Principles of preventing pregnancy complications in thrombophilia (part 1)

Thrombophilia during pregnancy without maintenance therapy and preventive treatment in most cases leads to an unfavorable outcome. Although many modern medical sources call thrombophilia a mild risk factor for pregnancy loss, our experience suggests the opposite. The disease provokes repeated miscarriages, delays in fetal development and even fetal death, and promotes placental abruption. In our clinic, patients with this diagnosis are not uncommon. Our happy mothers tell each other that we carry out a natural birth and, under our supervision, the pregnancy ends with the birth of a healthy baby. Pregnancies with a complicated medical history are managed by the chief physician of the clinic, Marine Isakovna Amyan.

According to statistics, thrombophilia during pregnancy is the cause of recurrent miscarriage in 17% of cases when women come to us with the problem of spontaneous miscarriages. The most dangerous thing in this case is that miscarriages occur during the period of 10-12 weeks, during which time most women are not registered at the antenatal clinic, and some women with irregular cycles may not even know that they are pregnant.

Why is diagnosing pregnancy complications important?

There is currently no cure for preeclampsia. Therefore, a number of complications require correct diagnosis and prediction of complications and further correct prevention. We can say that it is correct only if we can find out at least proven risk factors.

In patients with thrombophilia, no matter what complications we talk about, be it a severe form of preeclampsia or recurrent miscarriage, because recurrent miscarriage today has received a slightly different name due to the emergence of antiphospholipid syndrome, and this is fetal loss syndrome, which combines various reproductive losses, starting from early stages, ending with late stages and neonatal death, and so on.

Violation of embryo implantation (genes TP53, LIF and others)

It has now been proven that the expression of the LIF protein is a crucial factor for the formation of the so-called “implantation window”.

In the endometrium of women with infertility, the expression of LIF is reduced, and it has also been shown that in case of infertility of unknown origin, the expression of LIF is significantly reduced in the middle secretory phase of the endometrium.

The level of LIF is regulated by the p53 protein; accordingly, mutations in the genes of the TH53 gene signaling pathway indirectly affect the expression of LIF in the endometrium. These are mutations of the genes TP53, MDM2, MDM4, USP7 and some others (D. d'Avila Paskulin et al., 2012)

Embryo implantation disorders (LIF and TP53 gene network)

Thrombophilia in early and late pregnancy

It all depends on the influence of thrombotic and non-thrombotic effects, because in the early stages this is usually a violation of angiogenesis, defects in trophoblast invasion, placentation defects.

Preparations of low molecular weight heparin, natural progesterone - drugs that affect angiogenesis, mechanisms of inflammation, anti-inflammatory defense, immune regulation.

It is these effects of progesterone antithrombotic drugs that prevail when prescribed in the first trimester. But we must take into account that in severe forms of thrombophilia they play a huge role; accordingly, in the second trimester it is, as a rule, an already formed placenta, and we are talking about how angiogenesis took place and how the placental bed was formed.

We may not know whether everything went well or not, and even more so if the patient did not receive an anticoagulant in the first trimester, but the use of antithrombotic drugs in the second trimester is aimed at preventing blood clots from forming in the vessels.

We are talking about the vessels of the umbilical cord, first of all, which is often the cause of intrauterine asphyxia, when, it would seem, just yesterday the patient had a Doppler test, everything was fine, no signs of severe hypoxia, and on the second day intrauterine fetal death suddenly occurs. This is often associated with thrombosis of large vessels, thrombosis of the umbilical artery.

The third trimester is the trimester that is the most dangerous not only from the point of view of thrombosis, the “mother-placenta-fetus” circulation, but also from the point of view of fatal thromboembolic complications in the mother. The same applies to the postpartum period, when the risk of thromboembolic complications is very high.

Throughout pregnancy and the postpartum period, thrombophilia poses a fairly high risk for complicated pregnancy and postpartum complications in women in labor.

Thrombophilia during pregnancy

Amyan Marine Isakovna - associate professor, candidate of medical sciences, chief physician, obstetrician-gynecologist at Diamed Shchelkovskaya
Nowadays, 1-2 miscarriages are considered normal. This is associated with poor ecology, overwork, and poor nutrition. A woman experiences miscarriage twice, gets pregnant again, and can you imagine how the uterus wears out? A woman with her sixth pregnancy came to see me,” Marine Isakovna Amyan, chief physician of the clinic on Shchelkovskaya, obstetrician-gynecologist, gynecologist-endocrinologist, gives an example from her practice. Only one of her pregnancies resulted in childbirth.

The family planned a second baby and could not bear it. Svetlana, that was the patient’s name, was in her eighth week of pregnancy at the time of treatment. The woman did not understand what was happening because she did not experience any symptoms before the miscarriages. The pain began already during the process of spontaneous abortion. All previous unsuccessful pregnancies, the woman was observed in the antenatal clinic, she had a confirmed diagnosis of genetic thrombophilia. As well as a complicated medical history: thyrotoxicosis, nodular goiter, myopia, chronic carriage of infections, including HPV. A woman was not registered until she was 12 weeks old, and she did not nurse until that time; miscarriages happened earlier.

Desperate, she turned to our clinic for help. On the advice of a friend, Svetlana came to me with a history of her illness, documents, tests and research. As I already said, it was the eighth week and the critical period was approaching when miscarriages occurred. The woman was noticeably nervous and worried. Based on the research, the picture immediately became clearer; we prescribed an additional examination for the patient, took blood, and performed an ultrasound. Since Svetlana’s miscarriages occurred in the first trimester, we could not hesitate for a minute. And we started treatment on the same day.

The first time we exhaled, as they say, was when the patient entered the second trimester of pregnancy. Next, we were able to gradually prevent the following possible complications:

• intrauterine growth restriction
• placental insufficiency
• high blood pressure
• premature birth

During pregnancy, we constantly measured blood levels, did ultrasound with a prenatal test, and monitored the fetal heart rate. It was hard work between the doctor and the patient. But we managed. Three months ago, Svetlana became a mother for the second time, gave birth to a beautiful girl, and recently she came to us to introduce her to her long-awaited baby.

Antiphospholipid syndrome - chameleon syndrome

Antiphospholipid syndrome is extremely characterized by early reproductive losses, but for the same syndrome, which is also called chameleon syndrome.

Due to various clinical multiple effects, it is called chameleon syndrome, because traumatic complications, early losses, and late losses, up to placental abruption and severe preeclampsia, are possible.

Any obstetric pathology can be a consequence of the circulation of antiphospholipid antibodies, therefore, the basic therapy for antiphospholipid syndrome today is anticoagulant and antiplatelet therapy.

If earlier, even before the discovery of the effect of antiphospholipid antibodies on the hemostatic system, preference was given to immunosuppressive drugs (glucocorticoids), then today glucocorticoids are not first-line drugs in the prevention and treatment of complications associated with antiphospholipid syndrome.

Nevertheless, glucocorticoids remain drugs that are prescribed to patients with antiphospholipid syndrome in the presence of systemic lupus erythematosus or other severe autoimmune connective tissue diseases that require the prescription of glucocorticoids for health reasons on the part of the mother.

Criteria for APS syndrome

Laboratory criteria for antiphospholipid syndrome are the circulation of lupus anticoagulant, quantitative determination of cardiolipin antibodies to beta-2-glycoprotein. And it is extremely important to study twice with an interval of 12 weeks.

Today, 12 weeks of pregnancy is an extremely long period of time to wait for confirmation of the diagnosis of “antiphospholipid syndrome,” especially if the patient has already had miscarriages, and only then decide whether or not to prescribe anticoagulants.

Therefore, in our practice, in such patients, if the presence of a high titer of antibodies to beta-2-glycoprotein or antibodies to other phospholipid cofactors (prothrombin, circulation of lupus anticoagulant, pronounced phenomenon of this anticoagulant) is confirmed, even once, we regard this as antiphospholipid syndrome and immediately begin anticoagulant therapy. Genetic thrombophilia can be very different, depending on its form, we can predict those forms that are characteristic of this thrombophilia and the risk of thrombotic complications.

If we are talking about a deficiency of protein C, protein S, then, as a rule, there are often early losses. However, the genetic form of thrombophilia is more characterized by late losses, when the pregnancy is terminated after 20 weeks of pregnancy.

Manifestations of genetic thrombophilia

• Premature abruption of a normally located placenta;
• intrauterine death; neonatal fetal death;
• syndrome of fetal growth retardation due to the thrombotic component in the vessels of the placenta.

Despite the fact that thrombophilia implies a tendency to form blood clots, it is very diverse.

For example, such a form of thrombophilia as hyperhomocystoinemia, when the level of homocysteine ​​in plasma increases, is a risk factor not only for thrombotic complications, including in the placental bed, but also for such complication factors as:

• risk of fetal deformity;
• early miscarriages;
• chromosomal aberrations,

since folic acid deficiency and high levels of homocysteine ​​affect the processes of meiosis and increase the risk of developing chromosomal aberrations. Due to oxidative stress, which is characteristic of high levels of homocysteine, it can affect the state of the vascular endothelium, that is, the internal lining of blood vessels, and cause severe and early forms of preeclampsia.

The concept of “thrombophilia” unites all hereditary and acquired disorders of hemostasis, in which there is a predisposition to the early manifestation and recurrence of thrombosis, thromboembolism, ischemia and infarction of organs [2]. For practical purposes, it is very important to distinguish congenital thrombophilia, since we are talking about thrombogenic factors that accompany patients throughout their lives. Congenital thrombophilia is a tendency to thrombosis due to congenital predisposing factors [13], regardless of the cause. For many years, antiphospholipid syndrome (APS) was classified as an acquired form of thrombophilia, but now there is evidence of the genetic nature of the origin of APS [5], which, however, does not prevent this condition from still being classified as thrombophilia. In patients with thrombophilia, thrombotic complications occur in situations where other people do not experience such complications: when oral contraceptives are prescribed, during pregnancy, during uncomplicated surgical operations, during long trips and in an uncomfortable position, etc.

Patients with thrombophilia are characterized by the occurrence of heart attacks and strokes at a young age - up to 50 years - without obvious predisposing factors, as well as thrombosis of unusual locations: retinal vessels, brain, veins of the upper half of the body, superficial epigastric, pudendal veins, ileofemoral thrombosis. Obstetric losses are characterized by early miscarriages, late miscarriages, repeated undeveloped pregnancies, the occurrence of severe forms of late gestosis with termination of pregnancy before 34 weeks, the development of fetal growth restriction syndrome, sudden fetal death syndrome, and premature abruption of a normally located placenta.

Clinical manifestations of thrombophilia are thrombotic complications or obstetric losses, as there are relevant publications in the medical literature [1, 3, 11]. This distinguishes thrombophilia from simple polymorphism of genes, the number of different combinations of which exceeds 1.5 million. Therefore, polymorphism of the genes fibrinogen, factor VIII (FVIII), factor XIII (FXIII), etc. should be considered simple polymorphism of genes, since to date they have not been proven connection with clinical pathology.

Congenital thrombophilias include the following conditions:

- deficiency of anticoagulant proteins: antithrombin III (AT III) below 70% (by activity), protein C (PS) below 65%, protein S (PS) below 55%;

- polymorphism of FV Leiden genes - homo- (A/A) or heterozygous carriage (A/G);

— polymorphism of the prothrombin gene FII G20210A — homo- (A/A) or heterozygous carriage (A/G);

- polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene C677T - homo- (T/T) or heterozygous carriage (C/T);

- polymorphism of the plasminogen activator inhibitor gene type I (plasminogen activator inhibitor - PAI-I) - homo- (4G/4G) or heterozygous carriage (4G/5G);

— antiphospholipid syndrome (APS), diagnosed according to modern diagnostic criteria in 2006 [10];

- hyperhomocysteinemia - homocysteine ​​content in fasting blood plasma more than 15 mmol/l.

APS can be diagnosed if 1 clinical and 1 laboratory criteria are met. Clinical criteria:

1. Arterial or venous thrombosis without inflammation of the vascular wall.

2. Pathology of pregnancy:

a) one fetal death after 10 weeks of pregnancy or more;

b) eclampsia, gestosis or placental insufficiency in less than 34 weeks of pregnancy;

c) 3 spontaneous abortions or more in less than 10 weeks of pregnancy without anatomical, hormonal, or chromosomal disorders.

Laboratory criteria:

1. Twice positive test for lupus anticoagulant with an interval of 12 weeks;

2. Anticardiolipin antibodies in high titers (more than 40 units), determined by ELISA with an interval of 12 weeks;

3. Presence of antibodies to β-2-glycoprotein-I.

It should be remembered that APS should not be diagnosed in cases where the time interval between clinical and laboratory manifestations is less than 12 weeks and more than 5 years, and superficial venous thrombosis is not included in the criteria for diagnosing APS.

Indications for examination of patients

Examination is prescribed for patients in the event of idiopathic thrombosis, stroke, heart attack, miscarriage, severe gestosis, premature abruption of a normally located placenta, premature birth before 34 weeks of gestation, a history of fetal growth restriction syndrome, thrombosis while taking oral contraceptives or hormone replacement therapy (HRT). Based on the 3-year experience of the Moscow Regional Research Institute of Obstetrics and Gynecology (570 pregnant women with thrombophilia, mainly caused by a combination of heterozygous carriage of the MTHFR and PAI-I genes, were observed), we consider it advisable to screen for thrombophilia in the complicated course of this pregnancy, even in the absence of obstetric complications history, which allows justifying treatment with anticoagulants and preventing the progression of complications.

Normal conditions are considered to be ATIII activity of 70% and above, protein C - 65% and above, protein S - 55% and above; FV Leiden - G/G, prothrombin FII G20210A - G/G, MTHFR C677T - C/C, PAI-I - 5G/5G, homocysteine ​​content in fasting blood plasma below 15 mmol/l.

It is also likely that thrombophilias should include polymorphism of the angiotensin converting enzyme gene (ACE I/D) and polymorphism of the endothelial receptor of protein C (ERPC), respectively associated with relapses of severe gestosis and repeated miscarriages in early pregnancy. .

Diagnosis of thrombophilias

For patients at risk - if there is a history of idiopathic or pregnancy-related thrombosis, or with the use of oral contraceptives, heart attacks, strokes, obstetric losses, severe gestosis, a history of abruption of a normally located placenta, failures when trying in vitro fertilization and embryo transfer - prescribed examination. It is advisable to obtain information as early as possible in order to make a decision on treatment: during prenatal examination, examination in the first trimester of pregnancy, if a complication occurs during this pregnancy.

Testing for thrombophilia includes:

— determination of the percentage of activity of anticoagulant proteins: AT III, PS, PS;

— study of gene polymorphism: FV Leiden, FIIG20210A, MTGFRS677T, PAI-I;

— determination of homocysteine ​​content on an empty stomach;

- study of lupus anticoagulant, antibodies to cardiolipins and antibodies to β2-glycoprotein I.

Blood sampling for genetic studies and determination of homocysteine ​​is carried out in a test tube with ethylenediamineacetic acid; for the determination of lupus anticoagulant, antibodies to cardiolipins and β2-glycoprotein-I in a citrate tube (for example, Monovet-S). When using heparin, test results may be distorted. If one thrombophilia factor is identified, the following diagnosis is made, for example: thrombophilia - heterozygous carriage of FIIG20210A A/G; if several thrombophilia factors are identified, a diagnosis of combined thrombophilia is made with a list of defective factors, for example: combined thrombophilia - heterozygous carriage of FV Leiden A/G, homozygous carriage of PAI-I 4G/4G, hyperhomocysteinemia.

Treatment of pregnant women with thrombophilias

Treatment with anticoagulants in patients with a deficiency of proteins—anticoagulants: antithrombin-III, protein C, protein S—reduced the risk of fetal loss [6].

Patients should be divided into two groups:

- having a history of obstetric losses;

- with a history of thrombotic complications and during current pregnancy.

Treatment is possible with both unfractionated heparin (UFH) and low molecular weight heparins (LMWH): fragmin, fraxiparin, clexane. UFH, compared to LMWH, have a more pronounced anticoagulant effect, inactivating active molecules of blood coagulation factors: II, X, IX, XI, XII, reducing the number of microvesicles, increasing the content of tissue factor inhibitor, activating fibrinolytic activity, and inhibiting complement system factors [7]. Treatment with UFH is possible in the form of subcutaneous injections or inhalations through an ultrasonic inhaler. LMWH drugs have their own pharmacokinetics and are not interchangeable. Treatment is carried out in a prophylactic dosage - for UFH 10,000 or 15,000 units subcutaneously and, as a rule, does not require laboratory monitoring.

If there is a history of obstetric losses, treatment begins in the early stages of gestation to ensure adequate placentation from 4-5 weeks to 34 weeks of pregnancy, usually subcutaneous UFH 5000 units 2 times a day with an interval of 12 hours. To exclude heparin-induced thrombocytopenia at 4, 8 and On the 15th day of treatment with UFH, the platelet count should be determined in a clinical blood test. After 34 weeks of gestation, natural involutive changes occur in the placenta, and the use of heparin does not improve pregnancy outcome, theoretically increasing the risk of hemorrhagic complications. In the form of inhalations, heparin is used in a dosage of 500-700 units/kg every 12 hours. If the patient is large (more than 90 kg), heparin can be used in the same dose every 8 hours.

If there are thrombotic complications in a patient with thrombophilia during current pregnancy and a history of treatment after treatment by vascular surgeons, UFH therapy is administered at 5000 units every 12 or 8 hours without laboratory control. Due to the increase in the number of thrombotic complications in pregnant women in the third trimester and in the postpartum period, especially in the first 4 weeks, it is advisable to prescribe a regimen of 5000 units 3 times a day. The use of UFH in a daily dose of up to 20,000 units does not require laboratory control. Delivery, surgery and puncture of the epidural space are safe if the thrombin and activated partial thromboplastin time are normal and the patient’s platelet count is normal [12].

If clinical and laboratory examination does not make it possible to diagnose APS, but there is a constantly high titer of anticardiolipin antibodies, antibodies to anti β2-glycoprotein I, a positive lupus anticoagulant is constantly determined, treatment with UFH is indicated in a prophylactic dose - 5000 units subcutaneously with an interval of 12 hours.

When treating pregnant women with LMWH, achieving prophylactic treatment levels (0.3-0.5 units of anti-Factor Xa activity) is difficult due to the increase in glomerular filtration rate and volume of distribution as pregnancy progresses, so the recommended level of anti-Factor Xa activity can be achieved only with individual dose selection for the patient [4, 8]. Often, treatment with LMWH does not prevent the development of fetal malnutrition, and the use of UFH is preferable.

Treatment of patients with thrombotic complications requires a minimal interruption in the use of drugs during delivery. When carrying out programmed labor and planned cesarean section, the last heparin injection is carried out the night before, before 15:00 the next day, delivery is carried out and 3 hours after birth, heparin therapy is resumed at 5000 units every 12 hours throughout the entire postpartum period. Prescription of a full therapeutic dose of heparin is possible one day after birth and is monitored by the level of activated partial thromboplastin time for UFH and the level of anti-Xa factor for LMWH. Since during normal pregnancy and its complications the D-dimer content is increased, this indicator cannot be used either for diagnostic purposes or to monitor the effectiveness of LMWH treatment [9].

During prophylactic treatment of patients with thrombophilia with heparin, as a rule, there is no need to prescribe other drugs that actively affect the blood coagulation system. The use of other medications is not contraindicated.

This practice of managing pregnant women with thrombophilia allows achieving a favorable pregnancy outcome.

Pregnancy after hormonal contraceptives

Two words about pregnancy, which occurred immediately after stopping oral contraceptives. This slide is specifically presented to show practicing doctors at antenatal clinics, since we often prescribe hormonal contraceptives to patients who are preparing for pregnancy, and after discontinuation, pregnancy occurs quite quickly. But the problem is that any estrogens, including those contained in contraceptives, cause a deficiency of B vitamins and magnesium.

Pregnancies that occur immediately after discontinuation of hormonal contraceptives are accompanied by a high risk of complications, and in particular neural tube defects, which is typical for deficiency of folate, B vitamins, underdevelopment of the neural tube, this also applies to the brain, and defects in the development of connective tissue.

If the patient is taking hormonal contraceptives, she should take both folic acid and B vitamins at the same time. It is advisable to monitor her homocysteine ​​levels before she becomes pregnant.

Folate cycle gene defects and pregnancy

Genes involved in the metabolism of folic acid and vitamin B12 may play a certain role in miscarriage.

Folic acid (vitamin B9) is responsible for the transfer of methyl groups (CH3-) during chemical reactions in the body - these are reactions during which DNA, RNA and a number of amino acids (glycine, methionine) are synthesized. Therefore, it is so important for pregnant women and the fetus not to have a deficiency of both folic acid itself and the enzymes involved in its metabolism.

High concentrations of the active form of folate are required to convert homocysteine ​​to methionine. The main genes whose products control the conversion of folic acid into metabolically active forms and regulate homocysteine ​​metabolism are MTHFR (methylenetetrahydrofolate reductase), MTR (methionine reductase), and MTRR (methionine synthetase reductase). A decrease in the activity of these enzymes is one of the important reasons for the accumulation of homocysteine ​​in the body.

Low molecular weight heparins

The general principles for the prevention of thrombotic and non-thrombotic effects of thrombophilia are, of course, the establishment of the nature of thrombophilia and the use of low molecular weight heparin as basic drugs. There are a lot of them today, much more than there are in our country in the world. But among the low molecular weight heparins that are present in our country, these are the well-known Enoxaparin sodium, Clexane, Hemopaxane, Fraxiparin, Calcium Nadroparin, etc.

All of them are low molecular weight heparins. The molecular weight, pharmacological effects, pharmacodynamics, and pharmacokinetics of these drugs may differ.

They are highly effective during pregnancy, do not pass through the placenta, and can be used in patients with thrombophilia to prevent both thrombotic and typical obstetric, non-thrombotic effects of thrombophilia.

Folic acid preparations

Today, no one doubts that folic acid should be used two months before the planned pregnancy by the patient when she is planning a pregnancy, in order to reduce the risk, namely, chromosomal abnormalities, neural tube defects, and microcephaly. Low doses, 400 mcg, are usually recommended for this purpose. The maximum is 800 mcg.

If we are talking about patients with high homocysteine ​​levels, that is, this is a moderate and severe form of hyperhomocysteine, of course, such doses are not enough to reduce homocysteine ​​levels. Such patients should receive doses of at least 5 milligrams per day, along with vitamins B, B6, B12. We start with injection therapy, then move on to tablet forms of B vitamins and antiplatelet agents.

Where to get help for thrombophilia

If thrombophilia is detected during pregnancy, treatment with leeches is contraindicated. Pregnancy with signs of thrombophilia is managed by obstetrician-gynecologists at antenatal clinics. You may be given subcutaneous injections of anticoagulants.

If you have been diagnosed with thrombophilia and are just planning a pregnancy, contact our center. The main situations in which we can help:

1. Preparing for pregnancy. Against the background of thromboembolism, the risk of spontaneous abortion and other complications increases. To reduce the likelihood of their development, it is worth preparing for pregnancy before conceiving a child. In our center, leeches, acupuncture and herbs are used for this.
2. Infertility due to thromboembolism. Treatment at our center has helped many women become pregnant without chemical drugs, without hormones, or without an expensive IVF procedure. The use of leeches “thin” the blood, improves endometrial function and promotes rapid pregnancy.
3. Preparing for IVF. Sometimes thromboembolism is combined with other factors of infertility: obstruction of the fallopian tubes, endometriosis, hormonal disorders. If you are considering IVF, undergo preparation before this procedure. Pre-treatment at a herbal medicine center is highly likely to allow you to get pregnant faster. Reviews from many of our patients indicate that they managed to achieve pregnancy after the first or second embryo transfer.

In our center, treatment is carried out using natural methods, under the supervision of experienced doctors. Natural healing of the body will compensate for thrombophilia, improve blood properties and reduce the risk of adverse pregnancy outcomes. With proper preparation, the likelihood that you will need additional anticoagulant treatment after pregnancy is greatly reduced.

To make an appointment with a specialist at our center, call the phone number listed on the website.

Antiplatelet agents

The antiplatelet agents we use in pregnant women are low doses of aspirin. The small doses that are currently used throughout the world in pregnant women include doses of no more than 100 milligrams. Although in practice we, as a rule, do not increase the dose of aspirin above 75-80 milligrams. But in some cases, the issue of aspirin resistance arises, which occurs in almost 30-40% of the population.

It is possible to check the presence of aspirin resistance only by studying platelet aggregation activity. This is also an extremely painful issue of modern diagnostics and the modern so-called “hemostasiogram” in quotes. Because today, each laboratory understands coagulogram and hemostasiogram as its own set of parameters of the coagulation and anticoagulation system.

The process of studying platelet aggregation activity is labor-intensive.

It is extremely necessary for pregnant women, especially in patients with antiphospholipid syndrome, thrombocytopenia, and thrombocytopathy. Because both high platelet function and low platelet function are two ends of a big problem. On the one hand, there is a risk of thrombosis, and on the other, there is a risk of bleeding. The correct selection of antiplatelet agents is extremely important.

Dipyridamole and Curantil

If we are talking about aspirin resistance or the inability to reduce platelet aggregation activity with aspirin, we can resort to prescribing an additional drug during pregnancy: Dipyridamole or Curantil, phosphodiesterase inhibitors. They have a different mechanism of action, unlike aspirin. In addition, Dipyridamole has effects on the endothelium, which is also extremely important. The combination of “Aspirin + Curantil” can be used in patients with high platelet activity. This is one of the advantages of the fact that we can use Curantil together with Aspirin. We also use concentrates of natural anticoagulants.

In a rather rare group of patients with genetic thrombophilia, with a deficiency of antithrombin 3, protein C, in whom, in addition to anticoagulant therapy with low molecular weight heparins, it is necessary to use replacement therapy with anticoagulants that they lack genetically - thrombin 3, protein C, and so on.

If we are talking about patients with recurrent miscarriage, there is no question whether to use progesterone drugs or not. Definitely apply. And this was repeatedly voiced at recent international congresses on controversies in obstetrics and gynecology.

Frequency of thrombophilias and likelihood of complications during pregnancy

One of the most common thrombophilias is the heterozygous Leiden mutation. It occurs in the population with a frequency of about 4%. Complications with this type of thrombophilia develop in only 6% of women. But the homozygous Leiden mutation is much more dangerous. It leads to complications in 80% of cases. Fortunately, this variant of the disease is quite rare: it affects one in 50 thousand women.

Similarly, a mutation of the prothrombin gene in the heterozygous form is common (3% in the population), and complications are rare - they occur in only one out of 30 pregnant women. But the homozygous form occurs in one out of 10 thousand women, but in every third it causes complications during pregnancy.

Deficiency of protein C and protein S is relatively common - affecting one in 200 women. With these thrombophilias, the risk of complications exceeds 10%.

Antithrombin deficiency occurs in one in 1000 women. Every second person develops complications during pregnancy.

There are a large number of other variants of thrombophilias. They are not accompanied by symptoms during pregnancy and can only be detected using laboratory tests.

Micronized progesterone preparations

During pregnancy, micronized progesterone preparations are used due to the fact that this group of drugs does not have any pathogenic effect on intrauterine development.

Let me step aside a little from the problem of thrombophilia. A huge number of researchers are specifically studying the problem of intrauterine programming of a child. There is no doubt that intrauterine development is nothing more than a certain program, which has its own laws and which is laid down very early.

But during intrauterine development, this programming can be disrupted, and this can be a consequence of the occurrence of various fetal deformities and behavioral disorders.

This is the same diabetes, metabolic syndrome and so on. The use of drugs during pregnancy, especially in the early stages of pregnancy, requires a very careful approach. To date, mechanized progesterone preparations have been recognized as absolutely safe: Utrozhestan, Crinon and an oil solution of progesterone.

Choosing a method of contraception.

When taking estrogen-containing contraceptives, blood clotting increases, which in the case of thrombophilia becomes simply dangerous to health and life.

Indications for prescribing a study for hereditary thrombophilia:

• the presence in the past of two or more fetal growth arrests in early pregnancy;
• the presence of severe pregnancy complications in the past (severe forms of late toxicosis, intrauterine fetal death, fetal growth retardation);
• the presence of relatives with thrombotic complications under the age of 50 years (deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, sudden death);
• several failed IVF attempts;
• increased levels of antiphospholipid antibodies and/or increased homocysteine ​​levels;
• planning gynecological operations;
• planning hormonal contraception

Risk factors for thrombophilias:

• genetic predisposition (cases of thrombosis in relatives);
• diseases such as atherosclerosis, arterial hypertension, varicose veins, autoimmune diseases, thrombocytosis, erythremia, malignant neoplasms;
• history of stroke or heart attack;
• pregnancy;
• injuries and surgical interventions;
• sedentary lifestyle;
• obesity;
• taking hormonal contraceptives.

The main blocks of genes involved in the development of thrombophilia:

1. Genes of the blood coagulation system (F2, F5, F7, FGB, SERPINE 1)
2. Platelet factor genes (ITGA2, ITGB3)
3. Folate cycle enzyme genes (MTHFR, MTRR, MTR)
4. Genes responsible for endothelial dysfunction (ACE, AGT, NOS3)
5. Genes responsible for monogenic hereditary thrombophilias (PROC, PROS)

Primary (genetically determined) thrombophilias include (10):

• G1691A mutation of the factor V gene (Leiden);
• G20210A mutation of the prothrombin gene (blood coagulation factor II);
• homozygous mutation C677T of the methyltetrahydrofolate reductase (MTHFR) gene;
• deficiency of natural anticoagulants (ATIII; protein C, S);
• sticky platelet syndrome;
• increased levels of homocysteine ​​in the blood;
• increased activity or amount of factor VIII;
• rare causes (dysfibrinogenemia, deficiency of factors XII, XI, heparin cofactor II, plasminogen)

Frequency of various thrombophilias (10):

• Antiphospholipid syndrome – 28%
• Resistance to activated protein C – 25:
• Increased factor VIII levels – 25%
• Protein C deficiency – 10%
• Protein S deficiency – 10%
• Homocysteinemia – 10%
• Prothrombin G20210A – 5-10%
• Plasminogen deficiency – 2-3%
• Dysfibrinogenemia – 1.5%
• High PAI level – 1-3%
• Tissue plasminogen activator deficiency – 1%

The main mutations leading to hereditary thrombophilia: