Analysis for genetic markers of thrombophilia. Testing for genetic thrombophilia: how important are facts about the disease?

What it is? Thrombophilia is a pathology of the circulatory system, manifested in hemostasis disorders and a tendency to thrombosis. The disease is characterized by multiple thromboses and their relapses. More than 40% of the population suffers from pathology, and this figure is increasing every year.

The formation of blood clots interferes with normal blood flow, which leads to life-threatening consequences: extreme manifestations are ischemic stroke and heart attack. The most common complications are tissue necrosis and chronic.

In most cases, the patient does not suspect that he has thrombophilia until a blood clot, a thrombus, forms in his body. This happens because the blood clotting process is disrupted. To stop any bleeding, our body needs to thicken the blood in this area.

Thrombophilia - what is it and how does it manifest?

If a person suffers from thrombophilia, the blood clot will exceed the size necessary to stop the bleeding. In the future, the thrombus may increase and completely block the lumen of the vessel.

The appearance of a blood clot in the body causes the following symptoms of thrombophilia:

• Rapid heartbeat - the heart requires more effort to move clotted blood;
• Shortness of breath and difficulty breathing (also associated with the previous factor);
• Numbness, pain and swelling in the extremities - mainly in the legs and feet, because... vascular clots most often form there;
• Unpleasant sensations in the chest during a deep breath;
• Cough with the release of substances containing blood;
• Multiple pathologies of pregnancy and miscarriages (the first onset of the disease in women may occur during pregnancy).

In the circulatory mechanism, there are coagulation factors and anticoagulants. Under normal conditions, their activity is in balance. Thrombophilia is a disorder of one of them: the patient either experiences a weakening of anticoagulation factors or increases the activity of blood coagulation factors.

Thrombophilia can be congenital or acquired (taking into account the cause of development). If a person does not have genetic pathologies, then increased blood clotting may develop due to:

• vascular injuries;
• diseases of the circulatory system;
• taking aggressive medications.

There is a small chance of acquiring a predisposition to blood clots, but it increases with certain diseases. Therefore, comprehensive measures are aimed at excluding the development of acquired thrombophilia as a complication of the underlying pathology (for example, against the background, etc.).

Hereditary thrombophilia - genes and factors

In most cases, doctors are faced with hereditary thrombophilia; a parent passes on thrombophilia genes to their child. There are several factors that contribute to the tendency to form blood clots:

1. Primary genetic abnormality. An error in the RNA code, which programs the structure of proteins. This is a complex pathology that includes an abnormality of prothrombin G 202110A, deficiency of proteins C and S and antithrombin III and the Leiden mutation (factor V pathology).

Anomalies can also appear separately.

2. Deficiency of C- and S-prothrombins. The liver synthesizes a protein called prothrombin C. It is activated by thrombin so that prothrombin S can stop bleeding. Clotting factors V and VIII are destroyed and the blood does not form clots.

An insufficient amount of C- and S-prothrombins leads to increased thrombosis.

3. Insufficient amount of antithrombin III. Protein deficiency is caused by disturbances in its synthesis. It is transmitted in an autosomal dominant manner, that is, it does not depend on the gender of the parent and child, and it always appears if it is inherited (i.e., with this pathology there are no healthy carriers of the pathological gene).

The likelihood of an abnormal gene being expressed depends on many factors. There may be cases when the impact on human health is minimal.

Antithrombin III is one of the most important components in regulating the blood clotting mechanism. When combined with thrombin (a protein whose function is to form blood clots), they inhibit each other's action. Antithrombin III deficiency prevents timely inactivation of thrombin, which leads to multiple clot formation.

4. The Leiden mutation is an abnormality of factor V. Under normal conditions, the fifth factor of blood coagulation is suppressed by the action of protein C. The Leiden mutation implies resistance of factor V to the influence of protein C, which stimulates blood clotting.

5. Prothrombin surplus. Prothrombin is the protein stage preceding thrombin. Its accelerated synthesis contributes to the formation of large blood clots. The consequences of a prothrombin abnormality can be blockage of blood vessels in the heart and brain, which manifests itself in heart attacks and strokes at a young age.

6. Antiphospholipid syndrome. Phospholipids are components that make up the membranes of nerve cells, blood vessels and platelets. If the body produces an excessive amount of antibodies, then phospholipids are destroyed and disrupt the functionality of cells that take part in the mechanism of blood clotting and thinning.

Genetic thrombophilia can be caused by several factors, but its manifestations will be the same in any case. They will consist of a violation of blood flow in a certain area of ​​the body or organ with all the ensuing consequences.

Thrombophilia during pregnancy - risks and actions

In most cases, hereditary thrombophilia and pregnancy are compatible. The probability of transmitting an abnormality of the blood coagulation mechanism to a child according to the autosomal dominant type is 50%. For the autosomal recessive type it is lower and amounts to 25%, i.e. in generations there may be carriers of a pathological gene in whom clinical manifestations of the disease are absent.

Often, thrombophilia in an expectant mother is diagnosed during pregnancy. This is due to the fact that during embryogenesis, blood clotting increases, since an additional circle of blood circulation appears in a woman’s body - the placental one. Nature has taken care to reduce blood loss during the birth process (during the separation of the placenta).

The main risk for a woman with thrombophilia is miscarriage - the level of blood clotting increases 5 times.

This can happen due to spontaneous placental abruption caused by problems with blood circulation. A miscarriage is possible both immediately after conception and at a later date.

A woman with thrombophilia can bear a fetus and give birth if she follows all the doctors’ recommendations. The normal date for the birth of a child in a woman in labor with this disease is considered to be 35-36 weeks. At this time, premature birth is no longer dangerous to the life of the fetus and mother.

Thrombophilia has a negative effect on the child in the womb after the 10th week of embryogenesis, manifesting itself in the form of fetal hypoxia. Microthrombi form in the blood vessels of the placenta, which prevent nutrients and oxygen from entering the baby’s body. If thrombophilia is not treated during pregnancy, fetal development is delayed or.

The second trimester often proceeds without complications, but from the beginning of the third trimester the risk of premature birth increases sharply. Pregnant women with thrombophilia are prescribed regular examination of the blood coagulation system (coagulogram) and, if necessary, the introduction of modern anticoagulants.

Diagnostics and tests for thrombophilia

It is almost impossible to determine thrombophilia by external factors. Thrombophilia testing begins with determining the level of red blood cells and platelets in the blood. If a general analysis shows an increase in the number of these cells, then the patient is indicated for certain examinations aimed at accurately determining the diagnosis.

Other blood composition indicators are also measured:

• The level of blood clot breakdown product increases due to an increase in the number of clots in the blood.
• APTT analysis: in laboratory conditions, the coagulation process is simulated. The degree of activity of coagulation factors will be reduced, and the “thrombin time” - the period of formation of a blood clot - will also decrease.
• Fibrinogen level. With excessive blood clotting, its amount increases.

It will help to decide whether the patient has hereditary thrombophilia by analyzing factors in the genetic map. Only a complete picture will allow us to examine in detail the genetic factors of thrombophilia:

1. Inhibitory mutation of plasminogen activator – suppression of the fibrinolysis process. This factor prevents the breakdown of blood clots.
2. Pathology of methionine metabolism is an increase in the level of homocysteine ​​in the blood plasma. The MTHFR gene encodes an enzyme that converts homocysteine ​​into methionine with the participation of B vitamins.
3. – the mutation causes too active fibrin synthesis. Globulin, under the action of the enzyme thrombin, is converted into fibrin and promotes thrombus formation.
4. Change in factor II level - mutation in prothrombin coding: replacement of guanine (G) with adenine (A). This does not affect the structure of the protein, but does affect the activity of its synthesis.
5. Changes in platelet aggregation. The amino acid leucine is replaced by proline, mutations occur in the integrin-beta protein.

These are the most common markers. There are also less common pathologies that a genetic map can identify. The choice of specific tests remains with the doctor caring for a particular patient. It is impossible to prescribe all studies in a row, because they are expensive.

Treatment of thrombophilia - drugs and diet

Treatment for mild thrombophilia involves taking blood thinning medications. The patient is prescribed medications such as Acenocoumarol, Warfarin. A special diet is also prescribed: foods that contribute to blood thickening are excluded from the diet. It is forbidden to consume green tea, spinach, lettuce, fatty nuts (walnuts, cashews) and liver of any origin.

• If blood clots continue to actively form, the patient is hospitalized and prescribed therapy based on intravenous administration of unfractionated heparin (using an infusion pump - a special device that administers the drug in doses).
• If the body of a person with thrombophilia does not perceive or reacts negatively to heparin structures, he is prescribed alternative therapy with enoxaparin sodium or fondaparinux.

Preparations containing acetylsalicylic acid, dipyridamole, pentoxifylline, and clopidogrel have been successfully used. Complex therapy should include vitamins B, E, folic acid, alprostadil and nicotinic acid.

The goal of treating thrombophilia is to lyse as many clots as possible. The standard duration of therapy is 20-25 days. On an individual basis, treatment can be extended up to a year or continuous medication can be prescribed.

In case of urgent need, the patient is indicated for a surgical operation, during which the vessels are “cleaned” of blood clots manually. After the procedure, you must take blood thinning medications for at least another 2-3 weeks.

Pregnant women receive similar treatment for thrombophilia, but the number of medications prescribed is much smaller. Expectant mothers are advised to minimize physical activity and follow a diet.

Forecast

Thrombophilia is only a predisposition to the formation of blood clots, and if the patient follows the recommendations regarding nutrition and taking preventive medications, the risks of stroke and heart attack are minimal.

In the case of pregnant women and those wishing to conceive, the likelihood of having a healthy child depends on individual genetic characteristics. Having determined the cause and mechanism of the pathology, you can calculate the likelihood of transmission and manifestation in the child.

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

Pro et contra genetic testing of pregnant women.

We call childless women unhappy. Never to experience the feeling of motherhood is a huge... HUGE Grief. We, doctors, inevitably become witnesses to the suffering of others. But today we can say “no” to this disaster. Now the doctor can really help, prevent, cure the disease, and restore the joy of existence.
In this article we will discuss a serious problem of our days - thrombophilia, its contribution to obstetric complications, genes that predetermine the development of thrombophilia in a woman, the consequences of 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 northern lights, and admire the heavenly aroma of a blooming 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 M. We must, we can make a woman’s life a fairy tale with a happy ending, and not a tragedy like NN’s life. So, dear doctor, here is the key to treating infertility, miscarriages, developmental abnormalities and much more. Saving the life of a woman and an unborn child is now a realistically feasible task. New life is 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 is the cause of obstetric complications in 75% of cases.
Classically, there are two types of TF – acquired (antiphospholipid syndrome, for example) and hereditary1. This article will discuss hereditary TF and the polymorphic genes2 (polymorphisms) that cause it.
Genetic polymorphism does not necessarily lead to a disease state; most often, provoking factors are needed: pregnancy, postpartum period, immobilization, surgery, trauma, tumors, etc.
Taking into account the peculiarities of the physiological adaptation of the hemostatic 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 mother's body undergoes a restructuring of the coagulation, anticoagulation and fibrinolytic systems, which leads to an increase in blood clotting factors by 200%. Also in the third trimester, the speed of blood flow 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 in combination with hypercoagulation 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 complete placental blood circulation depends on a balanced ratio of procoagulant and anticoagulant mechanisms. Hereditary TFs lead to disruption of this balance in favor of procoagulant mechanisms. With TF, the depth of trophoblast invasion is reduced, and implantation is incomplete. This is the cause of infertility and early preembryonic losses. And disruption of 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, recurrent miscarriage syndrome, abruption of a normally located placenta, preeclampsia, intrauterine growth retardation, fetal loss syndrome (undeveloped pregnancy, stillbirth , neonatal mortality as a complication of premature birth, severe gestosis, placental insufficiency), HELLP syndrome, unsuccessful IVF attempts.

Prevention (general provisions)

*Prevention of obstetric complications in thrombophilia should begin before pregnancy.
*The patient’s relatives who have the same defects should receive appropriate prophylaxis.
*Specific prevention 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 penetrate the placenta, creates a low risk of bleeding, no teratogenic or 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, low molecular weight heparin therapy is recommended to be discontinued. Prevention of thromboembolic complications in the postpartum period is resumed after 6-8 hours and carried out for 10-14 days.
*Multivitamins for pregnant women
*Polyunsaturated fatty acids (omega-3 – polyunsaturated fatty acids) and antioxidants (microhydrin, vitamin E)
*Specific treatment for a specific mutation (see sections on polymorphisms)

Therapy effectiveness criteria:
*Laboratory criteria: normalization of the level of thrombophilia markers (thrombin-antithrombin III complex, P1+2 prothrombin fragments, fibrin and fibrinogen degradation products), platelet count, platelet aggregation
*Clinical criteria: absence of thrombotic episodes, gestosis, placental insufficiency, premature placental abruption

At-risk groups:
*pregnant women with a burdened obstetric history (severe forms of gestosis, eclampsia, recurrent miscarriage and other obstetric pathologies)
*patients with recurrent thrombosis or an episode of thrombosis in history or during this pregnancy
*patients with a family history (relatives with thrombotic complications under the age of 50 - 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 (Leiden mutation) G1691A
fibrinogen gene FGB G-455A
glycoprotein Ia gene (integrin alpha-2) GPIa C807T
platelet fibrinogen receptor gene GPIIIa 1a/1b
polymorphisms responsible for deficiency of proteins C and S, antithrombin III
protein S receptor gene PROS1 (large deletion)
"Thick-blooded" genes
plasminogen activator inhibitor gene PAI-1 4G/5G
Genes for vascular tone disorders
NO synthase gene NOS3
angiotensin converting enzyme gene ACE (ID)
GNB3 gene C825T
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, therefore, changes in prothrombin itself do not occur in the presence of this mutation. We can detect one and a half to two times increased amounts of chemically normal prothrombin. The result is a tendency towards increased thrombosis.

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

Clinical manifestations:
*unexplained infertility, gestosis, preeclampsia, premature abruption 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 and myocardial infarction.
A mutation in the prothrombin gene is one of the most common causes of congenital thrombophilias, but prothrombin functional tests cannot be used as complete screening tests. It is necessary to carry out PCR diagnostics to identify a possible defect in the prothrombin gene.
Clinical relevance:
GG genotype is normal
The presence of a pathological A-allele (GA, GG genotype) – increased risk of TF and obstetric complications

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

Factor 5 gene (Leiden mutation) G1691A

Function: encodes a protein (factor V), which is essential
component of the blood coagulation system.

Pathology: The 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 the 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, and disruption of uteroplacental blood flow.

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

Indications for testing:
*Repeated VTE in history
*First episode of VTE before age 50 years
*First episode of VTE with an unusual anatomical location
*The first episode of VTE developed in connection with pregnancy, childbirth, oral contraceptives, or 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 rarely occur, so long-term anticoagulant therapy is carried out only if there is a history of repeated thrombosis
*Low doses of aspirin and subcutaneous injections of low molecular weight heparin before pregnancy, throughout pregnancy and six months after birth.

Methylenetetrahydrofolate reductase gene MTHFR C677T

Function: Encodes the enzyme methylenetetrahydrofolate reductase, which is a key enzyme in the folate cycle and catalyzes
the reaction of converting homocysteine ​​into methionine.

Pathology: Normally, during pregnancy the level of homocysteine ​​in plasma is reduced. This can be considered as a physiological adaptation of the mother’s body, aimed at maintaining adequate blood circulation in the placenta.

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 homocysteine ​​levels in the blood, which causes endothelial dysfunction during pregnancy.

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

Clinical manifestations:
*preeclampsia, premature abruption of a normally located placenta, intrauterine growth retardation, antenatal fetal death
*developmental defect of the fetal neural tube (spina bifida), anencephaly, mental retardation of the child, “cleft lip”, “cleft palate”
*premature development of cardiovascular diseases (atherosclerosis!), arterial and venous thrombosis.
It should be remembered that this polymorphism is independently capable of causing resistance of factor 5 to activated protein C due to the binding of 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
*adding folic acid to the diet: found in large quantities in the leaves of green plants - dark green leafy vegetables (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 the plasminogen activator inhibitor protein, which plays a critical role in the regulation of fibrinolysis, and is also an integral component in the process of implantation of the ovum.
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 4G/5G population – 50%
*4G/4G homozygote frequency – 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 abruption of a normally located placenta, feto-placental insufficiency, preeclampsia, eclampsia, HELLP syndrome
*thromboembolic complications, arterial and venous thrombosis, myocardial infarction, stroke, oncological complications

Clinical relevance:
5G/5G genotype is the norm
Pathological 4G allele (4G/4G, 4G/5G genotype) – high risk of developing TF and obstetric complications.

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

Fibrinogen gene FGB G455A

Function: encodes the protein fibrinogen (more precisely, one of its chains), produced in the liver and converted 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, the result of which is hyperfibrinogenemia and a high risk of developing TF and blood clots.

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

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

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 platelet surface receptor GPIIb/IIIa integrin complex, also known as glycoprotein-3a (GPIIIa). It ensures the interaction of the platelet with fibrinogen in the blood plasma, which leads to rapid aggregation (sticking together) of platelets and, thus, to the subsequent repair of the damaged epithelial surface.

Pathology: nucleotide replacement in the second exon of the GPIIIa gene, which leads to the replacement of leucine with proline at position 33.
*There is a change in the protein structure, which leads to an increase in platelet aggregation ability.
*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 blood clotting disorder.

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

Clinical manifestations:
*Arterial thrombotic complications
*Aggravates the effect of other polymorphisms, for example, the Leiden mutation.

Clinical relevance:
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

Gene GNB3 C825T

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 - replacement of cytosine (C) with thymine (T) at position 825 leads to disruption of the function of this secondary transporter. As a result, signals stop entering the nucleus, and the humoral regulation of platelet aggregation is disrupted.

Clinical relevance: The polymorphism itself does not play a major role in the pathogenesis of thrombophilia, however, only in its presence is the manifestation of the GPIIIa 1a/1b polymorphism described above possible.

NO synthase gene NOS3 (4a/4b)

Function: encodes 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 vascular contraction of neuronal, endocrine or local origin.

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

Clinical manifestations:
Endothelial dysfunction.
Polymorphism contributes to the development of gestosis, preeclampsia, fetal hypoxia, and intrauterine growth retardation.
Also, this polymorphism determines the development of metabolic syndrome, which negatively affects a woman’s hormonal levels, which can also adversely affect the course of pregnancy.

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

Glycoprotein Ia (integrin alpha-2) gene 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 platelet attachment to the wall of the damaged vessel and their activation. Thus, glycoprotein Ia plays an 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 diseases, thrombosis, thromboembolism, myocardial infarction,
*mild thrombotic tendency (increased effect of other polymorphisms that predispose the body to thrombophilia)

Clinical relevance:
CC genotype is normal
T-allele – increased risk of thrombosis and pregnancy pathology

Additional treatment and prevention:
No pathogenetic treatment has been developed to date.

Angiotensin converting enzyme gene ACE (ID)

Function: conversion of the 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 the 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, premature birth, fetal loss syndrome

Clinical relevance:
II genotype – normal
D-allele – increases the risk of developing endothelial dysfunction, which is the basis of all the above-described obstetric complications.

Additional treatment and prevention:
No pathogenetic therapy has 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 metabolic syndrome, the presence of which disrupts a woman’s hormonal balance. This can certainly have an adverse effect on the course of pregnancy. Therefore, to prevent the development of metabolic syndrome or if a woman has excess body weight, insulin resistance, or 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 thrombus formation.

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 corresponding disorders of fetoplacental blood flow
*neonatal, coagulopathy; syndrome of neonatal fulminant purpura (manifested by ecchymosis around the head, trunk, limbs, often accompanied by cerebral thrombosis and infarction; numerous skin ulcerations and necrosis)5

Clinical relevance:
There are many known polymorphisms that determine 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 a biochemical blood test.
Concentration 0.59-1.61 µmol/l is normal
Concentration 30-65% of normal (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 rarely occur, so long-term anticoagulant therapy is carried out only if there is a history of repeated thrombosis
*development of necrosis of the skin and subcutaneous fat is possible when taking indirect anticoagulants
*low molecular weight heparin must be used simultaneously with warfarin

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 thrombus formation.

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
There are three types of protein S deficiency: 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 with its normal antigen level (type 2), a normal total antigenic level of protein S with a decrease activity (type 3)
Protein S Deficiency Data:
*incidence in pregnant women with VTE is 2-10%
*autosomal dominant type of examination

Clinical manifestations:
*superficial thrombophlebitis, deep vein thrombosis, pulmonary embolism, arterial thrombosis
*spontaneous abortions, intrauterine fetal death
Clinical relevance:
Today, many mutations are known that predispose the body to protein S deficiency, but it is not yet possible to single out the leading polymorphism from them.
More recently, a polymorphism was discovered that in 95% of cases causes type 1 protein S deficiency. This is a mutation in the protein S receptor gene PROS1 (large deletion). However, the role of this mutation in the development of obstetric pathology is not yet clear enough.
To identify this pathology, a biochemical blood test should be performed.

Additional therapy and prevention:
*with protein S deficiency, relapses rarely occur, so long-term anticoagulant therapy is carried out only if there is a history of repeated 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 thrombus formation.

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)

Data on antithrombin III deficiency:
*frequency of occurrence in the population – 0.02%
*incidence rate in pregnant women with VTE is 1-5%
*autosomal dominant inheritance

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

Additional therapy and prevention:
1) infusion of antithrombin III concentrate;
2) it should be remembered that in patients with such a 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
*fibrinolysis tests are normal

Particularly 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 factor 5 gene (Leiden mutation G1691A) + deficiency of protein C or protein S
*A allele of factor 5 gene (Leiden mutation G1691A) + deletion in the PROS1 gene
*T allele MTHFR (C677T) + A allele FGB (G455A)
*4G/4G in the PAI-1 gene + MTHFR T-allele (C677T)
*Pro33-allele 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 fulfilling your sacred duty. Contact us, we are waiting for you.

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

1) Hemorheological forms characterized by polyglobulia, increased hematocrit, increased viscosity of blood and plasma in combination with or without hyperthrombocytosis (screening - measurement of blood and plasma viscosity, determination of the number of cells and hematocrit)
2) Forms caused by disorders of platelet hemostasis, caused by an increase in the aggregation function of platelets (spontaneous and under the influence of main agonists), the level and multimerism of the von Willebrand factor, (screening (c) - counting the number of platelets, measuring their aggregation under the influence of small doses of FLA and ristomycin)
3) Forms associated with deficiency or abnormalities of plasma coagulation factors: (c - disorders in the protein C system, thrombin and ancistronic coagulation time, determination of fibrin lysis time) abnormality of factor 5a and its resistance to activated protein C, abnormality 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), 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 of diabetic angiopathy, hyperlipidemic forms, thrombophilia with homocysteinemia
-Iatrogenic (including medications) when taking hormonal contraceptives, heparin thrombocytopenia, fibrinolytic therapy, when treated with L-asparaginase.

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

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

4. inheritance: can be dominant or recessive (this article does not talk about inheritance linked to sex, that is, to the sex chromosome). Dominant will manifest itself in a child if the corresponding gene is present in one of the parents, and recessive requires the same genes for this trait in both parents.

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

Thrombophilia is a collective term; it refers to disorders of hemostasis in the human body, leading to thrombosis, that is, the formation of blood clots and blockage of blood vessels by them, accompanied by characteristic clinical symptoms. It is currently believed that the hereditary component is important in the development of thrombophilia. It was found that the disease occurs more often in people predisposed to it - carriers of certain genes. Now it is possible to conduct an analysis for thrombophilia, that is, to determine the predisposition, determined by a set of genes, to the formation of blood clots. The specifics of the analysis will be discussed below.

To whom is it assigned?

Any person can take a test for genetic thrombophilia, since the test is simple to perform and has no contraindications. However, according to doctors, it makes no sense to diagnose everyone. Therefore, thrombophilia markers are recommended to be determined for the following categories of patients:

• Almost all men.
• People over 60 years old.
• Blood relatives of people who have had thrombosis of an unknown nature.
• Women during pregnancy at risk of developing thrombosis, as well as patients planning pregnancy and taking oral contraceptives.
• People with cancer, autoimmune processes and metabolic diseases.
• Patients after surgical treatment, serious injuries, infections.

Special indications for testing for thrombophilia, the cause of which is a polymorphism of genes that programs blood clotting processes, are pre-existing pregnancy pathologies in women: spontaneous abortion, stillbirth, premature birth. This category also includes women who had thrombosis during pregnancy. It is these groups of patients that should be examined first. The test will identify changes associated with polymorphism of coding genes and prescribe the necessary treatment. Therapy will help prevent intrauterine fetal death, thrombosis in the early and late postpartum periods, and fetal pathology during the next pregnancy.

A number of genes are responsible for the formation of blood clots.

The essence of the study

In genetics there is such a thing as gene polymorphism. Polymorphism involves a situation where different variants of the same gene may be responsible for the development of the same trait. The genes responsible for polymorphism and being the “initiators” of thrombophilia are:

1. Genes of the blood coagulation system.
2. The gene encoding prothrombin.
3. The gene encoding fibrinogen.
4. Glycoprotein Ia gene.
5. Genes responsible for vascular tone, etc.

That is, there are many genes responsible for polymorphism. This explains the frequency of occurrence of the condition, the difficulties of diagnosis, as well as the possible difficulties of searching for the causes of some pathologies. As a rule, people think about polymorphism and hereditary or congenital thrombophilia when all other causes leading to thrombosis are excluded. Although in fact, gene polymorphism occurs in 1-4% of people in the population.

How is it carried out?

The test is carried out in a regular laboratory, which has created the necessary conditions for sterile collection of material. Depending on the resources of the medical institution, the following may be taken for analysis:

• Buccal epithelium (buccal epithelium).
• Venous blood.

No special preparation is required for the analysis. The only possible condition may be to donate blood on an empty stomach. You need to talk about all the details in advance with the specialist who referred you for the test. The doctor will tell you how to take the test and what it is called correctly.

results

Decoding the analysis has its own characteristics. The fact is that different patients, taking into account information about previous diseases, general condition, as well as why the test is prescribed, may be prescribed a study of various indicators. A list of the most frequently recommended ones will be presented below.

Plasminogen activator inhibitor. This analysis determines the “work” of the gene responsible for activating the process of fibrinolysis, that is, the breakdown of a blood clot. The analysis reveals the predisposition of patients with hereditary thrombophilia to the development of myocardial infarction, atherosclerosis, obesity, and coronary heart disease. Analysis transcript:

• 5G\5G – level is within normal limits.
• 5G\4G – intermediate value.
• 4G\4G – increased value.

There are no normal values ​​for this indicator. In this way, exclusively gene polymorphism is determined.

The plasminogen activator inhibitor assay determines the functionality of the gene responsible for the breakdown of blood clots.

The level of fibrinogen, the most important substance involved in the process of thrombus formation, is determined by the marker fibrinogen, beta polypeptide. Diagnostics makes it possible to identify polymorphism of the gene responsible for the level of fibrinogen in the blood, which is important in case of previous pathologies of pregnancy (miscarriage, pathologies of the placenta). Also, the results of the thrombophilia test suggest the risk of stroke and thrombosis. Explanation:

• G\G – the concentration of the substance corresponds to the norm.
• G\A – slight increase.
• A\A – significant excess of the value.

The functioning of the coagulation system and the presence of genetic thrombophilia are also assessed by the level of clotting factor 13. Deciphering the analysis allows us to identify a predisposition to thrombosis and the development of myocardial infarction. Diagnostics reveals the following possible variants of gene polymorphism:

• G\G – factor activity is normal.
• G\T – moderate decrease in activity.
• T\T – significant decrease. According to studies, in a cohort of people with the T\T genotype, thrombosis and concomitant pathologies are significantly less common.

Diagnosis of the Leiden mutation, which is responsible for the early development of thromboembolism, thrombosis, preeclampsia, thromboembolic complications that occur during pregnancy, and ischemic strokes, can be done by determining the level of coagulation factor 5, encoded by the F5 gene. Clotting factor is a special protein contained in human blood and is responsible for blood coagulation. The frequency of occurrence of the pathological allele of the gene is up to 5% in the population. Diagnostic results:

• G\G – the concentration of the substance corresponds to the norm. There is no genetic thrombophilia.
• G\A – slight increase. There is a predisposition to thrombosis.
• A\A – significant excess of the value. Diagnostics showed a predisposition to increased blood clotting.

Diagnosis of the Leiden mutation determines the blood clotting factor.

In women with proposed future therapy with female sex hormones or patients with the need to use oral contraceptives, it is recommended to diagnose the level of factor 2 of the blood coagulation system. Its determination makes it possible to identify the risk of developing thromboembolism, thrombosis, myocardial infarction during pregnancy and during treatment. Factor 2 of the blood coagulation system is encoded by the F2 gene, which has a certain polymorphism. The factor is always present in the blood in an inactive state and is a precursor of thrombin, a substance involved in the coagulation process. At the end of the diagnosis, the following result may be indicated:

• G\G – there is no genetic thrombophilia or increased blood clotting.
• G\A – there is a predisposition to thrombosis. Heterozygous form of thrombophilia.
• A\A – high risk of thrombosis.

In addition to genetic markers of thrombophilia, the doctor may prescribe related studies, for example, determination of D-dimer, which is a marker of thrombosis. D-dimer is a fragment of split fibrin and appears during the process of dissolution of the blood clot. With the exception of pregnant women, test results will be considered normal if they are within the reference values ​​of 0-0.55 mcg/ml. As the gestational age increases, the indicator values ​​increase. An increase in value can be observed not only in thrombophilia, but also in a number of oncological diseases, pathologies of the cardiovascular system and liver, after injuries and recent operations. In these cases, diagnosis of thrombophilia will be uninformative.

APTT analysis is done to show the overall functioning of the blood coagulation cascade.

An almost routine analysis is an analysis called APTT, that is, the determination of activated partial thromboplastin time, that is, the time period during which a blood clot forms. The significance of the analysis shows not so much the presence of hereditary thrombophilia, but rather the overall functioning of the cascade of the blood coagulation system.

Other markers of congenital thrombophilia are also prescribed: determination of beta-3 integrin, alpha-2 integrin, blood clotting factors 7 and 2, methylene folate reductase. Also, to diagnose the functioning of the coagulation system, the levels of fibrinogen, triglycerides, homocysteine, cholesterol, antithrombin 3 and thrombin time are determined. The exact volume of tests that needs to be performed is determined by the doctor, taking into account the immediate indications for diagnosis.

Average prices

Analysis of the work of genes responsible for polymorphism and the presence of congenital thrombophilia is not a routine study, so diagnosis is hardly possible in an average medical institution. In larger medical centers and commercial clinics, the examination is performed using a special Cardiogenetics Thrombophilia test system. The cost of such a study may vary significantly. You can find out how much the test costs directly from the medical institution where it will be carried out.

Average prices

It is better to find out in more detail about how much a test to detect thrombophilia costs directly on site, since the cost indicated online may not correspond to real values ​​due to the irrelevant information provided.

In their work, obstetrician-gynecologists of the Center constantly answer the questions: what is thrombophilia? What is genetic thrombophilia? What thrombophilia test 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. This is such a love for a blood clot, or rather an increased tendency to thrombosis- formation of blood clots in vessels of different diameters and locations. Thrombophilia is disruption of the system.
Hemostasis is a mechanism that ensures correct blood reaction to external and internal factors. Blood should flow through the vessels quickly, without stopping, but when it becomes necessary to reduce the flow speed and/or form a clot, for example, to “repair” an injured vessel, the “right” blood should do this. Next, after making sure that the blood clot has done its job and is no longer needed, dissolve it. And run further)
Of course, not everything is so simple and the coagulation system is a complex multicomponent mechanism with regulation at different levels.

A little history...
1856 - German scientist Rudolf Virchow wondered about the pathogenesis of thrombosis, conducted a number of studies and experiments in this regard and formulated the basic mechanism of thrombus formation. Any medical student, when mentioning Virchow's triad, is required to report - injury to the inner wall of the vessel, a decrease in the speed of blood flow, and an increase in blood clotting. In fact, the great Virchow was the first to solve the riddle “why the same blood can flow freely, but can clog a vessel.”
1990 - The British Committee on Hematological Standards defined the concept of “thrombophilia” as a congenital or acquired defect of hemostasis, leading to a high degree of susceptibility to thrombosis.
1997 – outstanding hematologist A.I. Vorobyov “hypercoagulation syndrome” is described, that is, a certain state of blood with an increased readiness to clot.

Is a blood clot dangerous?
The answer is yes. Except for physiological necessity, of course, thrombosis is bad. Because blockage of any vessel is dangerous. The larger the vessel, the more significant it is, the more dangerous the complications. The vessel should not have blocked blood flow. This immediately or gradually entails a decrease in oxygen delivery to tissues (hypoxia) and triggers a series of pathological changes. It may not be noticeable and not as scary as I described, but it can also be very painful, and sometimes fatal. Thrombosis entails significant damage to the function of one or another organ, and sometimes the body as a whole. Thrombosis is 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 the polymorphism of hemostasis genes during pregnancy.
As for obstetric complications, the problem of increased thrombus formation primarily concerns the organ, which consists entirely of vessels. This is the placenta. Very detailed and with pictures - here:
All women experience physiological hypercoagulation during pregnancy, that is, the blood normally slightly increases its coagulability. This is a normal physiological mechanism aimed at preventing blood loss after pregnancy - during childbirth or with possible pathological outcomes (early termination of pregnancy, placental abruption, etc.).
But if a woman is a carrier of 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 thrombophilias are there?
Thrombophilias are divided into hereditary and acquired, and there are also mixed types.

Acquired (non-genetic) thrombophilia
Purchased forms of thrombophilia are realized under certain “special” conditions. This occurs when the body is going through difficult times; Quite serious pathological changes entail an “over” reaction of the coagulation system. For example, oncological diseases accompanied by chemotherapy, severe infectious, autoimmune, allergic processes, liver and kidney diseases, cardiovascular pathologies, connective tissue diseases - systemic lupus erythematosus, various vasculitis, etc. In such cases, the cascade of thrombus formation can be launched and without carrier defective hemostasis genes. Predisposing factors may include prolonged and persistent dehydration, physical inactivity, obesity, pregnancy, taking hormonal medications, etc.

To be continued. In the next blog issue -.

Genetic risk of thrombophilia (advanced)

A comprehensive genetic analysis that allows you to determine the risk of thrombophilia. It is a molecular genetic study of the genes of blood clotting factors, platelet receptors, fibrinolysis, metabolism, changes in the activity of which directly or indirectly determine the tendency to increased thrombosis.

What biomaterial can be used for research?

Buccal (buccal) epithelium, venous blood.

How to properly prepare for research?

No preparation required.

More about the study

As a result of various pathological processes, blood clots can form in the vessels, blocking blood flow. This is the most common and unfavorable manifestation of hereditary thrombophilia - an increased tendency to form blood clots associated with certain genetic defects. It can lead to the development of arterial and venous thrombosis, which in turn often causes myocardial infarction, coronary heart disease, stroke, pulmonary embolism, etc.

The hemostasis system includes factors of the blood coagulation and anticoagulation systems. In a normal state, they are in balance and provide the physiological properties of the blood, preventing increased thrombus formation or, conversely, bleeding. But when exposed to external or internal factors, this balance can be disrupted.

As a rule, genes for blood coagulation factors and fibrinolysis, as well as genes for enzymes that control folic acid metabolism, are involved in the development of hereditary thrombophilia. Disturbances in this metabolism can lead to thrombotic and atherosclerotic vascular lesions (through increased levels in the blood).

The most significant disorder leading to thrombophilia is a mutation in the clotting factor 5 gene ( F5), it is also called Leiden. It is manifested by the resistance of factor 5 to activated protein C and an increase in the rate of thrombin formation, which results in an increase in blood clotting processes. Also an important role in the development of thrombophilia is played by a mutation in the prothrombin gene ( F2), associated with an increase in the level of synthesis of this clotting factor. In the presence of these mutations, the risk of thrombosis increases significantly, especially due to provoking factors: taking oral contraceptives, excess weight, physical inactivity, etc.

• bed rest (more than 3 days), prolonged immobilization, long static loads, including those related to work, sedentary lifestyle;
• use of oral contraceptives containing estrogens;
• excess body weight;
• history of venous thromboembolic complications;
• catheter in the central vein;
• dehydration;
• surgical interventions;
• injury;
• smoking;
• oncological diseases;
• pregnancy;
• concomitant cardiovascular diseases, malignant neoplasms.

When is the study scheduled?

• If there is a family history of thromboembolism.
• If there is a history of thrombosis.
• For thrombosis under the age of 50 years, repeated thrombosis.
• In case of thrombosis at any age in combination with a family history of thromboembolism (pulmonary embolism), including thrombosis of other locations (cerebral vessels, portal veins).
• For thrombosis without obvious risk factors over the age of 50 years.
• In the case of the use of hormonal contraceptives or hormone replacement therapy in women: 1) with a history of thrombosis, 2) whose 1st degree relatives had thrombosis or hereditary thrombophilia.
• With a complicated obstetric history (miscarriage, fetoplacental insufficiency, thrombosis during pregnancy and in the early postpartum period, etc.).
• When planning pregnancy by women suffering from thrombosis (or in the case of thrombosis in their 1st degree relatives).
• Under such high-risk conditions as abdominal surgery, prolonged immobilization, constant static loads, and a sedentary lifestyle.
• With a family history of cardiovascular diseases (cases of early heart attacks and strokes).
• When assessing the risk of thrombotic complications in patients with malignant neoplasms.

What do the results mean?

Based on the results of a comprehensive study of 10 significant genetic markers, a conclusion from a geneticist is issued, which will allow assessing the risk of thrombophilia, predicting the development of diseases such as thrombosis, thromboembolism, heart attack, or the likelihood of complications associated with impaired hemostasis during pregnancy, choosing directions for optimal prevention, and already existing clinical manifestations, understand their causes in detail.