by suppressing reparative fibrinolysis), the facts noted by us can be considered as the absence of endothelial reaction in pregnant women with APS aimed at the synthesis of the endothelial component of IAP 1, synthesized by the vascular endothelium walls, and, more importantly, the absence of a placental component of IAP 2, produced by the blood vessels of the placenta. A possible explanation for the factors noted by us may be a disruption in the function of endothelial cells and, primarily, of the placental vessels in pregnant women with antiphospholipid syndrome, probably due to fixation of antigen-antibody complexes on the endothelium.

It is worth noting that a significant decrease in the activity of PrS in the second trimester of pregnancy is 29% lower than in the control group.

Evaluation of the fibrinolytic system showed the following results: plasminogen activity in most cases was high in the first trimester 102 ± 6.4% and concentration 15.7 ± 0.0Eg / l; in the second trimester, plasminogen activity was subject to even greater fluctuations from 112 to 277% and a concentration of 11.7 g / l to 25.3 g / l, averaging 136.8 ± 11.2% concentration of 14.5 + 0.11 g / l. In the third trimester, similar conditions were preserved: the activity of plasminogen ranged from 104 to 234% (norm 126.8 ± 9.9%) concentration from 10.8 to 16.3 g / l, averaging 14.5 ± 0.11 g / l . Thus, the fibrinolytic potential in pregnant women with antiphospholipid syndrome is quite high.

In contrast, the content of the main fibrinolysis inhibitor alpha2-macroglobulin (alpha 2Md) was quite high in the first trimester of pregnancy, ranged from 3.2 to 6.2 g / l (normal 2.4 g / l), an average of 3.36 ± 0,08 g / l; in the second trimester, respectively, from 2.9 to 6.2 g / l, an average of 3.82 ± 0.14 g / l.

Similar data were obtained with respect to the content of alpha1-antitrypsin (alphaALAT), which in all trimesters of pregnancy ranged from 2.0 to 7.9 g / l. Since CL-Mg and a1-AT are buffer inhibitors of delayed and indirect action, their effect on the activation of the fibrinolytic system, even under conditions of high plasminogen content, was manifested by a decrease in the fibrinolytic potential in pregnant women with an antiphospholipid syndrome similar to that in the physiological course of pregnancy.

The above features of the hemostatic system emphasize the great importance of control studies of hemostasis in pregnancy for optimization of antithrombotic therapy and prevention of iatrogenic complications.

A study of the hemostasis system before delivery showed that the haemostatic potential remains intact and despite the antiplatelet therapy, the tendency to hyperfunction of platelets remains.

Given that patients with antiphospholipid syndrome in the course of pregnancy receive antithrombotic drugs, and after delivery there is a high risk of thrombembolic complications inherent in patients with antiphospholipid syndrome, it is extremely important to study hemostasis in the postpartum period.

Underestimation of hemostasiograms, discontinuation of therapy immediately after birth can lead to rapidly developing hypercoagulation and thrombembolic complications. Studies have shown that, after childbirth, the blood clotting potential remains high, even in those cases where patients received heparin therapy. Studies of the hemostasis system should be carried out on days 1, 3 and 5 after delivery. Mild hypercoagulability was noted in 49% of the puerperas, and in 51% of the puerperas, activation of the hemostatic system was noted - the increase in hypercoagulation and the appearance of PDF.

Congenital defects of hemostasis

Currently, much attention is paid to genetically determined forms of thrombophilia, which like antiphospholipid syndrome are accompanied by thromboembolic complications in pregnancy and lead to loss of pregnancy at any stage. The main causes of hereditary thrombophilia: deficiency of antithrombin, protein C and S, heparin cofactor H, factor XII deficiency, dis- and hypoplasmogenemia, dysfibrinogenemia, tissue plasminogen activator deficiency, Leiden mutation of the gene of the clotting factor.

In addition to these disorders, in recent years, hereditary thrombophilic states include hyperhomocysteinemia, a condition in which a risk of venous and arterial thrombosis is due to a hereditary defect in the methylenetetrahydrofolate reductase enzyme and, in connection with this, a loss of pregnancy with possible early development of eclampsia. It should be noted that one of the latest publications noted that hyperhomocysteinemia was detected in 11% of the population of Europeans. Unlike other hereditary hemostasis defects in this pathology, early pregnancy loss is already in the first trimester. When hyperhomocysteinemia is very effective prevention of thrombosis is the use of folic acid.

When identifying pregnant women with hereditary thrombophilia, a very careful evaluation of the family history is necessary. If there is a history of thromboembolic complications at a young age, pregnancy, hormonal therapy, including oral contraceptives, an examination of hereditary hemostasis defects is necessary in which the risk of thromboembolic complications is extremely high.

Antithrombin inactivates thrombin, factors IXa, Xa, XIa and HPa. Deficiency of alpha1-antithrombin is highly thrombogenic and gives up to 50% of cases of thrombosis during pregnancy. In connection with the heterogeneity of the disturbances, the frequency of occurrence of this defect varies from 1: 600 to 1: 5000.

Protein C inactivates factors Va and VIIIa. Protein S acts as a cofactor of protein C, enhancing its effect. Deficiency of protein C and S occurs at a frequency of 1: 500. Protein C does not change during pregnancy, protein S decreases in the second half of pregnancy and returns to normal soon after childbirth. Therefore, if the determination of Protein S is carried out during pregnancy, false-positive results can be obtained.

In recent years, many publications on thrombophilia due to mutation of the V gene factor, this is the so-called Leiden mutation. As a result of this mutation, protein C does not affect the V factor, which leads to thrombophilia. This pathology finds 9% of the European population. This mutation must be confirmed by DNA testing for factor V Leiden. The frequency of occurrence of the Leiden mutation varies considerably. Thus, according to Swedish researchers, the incidence of this hemostasis defect in pregnant women with thrombosis was between 46 and 60%, while in England only 14% and in Scotland 8%.