Thrombophilia (Genetic predisposition). Genetic thrombophilia: diagnosis, treatment and danger during pregnancy Genes of hereditary thrombophilia

Nowadays, phlebologists and vascular surgeons very often prescribe laboratory tests for genetic thrombophilia, full complex research is expensive and not everyone can afford it. In this regard, the question arises as to whether it is necessary to succumb to the persuasion of a doctor and take tests for genetic diseases.

Geneticists are those who know what our ancestors suffered from

General provisions

Thrombophilia is a disease associated with the ability of blood to form blood clots inside the vessel. Mutations in genes can provoke a violation of the blood coagulation system and thereby provoke thrombosis.

By their nature, disturbances in the circulatory system can be caused by increased action fibrin, impaired anticoagulant function, impaired work of procoagulants. In all three groups of diseases, there can be pathologies that are severe and vice versa.

There is no standard instruction for managing the disease, since there are thousands of genetic mutations, and the lifestyle of each person is significantly different from others, therefore, the manifestations of the disease will be different. The occurrence of deep vascular thrombosis, including venous strokes, in young age requires careful monitoring of patients, as well as careful diagnosis of diseases.

Who should seek help

Most often, tests for thrombophilia are prescribed by a phlebologist or hematologist, when a suspicion of genetic diseases can play a decisive role in later life.

When is it most likely:

1. The course of pregnancy, which is accompanied by venous thrombosis in the mother. Such a measure is often mandatory, since the disease is inherited. Having a baby with thrombophilia is often a medical emergency.
2. Young people with deep vein thrombosis, as well as with an abnormal location of blood clots. It is known that the first outbreaks of thrombosis often manifest themselves in childhood or adolescence. Normally, signs of “thick blood” are found in people older than 40-50 years.
3. Children of patients with diagnosed thrombophilia. The disease is inherited from generation to generation for many years, so identifying gene mutations in the next generation is an important aspect of life. Patients with hereditary pathology must take preventive measures so as not to provoke the appearance of blood clots.
4. Patients in whom thrombosis began to occur due to trauma, or after extensive surgical interventions. The decision on the need to do an analysis for congenital thrombophilia is made by the surgeon, but it is important to take into account the data of the coagulogram, if it does not cause concern to the doctor, then there is no need for an examination.
5. Patients with frequent recurrent thromboses and their children. Perhaps the cause of recurrent thrombosis is thrombophilia, so their prevention becomes an important link in the quality of life of patients.
6. Patients with resistance to anticoagulants. A reduced response to a number of anticoagulant drugs is a direct indication for diagnosing a patient, otherwise the treatment of thrombosis due to heredity can take a long time.

How does this happen

Analysis is a fairly standard procedure. Everyone must have passed a standard set of tests for getting a job, school, or kindergarten. In general, the conduct of a laboratory study for genetic mutations differs only within the walls of the laboratory, and for ordinary patients, the procedure is quite familiar.

Deoxygenated blood

Venous blood contains not only genetic information, but also detailed information about the composition, viscosity, and the presence of disease markers. In some cases, the doctor prescribes not only an analysis for mutations in the genes. The information contained in the blood helps to correctly adjust the treatment of the patient in the future.

So what needs to be done:

1. Choose a clinic or laboratory. If you trust any clinic, because you have used the services many times, and you know that they provide reliable information, then it is better to contact them. If there is no such clinic, then ask your doctor to recommend such a laboratory.
2. Switch to proper nutrition. Fatty foods significantly affect many indicators, the analysis for hereditary thrombophilia does not require special restrictions, however, at least 24 hours before the procedure, it is better to refrain from eating fatty foods.
3. Give up bad habits . It is better to exclude alcohol and cigarettes a week before the tests, but in the case of heavy smokers, this condition becomes almost impossible, so the interval between blood donation and the last smoke break should be at least 2 hours.
4. come hungry. All laboratory blood tests must be taken on an empty stomach. In general, it is enough to have dinner and refuse breakfast, if you do not sleep at night and it is difficult to figure out what “fasting” is, then refuse food 6-8 hours before going to the clinic.
5. trust the nurse. There are no manipulations that go beyond the usual. If you have ever donated blood from a vein, the procedure will be similar. For clarity, the process of blood sampling is shown in the photo.

Buccal epithelium for diagnosis

Sometimes the study is carried out by taking the epithelium. This method is painless and quite suitable for children of any age.

What you need to know about this method:

1. As in the case of venous blood, it is necessary to decide on the clinic.
2. Be sure to maintain oral hygiene.
3. Before testing for hereditary thrombophilia, rinse your mouth with boiled water.
4. scrapings are taken cotton swab, which means no discomfort it won't deliver.

On a note! Usually there is a glass of water in any clinic, but just in case, it is better to take a bottle of boiled water with you.

Is it worth doing

In most cases, patients are stopped either by fear of the procedure or by the price.

Of course, not everyone can afford a comprehensive examination at a cost of about 15 thousand, but why it is important to know about the disease:

1. The presence of congenital thrombophilia requires the patient to be attentive to lifestyle. To avoid thromboembolism, it is necessary to observe certain rules and in some cases even take medications.
2. Combined thrombophilia. The presence of one pathology does not exclude the presence of another; genetic mutations can be inherited from two parents with different types of thrombophilia.
3. Stillbirth and miscarriages. Children who inherit the same gene from two parents are stillborn. In this way, genetic analysis blood for thrombophilia during pregnancy planning is fully justified. It is diagnostically significant to obtain data on the mutation of two parents, and not one.
4. Calm. You can agree to the study for your own peace of mind, because if the parents had thrombophilia, then the child will not necessarily be born with such a mutation.

Undoubtedly, it is possible to individual studies for a certain type of mutation. That is, parents with a certain type of thrombophilia, if it is confirmed, can diagnose the child for this particular type of disorder.

Also, given that there are not so many common thrombophilias, it is possible to analyze only the most common pathologies.

It:

• Factor V-Leiden disease;
• Prothrombin mutation;
• Mutation in antithrombin 3 genes;
• Defect of C or S proteins;
• Hyperhomocysteinemia.

If you want to learn a little more about these types of thrombophilias, you can refer to the video in this article. All these mutations may not manifest themselves in any way, or, on the contrary, have obvious clinical manifestations. Some of them can be acquired over the course of life, which means that analysis for congenital pathology will not show the presence of a mutation.

A comprehensive examination, unfortunately, also does not include all types of thrombophilia, but only the most common and clinically significant. Data about comprehensive examination are presented in the table below.

Decryption rules

A few facts about decryption:

1. Deciphering such tests is done by a geneticist.
2. In the usual sense, genotype tests are not deciphered; there are no acceptable or unacceptable norms here. The genotype of a person can be favorable, that is, without signs of mutation, or unfavorable.
3. Regardless of what it was biological material(blood, epithelium), the values ​​will be the same throughout life.
4. The presence of the disease indicates a genetic predisposition, but at the same time, outbreaks of thrombosis in a person may not manifest themselves throughout life.
5. Testing for mutations in genes is a long-term procedure. You will have to be patient, in some laboratories the study is carried out within 14 days.
6. Re-analysis is not required. Human genes do not change with age, so a comprehensive test is done once in a lifetime.
7. Decoding is required for vascular surgeons, obstetrician-gynecologists, hematologists, phlebologists, cardiologists. The fact of thrombophilia greatly facilitates the diagnosis of many diseases in these areas.
8. Genetic analysis is an expensive procedure, and if the patient does not have the opportunity to undergo it, then no one can force him.

Note! Elderly people are most prone to the appearance of vascular diseases and venous thrombosis, therefore, for them, a blood test for gene polymorphism in thrombophilia is practically not used.

What is the result if the analysis showed the presence of a mutation or vice versa

Depending on the test results, the doctor must adjust the treatment. So, for example, protein C deficiency can be caused by liver pathology, and not by hereditary mutations in genes.

In this case, the patient will be transferred to the hands of another specialist in the profile. Since the level of proteins can change under the influence of not only hepatological diseases, but also against the background of pregnancy, oncology, age and other factors.

If a genetic analysis for thrombophilia confirmed its presence, then the doctor will issue appropriate recommendations that prevent the occurrence of thromboembolism in a particular type of disease. Or correct the treatment of the disease or condition (deep vein thrombosis, miscarriage) with which the patient went to the hospital.

Thrombophilia is pathological condition circulatory system a person with a high risk of thrombosis in vascular structures. This happens because the natural processes of hemostasis are disturbed, and increases markedly. As a result, the blood does not coagulate where and when it is needed, which provokes the appearance of blood clots. The latter, in turn, are able to develop in all vessels human body, giving rise to the most dangerous pathologies.

Often, due to thrombophilia, tissue necrosis or chronic venous insufficiency develops. More serious consequences of the disease are stroke brain damage and heart attack. Given this, to any problems with cardiovascular system should be treated with due responsibility. Today we’ll talk about what a thrombophilia test is, how it is performed and what is its norm.

Thrombophilia is a pathological condition that is characterized by a violation of the blood coagulation system.

Thrombophilia is a very dangerous pathology, which could be understood from the material presented earlier. By the nature of the flow this disease unremarkable and rarely pronounced. As a rule, patients with thrombophilia do not learn about its course until the thrombosis worsens or its complications appear.

Given this state of affairs, it is important to state the need preventive examinations organism for a tendency to this pathology.

In modern medicine, there are few specialized appointments for the analysis of thrombophilia. The main indications include:

• the presence of pathology in close relatives
• the course of such thrombotic diseases and their complications
• previous thrombosis or risks of its development
• the need for an operation that can provoke thrombosis
• long-term use of certain drugs (hormonal drugs, oral contraceptives, etc.)
• the very fact of pregnancy or problems in the process of its course

In principle, there are really few appointments for diagnostics. Despite this, the need for its implementation can be determined by both a professional doctor and the person himself. Again, preventive diagnostics are of no small importance for a long and high-quality life of people.

Do you need to prepare for the study?

An analysis for thrombophilia is a blood test, during which the diagnostician provokes the processes of its coagulation. There are many types of such diagnostics, but in any case, the essence of this lies in a thorough examination of human biomaterial.

The analysis does not require profile preparation. Often enough:

1. donate blood in the morning
2. do it on an empty stomach
3. do not smoke a few hours before the study
4. give up alcohol and fatty foods 1-2 days before biomaterial sampling
5. exclude physical and psycho-emotional stress the day before the diagnosis

In addition, it is important to warn the diagnostician about the drugs taken, if any. It should be remembered that some drugs increase or, conversely, lower. For an accurate interpretation of the results, it will not be superfluous to provide the diagnostician with a medical history. Thus, the presence of thrombosis and similar pathologies can indirectly indicate thrombophilia.

The preparation noted above applies only to tests aimed at detecting blood pathologies. In the course of other diseases of the body, accompanied by disturbances in the functioning of the heart or blood vessels, it is often prescribed additional diagnostics also revealing thrombophilia. Naturally, preparatory procedures for such studies may have a specific formation. The need for specialized training should be clarified directly with the diagnostician a few days before the diagnosis.

Types of examination for thrombophilia

As noted earlier, the basic analysis for thrombophilia is carried out through a blood test.

In most cases, to detect this pathology, two types of examination are implemented:

• , aimed at identifying the basic indicators of the state of the biomaterial (level, etc.).
• necessary to determine its coagulability.

Often, biomaterial is taken for research from both the phalanx of the finger and from the vein. Comprehensive diagnostics for the detection of thrombophilia includes following procedures:

• - a comprehensive study of human venous blood.
• – creation of artificial conditions for the coagulation of the biomaterial.
• Determination of the prothrombin index is a measure necessary for the accurate diagnosis of clotting disorders.
• Study of the reaction of the blood substance to the breakdown of certain proteins (D-dimer, S proteins, etc.) - measures to determine the root cause of problems with the coagulability of the biomaterial.

In principle, an analysis for thrombophilia is always a complex of specific studies. Its focus is to identify problems with hemostasis. modern medicine has advanced quite far, so it is very simple to identify pathological processes in the blood substance.

Diagnosis of thrombophilia in public health facilities is rare. As a rule, to pass such an analysis, people have to contact paid laboratory diagnostic centers. The cost of research in such organizations depends on how complex it will be.

Diagnosis of genetic pathology of blood

If genetic thrombophilia is suspected, a thorough and highly specific blood test is required. The specificity of this type of pathology comes down to the fact that mutations in the blood substance occur at the gene level and are inherited by the patient. The above-mentioned tests for thrombophilia reveal only acquired blood diseases, but there are no congenital lesions.

Accurate diagnosis of genetic thrombophilia requires polymerase-based testing. chain reaction(). Such diagnostics is more global in nature, as it examines both specific indicators of blood coagulation and processes in it at the gene level.

Analysis of such a formation in without fail accompanied by the following tests:

• determination of the Leiden mutation;
• prothrombized mutation check;
• detection of mutations in the MTHFR gene and some plasminogens.

A cumulative study of the gene structure of blood makes it possible to identify its polymorphism. This condition provokes a different variation of genes, which is incorrect and provokes a violation in the processes of blood formation. It is polymorphism that indicates genetic thrombophilia, which is why it is so important in identifying this disease.

A specific analysis of the considered type has one goal - to determine the presence or absence of mutational processes in the blood substance.

The very fact of impaired coagulability, as a rule, is detected in advance and does not require confirmation. Unfortunately, it is impossible to eliminate the gene mutation, so the patient is prescribed a corrective course of therapy. The essence of this is not to eliminate the root cause of the problem with blood clotting, but to eliminate the risks of thrombosis. With a competent approach to treatment, people with genetic thrombophilia do not experience significant discomfort and live for many years.

Possible results

Many doctors are involved in the appointment of tests for thrombophilia and their specific formation: surgeons, general therapists, phlebologists and other specialists. However, deciphering the results of such diagnostics is the prerogative of the hematologist. Only this doctor has the necessary knowledge for an accurate diagnosis. Also, the hematologist often determines the further course of therapy for the patient and the severity of his illness.

In the results of the analysis for thrombophilia, you can find a huge number of specific indicators. Their final list depends on the type of diagnostics performed and the laboratory procedures implemented in the process.

Deciphering the results of such an examination is not an easy procedure and requires certain knowledge, therefore it should always be carried out by a professional doctor. At a minimum, when making a diagnosis, it is important to consider:

• patient's medical history
• his condition at the time of the study
• features of a particular case (drugs taken by the subject, type of analysis performed, etc.)

After decoding, the hematologist makes an accurate diagnosis to the patient with the rationale for the conclusions drawn. Depending on the results of the diagnosis, further appointments are determined for the person being examined. Often, therapy for thrombophilia includes diet, medication, and lifestyle changes. Sometimes the list of prescriptions is supplemented by something else.

The danger of thrombophilia

At the end of today's article, we will again pay attention to the phenomenon of thrombophilia. It has already been noted above that this pathology is a violation of hemostasis in the blood substance, which provokes abnormal blood clotting.

Bottom line similar condition of the circulatory system is the blockage of vascular structures by clots of biomaterial, which can cause the most dangerous complications.

Relatively harmless consequences of thrombophilia are considered to be:

1. thrombosis of varying severity
2. problems with the structure of vascular structures
3. various types of blood insufficiency, provoking tissue necrosis

The consequences of the noted states can be even more dangerous diseases. Often thrombophilia leads to a stroke or heart attack, of course, if not treated properly and in an adequate regimen.

It is important to pay special attention to problems with pregnant women. Because during pregnancy female body experiences enormous loads, then thrombosis during this time can happen at any time. Naturally, the presence of thrombophilia increases the risks several times.

In most clinical cases, when a pregnant woman had thrombophilia, a miscarriage or a premature birth occurred.

Given such statistics, it is better for expectant mothers suffering from an illness not to take risks and be periodically examined in a clinic. In addition, a comprehensive and high-quality approach to the treatment of thrombophilia is important, as well as minimizing potential complications. As practice shows, tracking the pathological state allows you to avoid the most dire consequences any pregnant woman.

You can learn more about thrombocilia from the video:

Perhaps, on this the most important provisions on the topic of today's article have come to an end. Thrombophilia is a dangerous phenomenon, so it is unacceptable to ignore its presence. Only timely tests, well-organized treatment and A complex approach to get rid of the disease can give maximum guarantees in terms of the absence of complications.

Otherwise, the consequences of pathology are a matter of time, and they can develop spontaneously. We hope that the material presented has helped all readers of our resource to understand the danger of thrombophilia and methods for its diagnosis. I wish you health and successful treatment of all diseases, and better - total absence those!

In their work, obstetricians-gynecologists of the CIR constantly answer the questions: what is thrombophilia? What is genetic thrombophilia? What test for thrombophilia should be taken to rule out hereditary factors? How are thrombophilia, pregnancy and polymorphisms related? And many others.

What is thrombophilia?
Thrombus (clot) + philia (love) = thrombophilia. Here is such a love for a blood clot, or rather an increased tendency to thrombosis- the formation of blood clots in vessels of different diameters and localizations. Thrombophilia is disruption in the system.
Hemostasis is a mechanism that provides correct blood reaction to external and internal factors. The blood must flow through the vessels quickly without lingering, but when it becomes necessary to reduce the flow rate and / or form a clot, for example, to “repair” an injured vessel, the “correct” blood should do it. Further, making sure that the clot has done its job and is no longer needed, dissolve it. And run on)
Of course, not everything is so simple, and the coagulation system is the most complex multicomponent mechanism that has regulation at different levels.

A bit of history...
1856 - German scientist Rudolf Virchow asked the question of the pathogenesis of thrombosis, conducted a series of studies and experiments in connection with this, and formulated the basic mechanism of thrombosis. Any medical student at the mention of the "Virchow triad" is obliged to report - an injury to the inner wall of the vessel, a decrease in the speed of blood flow, an increase in blood clotting. In fact, the great Virchow was the first to solve the riddle “why the same blood can flow freely, or can clog a vessel.”
1990 - The British Committee for Hematological Standards defined the concept of "thrombophilia" as a congenital or acquired defect in hemostasis, leading to high degree predisposition to thrombosis.
1997 - an outstanding hematologist Vorobyov A.I. describes the "hypercoagulation syndrome", that is, a certain state of the blood with an increased readiness for clotting.

Thrombus dangerous?
The answer is yes. Except for the physiological need, of course, thrombosis is bad. Because blockage of any vessel is dangerous. How larger vessel the more significant it is, the more dangerous complications. The vessel must not have blocked blood flow. This immediately or gradually entails a decrease in oxygen delivery to the tissues (hypoxia) and triggers a series of pathological changes. It may not be noticeable and not as scary as I described, but it can be very painful, and sometimes deadly. Thrombosis entails a significant damage to the function of a particular organ, and sometimes the body as a whole. Thrombosis is a pulmonary embolism, it is heart failure (including acute coronary), damage to the legs (deep vein thrombosis), intestines (mesenteric), etc.

How is thrombophilia related to pregnancy?
Pregnancy is a special “test” period that reveals the carriage of genetic thrombophilia, and most women first learn about hemostasis gene polymorphism during pregnancy.
As for obstetric complications, the problem of increased thrombus formation primarily concerns the organ, which consists entirely of blood vessels. This is the placenta. Very detailed and with pictures - here:
All women during pregnancy undergo physiological hypercoagulability, that is, the blood normally slightly increases its coagulability. This is a normal physiological mechanism aimed at preventing blood loss after the completion of pregnancy - in childbirth or with possible pathological outcomes (early termination of pregnancy, placental abruption, etc.).
But if a woman has a defective hemostasis gene (or several), then, contrary to the mathematical rule, minus by minus will give an even greater minus - it will significantly increase the risk of blood clots in the vessels of the placenta, which can cause many complications.

What types of thrombophilia are there?
Thrombophilias are divided into hereditary and acquired, there are also mixed types.

Acquired (non-genetic) thrombophilia
Acquired forms of thrombophilia are realized under certain "special" conditions. This happens when the body is going through hard times; rather serious pathological changes entail "over" - the reaction of the coagulation system. For example, oncological diseases accompanied by chemotherapy, pronounced infectious, autoimmune, allergic processes, diseases of the liver, kidneys, cardiovascular pathologies, diseases connective tissue- systemic lupus erythematosus, various vasculitis, etc. In such cases, the thrombus formation cascade can be triggered and without carriage defective hemostasis genes. Predisposing factors can be prolonged and persistent dehydration, physical inactivity, obesity, pregnancy, taking hormonal drugs etc..

To be continued. In the next blog post - .

“To know in order to foresee;
to foresee in order to act;
act to warn.”
August Comte.

Pro et contra genetic testing of pregnant women.

We call childless women unhappy. Never experience the feeling of motherhood - a huge ... HUGE SORRY. We, doctors, involuntarily become witnesses of other people's suffering. But today we can say "no" to this trouble. Now a doctor can really help, prevent, cure a disease, restore the joy of existence.
In this article, we will discuss serious problem of our days - thrombophilia, its contribution to obstetric complications, genes that predetermine the development of thrombophilia in a woman, the consequences this disease methods of prevention and treatment.
Why are we discussing this topic? Because there is no greater miracle in the world than the miracle of birth. We marvel at the beauty of the sunset and the northern lights, admire the heavenly scent of a blossoming rose. But all the wonders and mysteries of our planet, all the secrets of nature and the mysteries of the world bow their heads before birth: A miracle with a capital letter. We must, we can make a woman's life a fairy tale with a happy ending, not a tragedy like NN's life. So, dear doctor, your attention is given the key to the treatment of infertility, miscarriages, developmental anomalies and much more. Saving the life of a woman and an unborn child is now a realistic task. New life in our hands!

Thrombophilia (TF) is a pathological condition characterized by increased blood clotting and a tendency to thrombosis and thromboembolism. According to numerous studies, this disease in 75% is the cause of obstetric complications.
Classically, two types of TF are distinguished – acquired (antiphospholipid syndrome, for example) and hereditary1. This article will focus on hereditary TF and polymorphic genes2 (polymorphisms) that cause it.
Genetic polymorphism does not necessarily lead to a disease state; provoking factors are most often needed: pregnancy, postpartum period, immobilization, surgical intervention trauma, tumors, etc.
Given the peculiarities of the physiological adaptation of the hemostasis system to pregnancy, the vast majority of genetic forms of thrombophilia are clinically manifested precisely during the gestational process and, as it turned out, not only in the form of thrombosis, but also in the form of typical obstetric complications. During this period, the coagulation, anticoagulation and fibrinolytic systems are reorganized in the mother's body, which leads to an increase in blood coagulation factors by 200%. Also, in the third trimester, the blood flow velocity in the veins of the lower extremities decreases by half due to partial mechanical obstruction of the venous outflow by the pregnant uterus. The tendency to blood stasis, combined with hypercoagulability during physiological pregnancy, predisposes to the development of thrombosis and thromboembolism. And with pre-existing (genetic) TF, the risk of thrombotic and obstetric complications increases tens and hundreds of times!
What harm are we talking about? How is TF related to obstetric complications? The thing is that a full-fledged placental circulation depends on a balanced ratio of procoagulant and anticoagulant mechanisms. Hereditary TFs lead to the disruption of this balance in favor of procoagulant mechanisms. With TF, the depth of trophoblast invasion decreases, and implantation is defective. This is the cause of infertility and early pre-embryonic losses. A violation of the uteroplacental and fetal-placental blood flow due to the development of vascular thrombosis is a pathogenetic cause of such complications as infertility of unknown origin, habitual miscarriage syndrome, abruption of a normally located placenta, preeclampsia, intrauterine growth retardation, fetal loss syndrome (undeveloped pregnancy, stillbirth). , neonatal mortality as a complication of preterm birth, severe preeclampsia, placental insufficiency), HELLP syndrome, unsuccessful IVF attempts.

Prevention ( general provisions)

*Prevention of obstetric complications in thrombophilia should begin before pregnancy.
* Relatives of the patient who have the same defects should receive appropriate prophylaxis.
*Specific prophylaxis for a specific mutation (see sections on polymorphisms)

Treatment (general provisions)
* Anticoagulant therapy, regardless of the mechanism of thrombophilia: low molecular weight heparin (does not cross the placenta, creates a low risk of bleeding, no teratogenic and embryotoxic effect). In women at highest risk (genetic TF, history of thrombosis, recurrent thrombosis), anticoagulant therapy is indicated throughout pregnancy. On the eve of childbirth, therapy with low molecular weight heparin is recommended to be canceled. Prevention of thromboembolic complications in postpartum period resume after 6-8 hours and spend within 10-14 days.
*Multivitamins for pregnant women
*Polyunsaturated fatty acid(omega-3 - polyunsaturated fatty acids) and antioxidants (microhydrin, vitamin E)
*Specific treatment at a specific mutation (see sections on polymorphisms)

Criteria for the effectiveness of therapy:
*Laboratory criteria: normalization of the level of thrombophilia markers (thrombin-antithrombin III complex, P1+2 fragments of prothrombin, degradation products of fibrin and fibrinogen), platelet count, platelet aggregation
*Clinical criteria: no thrombotic episodes, preeclampsia, placental insufficiency, placental abruption

At-risk groups:
* pregnant women with a burdened obstetric history (severe forms of preeclampsia, eclampsia, recurrent miscarriage and other obstetric pathologies)
*patients with recurrent thrombosis or an episode of thrombosis in history or in this pregnancy
*patients with a burdened family history (the presence of relatives with thrombotic complications under the age of 50 years - deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, sudden death)

Let us dwell in detail on the polymorphisms that are the instigators of TF:
Genes of the blood coagulation system
prothrombin gene (factor II) G20210A
factor 5 gene (mutation Leiden) G1691A
fibrinogen gene FGB G-455A
glycoprotein Ia gene (integrin alpha-2) GPIa C807T
platelet fibrinogen receptor gene GPIIIa 1a/1b
polymorphisms responsible for the deficiency of proteins C and S, antithrombin III
protein S receptor gene PROS1 (large deletion)
Genes of "thoracity"
plasminogen activator inhibitor gene PAI-1 4G/5G
Genes for violation of vascular tone
NO synthase gene NOS3
angiotensin-converting enzyme ACE gene (ID)
GNB3 C825T gene
Metabolism Genes
methylenetetrahydrofolate reductase gene MTHFR C677T

Prothrombin gene (factor II) G20210A
Function: encodes a protein (prothrombin), which is one of the main factors of the coagulation system
Pathology: the replacement of guanine with adenine at position 20210 occurs in an unreadable region of the DNA molecule, so there are no changes in prothrombin itself in the presence of this mutation. We can detect one and a half to two times higher amounts of chemically normal prothrombin. The result is a tendency to increased thrombosis.

Polymorphism data:
*frequency of occurrence in the population - 1-4%
*incidence in pregnant women with a history of venous thromboembolism (VTE) - 10-20%
4

Clinical manifestations:
*unexplained infertility, preeclampsia, preeclampsia, premature detachment of a normally located placenta, recurrent miscarriage, feto-placental insufficiency, intrauterine fetal death, fetal growth retardation, HELLP syndrome
* venous and arterial thrombosis and thromboembolism, unstable angina pectoris and myocardial infarction.
Mutation in the prothrombin gene is one of the most common causes of congenital thrombophilias, but prothrombin functional tests cannot be used as valid screening tests. It is necessary to carry out PCR diagnostics in order to identify a possible defect in the prothrombin gene.
Clinical Significance:
GG-genotype - the norm
The presence of a pathological A-allele (GA, GG-genotype) - an increased risk of TF and obstetric complications

*Low-dose aspirin and subcutaneous low molecular weight heparin before pregnancy
When taking oral contraceptives, the risk of thrombosis increases hundreds of times!

Factor 5 gene (mutation Leiden) G1691A

Function: codes for a protein (factor V), which is the most important
component of the blood coagulation system.

Pathology: Leiden mutation of the coagulation factor V gene (replacement of guanine with adenine at position 1691) leads to the replacement of arginine with glutamine at position 506 in the protein chain that is a product of this gene. The mutation leads to resistance (resistance) of factor 5 to one of the main physiological anticoagulants - activated protein C. The result is a high risk of thrombosis, systemic endotheliopathy, microthrombosis and placental infarction, impaired uteroplacental blood flow.

Polymorphism data:
*frequency of occurrence in the population - 2-7%
*incidence in pregnant women with VTE - 30-50%
*autosomal dominant inheritance
Clinical manifestations:
*unexplained infertility, preeclampsia, preeclampsia, premature detachment of a normally located placenta, habitual miscarriage, feto-placental insufficiency, intrauterine fetal death, fetal growth retardation, HELLP syndrome,
*venous and arterial thrombosis and thromboembolism.3
Clinical Significance: GG genotype is normal. Pathological A-allele (GA, GG-genotype) - an increased risk of TF and obstetric complications.
It should be remembered that the combination of the Leiden mutation with pregnancy, taking hormonal contraceptives, an increase in the level of homocysteine, the presence of antiphospholipid antibodies in plasma - increases the risk of developing TF.

Indications for testing:
*History of repeated VTE
*First episode of VTE before age 50
*First episode of VTE with unusual anatomical location
*The first episode of VTE developed in connection with pregnancy, childbirth, oral contraceptives, hormone replacement therapy
*Women with spontaneous abortion in the second and third trimester of unknown etiology

Additional therapy and prevention:
* In the case of heterozygotes (G / A), relapses are rare, therefore, long-term anticoagulant therapy is carried out in them only with a history of recurrent thrombosis
*Low-dose aspirin and subcutaneous injections of low molecular weight heparin before pregnancy, throughout pregnancy and six months after delivery.

MTHFR C677T methylenetetrahydrofolate reductase gene

Function: encodes the enzyme methylenetetrahydrofolate reductase, which is a key enzyme in the folate cycle and catalyzes
conversion of homocysteine ​​to methionine.

Pathology: Normally, plasma homocysteine ​​levels are low during pregnancy. This can be seen as a physiological adaptation of the mother's body, aimed at maintaining adequate blood circulation in the placenta.

The replacement of cytosine with thymine at position 677 leads to a decrease in the functional activity of the enzyme to 35% of the average value.
The result is an increase in the level of homocysteine ​​in the blood, which causes endothelial dysfunction during pregnancy.

Polymorphism data:
* the frequency of occurrence of homozygotes in the population is 1o-12%
* frequency of occurrence of heterozygotes in the population - 40%
*incidence in pregnant women with VTE - 10-20%
*autosomal recessive inheritance

Clinical manifestations:
* preeclampsia, premature detachment of a normally located placenta, intrauterine growth retardation, antenatal fetal death
*fetal neural tube defect (spina bifida), anencephaly, mental retardation child, "cleft lip", "cleft palate"
*premature development cardiovascular disease(atherosclerosis!), arterial and venous thrombosis.
It should be remembered that this polymorphism alone is capable of inducing factor 5 resistance to activated protein C by binding homocysteine ​​to activated factor 5.
This means that it can cause all the clinical manifestations of the Leiden mutation (see above).
Additional therapy and prevention:
* folic acid (4 mg/day) in combination with vitamin B6, B12
*folic acid supplementation in the diet: found in large quantities in the leaves of green plants - dark green vegetables with leaves (spinach, lettuce, asparagus), carrots, yeast, liver, egg yolk, cheese, melon, apricots, pumpkin, avocado, beans, whole wheat and dark rye flour.
Plasminogen activator inhibitor gene PAI-1 4G/5G

Function: encodes a plasminogen activator inhibitor protein, which plays an important role in the regulation of fibrinolysis, and is also an integral component in the process of implantation of the fetal egg.
Pathology: the presence of 4 guanines instead of 5 in the structure of the plasminogen activator inhibitor gene leads to an increase in its functional activity.
The result is a high risk of thrombosis.
Polymorphism data:
*frequency of occurrence in heterozygotes of 4G/5G population – 50%
*frequency of 4G/4G homozygotes - 26%
*frequency of occurrence in pregnant women with TF - 20%
*autosomal dominant inheritance

Clinical manifestations:
*early and late miscarriages, development of early and late gestosis, premature detachment of a normally located placenta, feto-placental insufficiency, preeclampsia, eclampsia, HELLP syndrome
* thromboembolic complications, arterial and venous thrombosis, myocardial infarction, stroke, oncological complications

Clinical Significance:
5G/5G genotype is normal
Pathological 4G allele (4G/4G, 4G/5G - genotype) - a high risk of developing TF and obstetric complications.

Additional therapy and prevention:
*low doses acetylsalicylic acid and small doses of low molecular weight heparin
*low sensitivity to aspirin therapy
* vitamins antioxidants C, E
*clean drinking water 1.5-2 l/day

Fibrinogen gene FGB G455A

Function: encodes the fibrinogen protein (more precisely, one of its chains), which is produced in the liver and turns into insoluble fibrin, the basis of a blood clot during blood clotting.

Pathology: replacement of guanine with adenine at position 455 leads to increased gene performance, which results in hyperfibrinogenemia and a high risk of developing TF, the formation of blood clots.

Polymorphism data:
The frequency of occurrence of heterozygotes (G / A) in the population - 5-10%

Clinical manifestations:
* Strokes, thromboembolism, deep vein thrombosis of the lower extremities,
* habitual miscarriage, habitual abortions, placental insufficiency, insufficient supply of nutrients and oxygen to the fetus
Clinical Significance:
GG-genotype - the norm
The presence of a pathological A-allele is an increased risk of hyperfibrinogenemia, and hence the pathology of pregnancy
It should be remembered that hyperhomocysteinemia (MTHFR C677T) also causes hyperfibrinogenemia.

The main therapy and prevention of obstetric complications in this case will be adequate treatment with anticoagulants (low molecular weight heparin).

Platelet fibrinogen receptor gene GPIIIa 1a/1b (Leu33Pro)

Function: encodes the beta-3 subunit of the integrin complex of the platelet surface receptor GPIIb/IIIa, also known as glycoprotein-3a (GPIIIa). It ensures the interaction of the platelet with the fibrinogen of the blood plasma, which leads to rapid aggregation (gluing) of platelets and, thus, to the subsequent relief of the damaged surface of the epithelium.

Pathology: nucleotide substitution in the second exon of the GPIIIa gene, which leads to the replacement of leucine by proline at position 33.
*There is a change in the structure of the protein, which leads to an increase in the aggregation ability of platelets.
* The second mechanism is that a change in the protein structure leads to a change in its immunogenic properties, an autoimmune reaction develops, which in turn causes a violation of blood clotting.

Polymorphism data:
*frequency of occurrence in the population - 16-25%

Clinical manifestations:
*Arterial thrombotic complications
*Exacerbates the effect of other polymorphisms, such as the Leiden mutation.

Clinical Significance:
Leu33 Leu33 - genotype - norm
Pro33 allele - increased risk of arterial thrombosis

Complementary Therapy and Prevention
*New generation antiplatelet drugs – IIb/IIIa receptor antagonists – pathogenetic therapy

GNB3 C825T gene

F function: is a secondary signal carrier from the receptor on the cell surface to the nucleus

Pathology: a point mutation in the G-protein gene - the replacement of cytosine (C) by thymine (T) at position 825 leads to a disruption in the function of this secondary carrier. As a result, signals cease to enter the nucleus, and the humoral regulation of platelet aggregation is disrupted.

Clinical Significance: the polymorphism itself does not play a big role in the pathogenesis of thrombophilia, however, only if it is present, the manifestation of the above-described GPIIIa 1a/1b polymorphism is possible.

NO-synthase gene NOS3 (4a/4b)

Function: codes for nitric oxide synthase (NOS), which synthesizes nitric oxide, which is involved in vasodilation (relaxation of vascular muscles), affects angiogenesis and blood coagulation.

Pathology: the presence of four repeats of the nucleotide sequence (4a) instead of five (4b) in the nitric oxide synthase gene leads to a decrease in the production of NO, the main vasodilator that prevents tonic contraction of vessels of neuronal, endocrine, or local origin.

Polymorphism data:
The frequency of occurrence in the population of homozygotes 4a / 4a is 10-20%

Clinical manifestations:
endothelial dysfunction.
Polymorphism contributes to the development of gestosis, preeclampsia, fetal hypoxia, intrauterine growth retardation.
This polymorphism also determines the development metabolic syndrome, which negatively affects the hormonal background of a woman, which can also adversely affect the course of pregnancy.

Clinical Significance:
4b/4b - normal variant of polymorphism in homozygous form; 4b/4a ​​- heterozygous form of polymorphism; 4a/4a - mutant variant of polymorphism associated with an increased risk of diseases, in a homozygous form
Additional Treatment and prevention:
There is currently no pathogenic treatment. However, it should be remembered that such polymorphism exacerbates the clinical picture of other polymorphisms that increase the risk of thrombotic complications.
It is possible to prescribe vasodilators to improve the blood supply to the fetus, but studies on this issue have not yet been conducted.
For the prevention of metabolic syndrome and if the pregnant woman is overweight, insulin resistance, dyslipidemia, it is necessary to prescribe a diet - a balanced normocaloric and an unbalanced normocaloric diet. Polymorphism predetermines the development of arterial hypertension in a person, so it is useful to prescribe physical activity - cardio training - not only during, but always after pregnancy.

Glycoprotein Ia gene (integrin alpha-2) GPIa C807T

Function: glycoprotein Ia is a subunit of the platelet receptor for collagen, von Willebrand factor, fibronectin and laminin. The interaction of platelet receptors with them leads to the attachment of platelets to the wall of the damaged vessel and their activation. Thus, glycoprotein Ia plays important role in primary and secondary hemostasis.

Pathology: replacement of cytosine with thymine at position 807 leads to an increase in its functional activity. There is an increase in the rate of platelet adhesion to type 1 collagen.
The result is an increased risk of thrombosis, stroke, myocardial infarction

Polymorphism data:
*frequency of occurrence in the population - 30-54%

Clinical manifestations:
*cardiovascular disease, thrombosis, thromboembolism, myocardial infarction,
* mild thrombotic tendency (increased action of other polymorphisms that predispose the body to thrombophilia)

Clinical Significance:
CC genotype - normal
T-allele - increased risk of thrombosis and pathology of pregnancy

Additional treatment and prevention:
Pathogenetic treatment has not been developed to date.

Angiotensin-converting enzyme ACE (ID) gene

Function: conversion of an inactive form of angiotensinogen to angiotensin
Pathology: deletion (deletion D) and insertion (insertion I) of a nucleotide sequence in the angiotensin-converting enzyme gene. If a person has a D-allele, the risk of developing endothelial dysfunction increases.
Endothelial dysfunction determines the thrombotic tendency of the body.

Clinical manifestations:
Venous thrombosis and thromboembolic complications, preterm birth, fetal loss syndrome

Clinical Significance:
II-genotype - the norm
D-allele - increases the risk of endothelial dysfunction, which is the basis of all the above obstetric complications.

Additional treatment and prevention:
Pathogenetic therapy has not been developed. However, it should be remembered that the D-allele of this gene enhances the pathological manifestations of other polymorphisms predisposing to thrombophilia.
It is also necessary to know that this polymorphism (D-allele) is a genetic component of the metabolic syndrome, the presence of which disrupts the hormonal background of a woman. This, of course, can adversely affect the course of pregnancy. Therefore, in order to prevent the development of metabolic syndrome or if a woman has overweight, insulin resistance, dyslipidemia, such a patient should be prescribed a normocaloric diet unbalanced in lipids and adequate physical activity (swimming, yoga, etc.).

Polymorphisms responsible for protein C deficiency

Function: protein C is the main inhibitor of thrombosis. Together with other components, they form a complex that prevents excessive thrombosis.

Pathology: to unregulated progression of the coagulation cascade and excessive thrombus formation.

Protein C deficiency data:
*frequency of occurrence in the population - 0.2-0.4%
Clinical manifestations:
* thrombosis, thromboembolism (pulmonary artery in particular), superficial recurrent thrombophlebitis
* microthrombosis of the placenta and the corresponding disorders of the fetoplacental blood flow
*neonatal, coagulopathy; neonatal fulminant purpura syndrome (manifested by ecchymosis around the head, trunk, limbs, often accompanied by cerebral thrombosis and infarcts; numerous skin ulcerations and necrosis)5

Clinical Significance:
There are many known polymorphisms that predetermine protein C deficiency, but there is no known polymorphism that determines the pathology with a high probability. Therefore, the leading method for detecting pathology is biochemical analysis blood.
Concentration 0.59-1.61 µmol / l - norm
Concentration 30-65% of the norm (less than 0.55 µmol / l) - heterozygous protein C deficiency

Additional therapy and prevention:
*infusion of protein C concentrate or activated protein S
*with protein C deficiency, relapses are rare, therefore, long-term anticoagulant therapy is carried out only with a history of recurrent thrombosis
* possible development of necrosis of the skin and subcutaneous adipose tissue when taking indirect anticoagulants
*simultaneously with warfarin, it is necessary to use low molecular weight heparin

Polymorphisms responsible for protein S deficiency

Function: protein S is the main inhibitor of thrombosis. Together with other components, they form a complex that prevents excessive thrombosis.

Pathology: Loss of interaction between this antithrombotic complex and coagulation cascade factors leads to to unregulated progression of the coagulation cascade and excessive thrombus formation
Three types of protein S deficiency are distinguished: a decrease in the antigenic level of protein S, both total and free, a decrease in the activity of protein S (type 1), a decrease in the activity of protein S at its normal antigen level (type 2), activity (type 3)
Protein S Deficiency Data:
*incidence in pregnant women with VTE - 2-10%
*autosomal dominant type of examination

Clinical manifestations:
*superficial thrombophlebitis, deep vein thrombosis, pulmonary embolism, arterial thrombosis
*spontaneous abortion, intrauterine fetal death
Clinical Significance:
To date, many mutations are known that predispose the body to protein S deficiency, but it is not yet possible to isolate the leading polymorphism from them.
More recently, a polymorphism has been discovered that in 95% of cases causes a deficiency of protein S of the first type. This is a mutation in the PROS1 protein receptor gene (large deletion). However, the role of this mutation in the development of obstetric pathology is not yet sufficiently clear.
To identify this pathology, a biochemical blood test should be performed.

Additional therapy and prevention:
* with a deficiency of protein S, relapses rarely occur, therefore, long-term anticoagulant therapy is carried out in them only with a history of recurrent thrombosis
* taking warfarin can cause necrosis of the skin and subcutaneous fat

Polymorphisms responsible for antithrombin III deficiency

Function: antithrombin III is the main inhibitor of thrombosis. Together with other components, it forms a complex that prevents excessive thrombosis.

Pathology: Loss of interaction between this antithrombotic complex and coagulation cascade factors leads to to unregulated progression of the coagulation cascade and excessive thrombus formation.
Hereditary deficiency of antithrombin III can be manifested either by a decrease in the synthesis of this protein (type I), or by a violation of its functional activity (type II)

Antithrombin III deficiency data:
*frequency of occurrence in the population - 0.02%
*incidence in pregnant women with VTE - 1-5%
*autosomal dominant inheritance

Clinical manifestations:
* antithrombin deficiency in a newborn - a high risk of developing respiratory distress syndrome, intracranial hemorrhage
* deep vein thrombosis of the lower extremities, renal veins and retinal veins
* microthrombosis of the placenta; violation of fetoplacental blood flow
Clinical Significance: At the moment, a large number of mutations have been identified that determine the deficiency of antithrombin III. However, for their manifestation, their combination is necessary. Today, no such mutation is known that would determine antithrombin III deficiency with a very high probability. Therefore, the diagnosis of this mutation is carried out according to biochemical parameters (biochemical blood test).

Additional therapy and prevention:
1) infusion of antithrombin III concentrate;
2) it should be remembered that in patients with this mutation, thrombosis recurs very often, and therefore, after the first manifestation of TF, they should receive anticoagulant therapy for life.

Laboratory signs:
*platelet aggregation is normal
*bleeding time is normal
*global coagulation tests unchanged
*low immunological level of antithrombin III
*low level of biological activity
*lack of adequate prolongation of APTT during heparin therapy
*tests for fibrinolysis are normal

Especially dangerous combinations of polymorphisms:
*A-allele of the factor 5 gene (mutation Leiden G1691A) + A-allele of the prothrombin gene (G20210A)
*A-allele of the factor 5 gene (Leiden mutation G1691A) + A-allele of the prothrombin gene (G20210A) + T-allele of the MTHFR gene (C677T)
*A-allele of the factor 5 gene (mutation Leiden G1691A) + deficiency of protein C or protein S
*A-allele of factor 5 gene (mutation Leiden G1691A) + deletion in the PROS1 gene
*T-allele MTHFR (C677T) + A-allele FGB (G455A)
*4G/4G in the PAI-1 gene + T-allele MTHFR (C677T)
*Pro33-allele of GPIIIa + T-allele of the GNB3 gene (C825T)

Conclusion:
genetic testing will allow you
1. identify a woman's predisposition to the development of thrombophilia during pregnancy
2. prescribe pathogenetic therapy that is most effective in each specific case
3. avoid most obstetric complications, including infertility and intrauterine fetal death
4. prevent thrombotic complications in a woman in the postpartum period and in subsequent years of life
5. prevent thrombotic complications in the newborn
6. prevent the teratogenic effect of thrombophilia (avoid spina bifida e.s.)
7. make a woman's life happy and fulfilling.

Genetics can help you, dear doctor, in the performance of your sacred duty. Contact us, we are waiting for you.

1. There is a more complex clinical classification based on clinical manifestations TF:

1) Hemorheological forms characterized by polyglobulia, increased hematocrit, increased blood and plasma viscosity in combination with hyperthrombocytosis or without it (screening - measuring blood and plasma viscosity, determining the number of cells and hematocrit)
2) Forms caused by impaired platelet hemostasis, caused by an increase in platelet aggregation function (spontaneous and under the influence of major agonists), the level and multimerity of the von Willebrand factor, (screening (c) - counting the number of platelets, measuring their aggregation under the influence of low doses of FLA and ristomycin)
3) Forms associated with deficiency or abnormalities of plasma coagulation factors: (c - disturbances in the protein C system, thrombin and ancistron clotting time, determining the time of fibrin lysis) anomaly of factor 5a and its resistance to activated protein C, anomaly of factor 2, thrombogenic dysfibrinogenemia
4) Forms associated with deficiency and / or abnormalities of primary physiological anticoagulants (determination of antithrombin III activity, screening for disorders in the protein C system) of proteins C and S, antithrombin III
5) Forms associated with impaired fibrinolysis (c - determination of the time of spontaneous and streptokinase-induced lysis of euglobulins, 12a-kallikrein-dependent fibrinolysis, cuff test)
6) Forms associated with increased activity and insufficient inactivation of factor 7
-Autoimmune and infectious-immune (with - determination of lupus anticoagulant)
- Paraneoplastic (Trousseau's syndrome)
- Metabolic forms diabetic angiopathy, hyperlipidemic forms, thrombophilia in homocysteinemia
- Iatrogenic (including medication) when taking hormonal contraceptives, heparin thrombocytopenia, fibrinolytic therapy, in the treatment of L-asparaginase.

2. Polymorphism - a gene variant formed from a point adaptive mutation and fixed in several generations and occurring in a population of more than 1-2 percent.

3. A recent study showed that the success rate of IVF embryo transfer in patients with the Leiden mutation is about 2 times higher than among patients who are not carriers of this mutation. These interesting data indicate that, despite the increased likelihood of complications, the fertility of patients with the Leiden mutation (the likelihood of pregnancy in each cycle) may be higher.

4. inheritance: it can be dominant and recessive (this article does not talk about sex-linked inheritance, that is, with the sex chromosome). The dominant one will manifest itself in a child if one of the parents has the corresponding jota gene, and the recessive one requires the same given feature genes from both parents.

5. the syndrome has been described in people who are twice homozygous for type 1 (quantitative and functional protein C deficiency) and type 2 (qualitative protein C deficiency); the syndrome is refractory to therapy with heparin or antiplatelet agents. If the patient does not have clinical and laboratory data for irreversible damage to the brain or organ of vision, then the optimal therapy would be the use of activated protein C concentrate, protein C or fresh frozen plasma in combination with heparin.

A blood disease in which disruption of blood clotting in the direction of increased thrombosis is called thrombophilia. A blood test for thrombophilia shows the number of platelets and red blood cells. With an increase in indicators, the patient is prescribed additional examinations to clarify the diagnosis.

In most cases, thrombophilia is a hereditary disease. A person does not suspect his diagnosis until blood clots begin to form in the body.