Disorders of the hemostasis system and pregnancy failure

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

Basic mechanisms of hemostasis

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

• the central organs of the system are 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 initiated coagulation process, necessary to stop bleeding, does not turn into a process of general intravascular coagulation during normal functioning of the system.

There are four main links in the hemostasis system:

1. Vascular-platelet link;
2. Procoagulants;
3. Fibrinolytic link;
4. A chain of blood coagulation inhibitors.

Vascular-platelet link

The vascular-platelet link of the hemostasis system is often referred to as primary hemostasis. The 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 powerful inhibitor of platelet aggregation - prostacyclin (a metabolite of arachidonic acid);
2. production of tissue fibrinolysis activator;
3. inability to contact activate the blood coagulation system;
4. creation of anticoagulant potential at the blood/tissue interface by fixing the heparin-antithrombin III complex to the endothelium;
5. the ability to remove activated coagulation factors from the bloodstream.

The participation of platelets in hemostasis is determined by their ability to adhere to the site of endothelial damage, the process of their aggregation and formation of a primary platelet plug, as well as their ability to maintain vascular spasm by secreting vasoactive substances - adrenaline, noradrenaline, serotonin, ADP, etc., as well as to form, accumulate and secrete substances that stimulate adhesion and aggregation.

Thus, numerous studies have led to the conclusion that primary hemostasis is carried out mainly by thrombocytes, and not by blood coagulation. The leading role in the implementation of primary hemostasis belongs to the adhesive-aggregation function of thrombocytes.

Adhesion is the adhesion of platelets to the damaged area of the vascular wall, to the collagen fibers of the vascular wall, to microfibrin and elastin. The most important plasma cofactors of this process are calcium ions and the protein synthesized in the endothelium - the von Willebrand factor and glycoproteins of the platelet membrane. The physiological purpose of adhesion is to close the defect of the vascular wall. Aggregation of platelets occurs simultaneously with adhesion. In this case, platelets not only stick together, but also adhere to adhered platelets, due to which a hemostatic plug is formed. Granules containing substances that enhance the aggregation process and form its second wave are actively secreted from platelets during the process of adhesion and aggregation. The reaction of release of platelet factors - ADP, adrenaline, noradrenaline, serotonin, antiheparin factor, beta-thromboglobulin, etc. Later, granules containing lysosomal enzymes are secreted (release reaction II). The release of adrenaline, noradrenaline and serotonin not only enhances aggregation, but also promotes secondary spasm of blood vessels, which is accompanied by reliable fixation of the platelet plug at the site of vessel damage. As a result of the interaction of platelet and plasma factors in the hemostasis zone, thrombin is formed, which not only enhances platelet aggregation, but also stimulates blood clotting, the fibrin formed in this case forms a thrombus, which becomes dense and impermeable to plasma and serum, its retraction occurs.

The mechanism of platelet aggregation became largely clear after the discovery of prostaglandins in platelets and the vascular wall. Various aggregating agents activate phospholipase A1, which causes the cleavage of arachidonic acid, a powerful aggregating substance, from phospholipids. Under the influence of prostaglandin synthetase, cyclic endoperoxides of prostaglandins are formed, stimulating the contraction of fibrils in platelets and exerting a powerful aggregating effect. Under the influence of thromboxane synthetase, thromboxane A1 is synthesized in platelets. The latter promotes the transport of Ca ²⁺ in the platelet, which leads to the formation of ADP, the main endogenous stimulator of aggregation. The level of cAMP, a universal biological carrier, is regulated by adenylate cyclase, which catalyzes the ATP-cAMP reaction.

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

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

Procoagulant link of hemostasis

Compounds contained in plasma (procoagulants) participate in the blood coagulation process. This is a complex multi-stage enzymatic process that can be divided into 3 stages.

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

The key moment in the formation of prothrombinase is the activation of factor X of blood coagulation, which can be carried out by two main mechanisms of initiating the coagulation process - external and internal.

In the extrinsic mechanism, coagulation is stimulated by the entry of tissue thromboplasmin (III or phospholipid-apoprotein III complex) into the plasma. This mechanism is determined by the prothrombin time (PT) test.

In the internal mechanism, coagulation occurs without the participation of tissue thromboplastin. The trigger factor for this coagulation pathway is the activation of factor X. Activation of factor X can occur due to contact with collagen when the vascular wall is damaged or by enzymatic means under the influence of kallikrein, plasmin or other proteases.

In both the extrinsic and intrinsic pathways of coagulation, the interaction and activation of factors occurs on phospholipid membranes, on which protein coagulation factors are fixed with the help of Ca ions.

Nomenclature of plasma coagulation factors:

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

The external and internal mechanisms of activation of the blood coagulation system are not isolated from each other. The inclusion of "bridges" between them serves as a diagnostic sign in recognizing intravascular activation of the coagulation system. When analyzing the results of basic coagulation tests, the following should be taken into account:

1. Of the plasma coagulation factors, only factor VII is involved in the extrinsic coagulation mechanism, and when it is deficient, only prothrombin time is prolonged.
2. Factors XII, IX, XI, VIII and prekallikrein participate only in the internal activation mechanism, and therefore, with their deficiency, the APTT and autocoagulation test are disrupted, while the prothrombin time remains normal.
3. In case of deficiency of factors X, V, II, I, on which both coagulation mechanisms are closed, the pathology is detected in all the listed tests.

In addition to the external and internal mechanisms of hemocoagulation, the body has additional reserve activation pathways that are activated on "demand". The most important pathway is the macrophage-monocyte mechanism of hemocoagulation. When activated by endotoxins or other infectious antigens, these cells begin to secrete a larger amount of tissue thromboplastin.

Endogenous coagulation inhibitors

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

Natural anticoagulants are divided into primary, constantly present in plasma and formed elements of blood and acting independently of the formation or dissolution of a blood clot, and secondary, which arise during blood coagulation and fibrinolysis, due to the proteolytic action of the enzyme on the substrate. Up to 75% of the natural anticoagulant potential is due to antithrombin III (AT III). Antithrombin III is able to block prothrombinase by both external and internal mechanisms, since, being an inhibitor of factors XII a, XIa, IX a, VIII a, kallikrein, A III binds plasmin. The activity of antithrombin III increases more than 100 times when complexes with heparin are formed. Heparin, without being associated with antithrombin III, does not have an anticoagulant effect. When the level of antithrombin III decreases, a severe thrombophilic condition occurs, which is characterized by recurrent thromboses, pulmonary embolism, and infarctions. When antithrombin III decreases below 30%, patients die from thromboembolism, and heparin does not have an anticoagulant effect on their blood. Deficiency of antithrombin III forms heparin resistance.

Natural anticoagulants include protein C, protein S, and alpha2-macroglobulin.

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

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

Pathological anticoagulants are absent in the blood under normal conditions, but appear in various immune disorders; these include antibodies to blood coagulation factors, most often to factors VIII and V (often occurring after childbirth 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 into plasmin. These include substances such as urokinase and bacterial enzymes. Active plasmin is quickly blocked by antiplasmins and eliminated from the bloodstream. Activation of fibrinolysis, as well as activation of blood coagulation, is carried out both by the external and internal pathways.

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

As a rule, in most clinical observations, activation of fibrinolysis is secondary and associated with disseminated intravascular coagulation.

In the process of coagulation and fibrinolysis, secondary, natural anticoagulants appear - PDF and other spent blood coagulation factors - biologically active, which act as antiplatelet agents and anticoagulants.

Currently, a distinction is made between immune thrombophilic complications and hereditary hemostasis defects.

Hemostasis system during pregnancy

The prevailing point of view is that certain conditions for the development of disseminated intravascular coagulation syndrome are created in the body of a pregnant woman. This is expressed in an increase in the total coagulant potential (total activity of coagulation factors), an increase in the functional activity of platelets with a slight decrease in their number, a decrease in fibrinolytic activity with an increase in FDP, a decrease in the activity of antithrombin III with a slight 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 during childbirth. Changes in the general hemodynamics in the body of a pregnant woman play a major role in the activation of the hemostasis system. For normal functioning of the fetoplacental system under conditions of high coagulation potential of the blood, compensatory and adaptive mechanisms come into play: an increase in the number of small-caliber terminal villi with hyperplasia and peripheral location of capillaries, a decrease in the thickness of the placental barrier with thinning of the syncytium, the formation of syncytiocapillary membranes, syncytial nodules.

The features of the hemostasis system functioning are associated with certain changes in the system of spiral arteries of the uterus. These are the invasion of trophoblast cells into the wall of the spiral arteries, the replacement of the internal elastic membrane and internal media with a thick layer of fibrin, the disruption of the integrity of the endothelium and the exposure of collagen subendothelial structures. In this process, the deployment of the intervillous space with its inherent morphological and hemodynamic features is also important.

The characteristics of the hemostasis system during a physiologically normal pregnancy are determined by the formation of the uteroplacental circulation.

The platelet level during uncomplicated pregnancy remains virtually unchanged, although there are studies that have noted a decrease in the platelet level. If the platelet level drops below 150,000/ml, studies are needed to identify the causes of thrombocytopenia.

During pregnancy, an increase in coagulant potential is observed, the body seems to be preparing for possible bleeding during childbirth. An increase in all coagulation factors is noted, with the exception of factors XI and XIII.

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

The activity of factor VIII (von Willebrand factor) also increases, not only in healthy women, but also in patients with hemophilia and von Willebrand disease. It should be taken into account that in mild and moderate cases of this disease, the level of this factor may be almost normal. In contrast to the general increase in coagulation factors, a slight decrease in factor XI at the end of pregnancy and a more noticeable decrease in factor XIII (fibrin-stabilizing factor) are noted during pregnancy. The physiological role of these changes is not yet clear.

The coagulation potential of the blood also increases due to the fact that the level of antithrombin III decreases, protein C increases mainly in the postpartum period, and protein S is reduced during pregnancy and significantly reduced after childbirth.

During pregnancy, a decrease in fibrinolysis was noted at the end of pregnancy and during labor. In the early postpartum period, fibrinolysis activity returns to normal. There are contradictory data in the literature regarding the presence of FDP in the bloodstream. According to the results of the study, a slight increase in FDP was noted in the last months of pregnancy. According to research data, in 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 fibrin degradation products increases from 16 weeks of pregnancy and reaches a plateau at 36-40 weeks. However, a significant increase in FDP during pregnancy is most likely a reflection of the fibrinolytic process due to the activation of intravascular coagulation.

Changes in the hemostasis system in pregnant women with antiphospholipid syndrome

The hemostasis system parameters in pregnant women with antiphospholipid syndrome differ significantly from those in women with physiological pregnancy. From the moment of pregnancy onset, most patients have changes in the platelet hemostasis link. Platelet aggregation with ADP stimulation is 55-33% higher than in physiological pregnancy. The tendency to increase aggregation persists against the background of antiplatelet therapy.

Platelet aggregation under the influence of collagen is 1.8 times higher than in the physiological course of pregnancy. Platelet aggregation under the influence of adrenaline is 39% higher than in the control group. If these indicators cannot be reduced under the influence of the therapy, such persistent platelet hyperactivity is the basis for increasing the dose of antiplatelet agents or prescribing additional antiplatelet agents. Ristomycin-aggregation indicators remain within the normal range on average in the first trimester. The studies have shown that from the early stages of pregnancy, patients with APS have an increased platelet response to the effects of biological inducers, identified mainly in platelet functional activity tests, such as aggregation under the influence of ADP 1x10 ³ M and 1x10 ⁵ M, arachidonic acid.

When assessing the qualitative characteristics by the types of aggregationograms, not a single observation showed disaggregation (reversible aggregation) under the influence of even weak stimuli of ADP 1 x 10 ⁷ M. This is evidenced by the change in the profile of the curves towards the so-called “atypical” hyperfunctional aggregationograms.

The plasma hemostasis parameters in the first trimester of pregnancy also changed compared to the control: a significant acceleration of the AVR was noted, the r+k parameter was shortened on the thromboelastogram, and the structural properties of the fibrin clot - ITP - parameter was significantly higher.

Thus, in pregnant women with APS, moderate hypercoagulation in the plasma link of hemostasis is observed already in the first trimester, developing earlier than hypercoagulation associated with the adaptation of hemostasis during a physiologically proceeding pregnancy. These changes, determining the hyperactivity of hemostasis as a whole in the first trimester of pregnancy, are not considered as pathological activation of intravascular thrombus formation, since we extremely rarely observed the appearance of DIC markers - fibrin and fibrinogen degradation products (FDP) at this stage of pregnancy. The FDP content in the first trimester did not exceed 2x10 g / l. This was the basis for assessing the hyperactivity of the platelet and plasma links of hemostasis as hypercoagulation that does not correspond to the gestational age and the background for the development of DIC.

In the second trimester of pregnancy, despite the therapy, changes in the plasma link of hemostasis were noted. It was found that APTT was 10% shorter and AVR was 5% shorter than in physiological pregnancy. These data indicate increasing hypercoagulation. The same tendency was noted in the thromboelastogram: the chronometric coagulation indices r+k, Ma parameters and ITP values were higher than in physiological pregnancy.

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

In the third trimester of pregnancy, the same tendency to increase hypercoagulation phenomena was noted, despite the therapy. The fibrinogen concentration indicators, AVR and APTT, indicate the development of hypercoagulation. Although due to greater control of hemostasiograms, therapeutic measures manage to maintain hypercoagulation within limits close to physiological parameters.

Considering that the main, natural inhibitors of blood coagulation are synthesized by the vascular wall, including the placental vessels, it is of great interest to evaluate the total activity of the plasminogen activator inhibitor (PAI) as pregnancy progresses in women with antiphospholipid syndrome. The determinations of the PAI content during pregnancy showed that pregnant women with antiphospholipid syndrome do not have an increase in the blocking effect of PAI 1 and placental PAI 2.

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

Studies of the components of the anticoagulant mechanisms of the hemostasis system have revealed a large variability in the content of protein C (PrC); in most observations, a decrease in its level does not depend on the gestational age. The maximum activity of PrC did not exceed 97%, in most observations - 53-78% (normal 70-140%).

Individual analysis of the plasminogen activator inhibitor content in the second trimester of pregnancy revealed a sharp increase in plasminogen activator inhibitor to 75 U/ml only in 1 case, while there was a combination of an increase in plasminogen activator inhibitor with severe AT III pathology, activity 45.5%, concentration 0.423 g/l. In all other observations, the content of plasminogen activator inhibitor fluctuated from 0.6-12.7 U/ml, on average 4.7±0.08 U/ml. Further, in the third trimester, the content of plasminogen activator inhibitor also remained low, fluctuations were from 0.8 to 10.7 U/ml, on average 3.2±0.04 U/ml, only in one observation - 16.6 U/ml. Considering that usually a sharp increase in the content of plasminogen activator inhibitor promotes a decrease in fibrinolytic activity and local thrombus formation (due to the suppression of reparative fibrinolysis), the facts noted by us can be considered as the absence of an endothelial reaction in pregnant women with APS aimed at the synthesis of the endothelial component of PAI 1 synthesized by the endothelium of the vascular wall, and, more importantly, the absence of the system of the placental component of PAI 2 produced by the vessels of the placenta. A possible explanation for the factors noted by us may be a violation of the function of endothelial cells and, first of all, placental vessels in pregnant women with antiphospholipid syndrome, probably due to the fixation of antigen-antibody complexes on the endothelium.

It is noteworthy that there is a significant decrease in PRS activity in the second trimester of pregnancy, 29% lower than in the control group.

The evaluation of the fibrinolytic system showed the following results: plasminogen activity in most observations was high in the first trimester 102±6.4% and concentration 15.7±0.0 g/l; in the second trimester, plasminogen activity was subject to even greater fluctuations from 112 to 277% and concentration from 11.7 g/l to 25.3 g/l, on average 136.8±11.2% concentration 14.5±0.11 g/l. In the third trimester, similar conditions persisted: plasminogen activity fluctuated from 104 to 234% (normal 126.8±9.9%) concentration from 10.8 to 16.3 g/l, on average 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 inhibitor of fibrinolysis, alpha2-macroglobulin (alpha 2Mg), was quite high in the first trimester of pregnancy, fluctuating 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 regarding the content of alpha1-antitrypsin (alpha1AT), 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 antiphospholipid syndrome, similar to that in the physiological course of pregnancy.

The listed features of the hemostasis system emphasize the great importance of control studies of hemostasis during pregnancy for optimizing antithrombotic therapy and preventing iatrogenic complications.

A study of the hemostasis system before childbirth showed that the hemostatic potential remains intact and, despite antiplatelet therapy, the tendency toward platelet hyperfunction persists.

Considering that patients with antiphospholipid syndrome receive antithrombotic agents during pregnancy, and after childbirth there is a high risk of thromboembolic complications inherent in patients with antiphospholipid syndrome, the study of hemostasis in the postpartum period is extremely relevant.

Underestimation of hemostasiograms, discontinuation of therapy immediately after delivery can lead to rapidly developing hypercoagulation and thromboembolic complications. Studies have shown that after delivery, the blood coagulation potential remains high, even in those observations where patients received heparin therapy. It is advisable to conduct studies of the hemostasis system on the 1st, 3rd and 5th day after delivery. Moderate hypercoagulation was noted in 49% of women in labor, and 51% of women in labor showed activation of the hemostasis system - an increase in hypercoagulation and the appearance of PDF.

Congenital defects of hemostasis

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

In addition to these disorders, in recent years hyperhomocysteinemia has been classified as a hereditary thrombophilic condition - a condition in which, due to a hereditary defect in the enzyme methylenetetrahydrofolate reductase, there is a risk of developing venous and arterial thromboses and, in connection with this, pregnancy loss 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 European population. Unlike other hereditary hemostasis defects, this pathology is characterized by early pregnancy losses already in the first trimester. In hyperhomocysteinemia, folic acid is a very effective prevention of thrombosis.

When pregnant women with hereditary thrombophilia are identified, a very careful assessment of the family history is necessary. If there is a history of thromboembolic complications in close relatives at a young age, during pregnancy, when using hormonal therapy, including oral contraceptives, it is necessary to examine for hereditary hemostasis defects, which carry an extremely high risk of thromboembolic complications.

Antithrombin inactivates thrombin, factors IXa, Xa, XIa and XPa. Alpha1-antithrombin deficiency is highly thrombogenic and accounts for up to 50% of thrombosis cases during pregnancy. Due to the heterogeneity of the disorders, the incidence 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 action. Deficiency of proteins C and S occurs with a frequency of 1:500. Protein C during pregnancy remains virtually unchanged, protein S decreases in the second half of pregnancy and returns to normal soon after delivery. Therefore, if protein S is determined during pregnancy, false-positive results may be obtained.

In recent years, there have been many publications on thrombophilia due to a mutation of the V factor gene, 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 is found in 9% of the European population. This mutation must be confirmed by DNA testing for the V Leiden factor. The frequency of occurrence of the Leiden mutation varies significantly. Thus, according to Swedish researchers, the frequency of occurrence of this hemostasis defect among pregnant women with thrombosis was from 46 to 60%, while in England - only 14% and in Scotland - 8%.