Antithrombin III that it is an analysis and the norm in the blood deviation role in the diagnosis

READ APTT ANALYSIS – this is an indicator that determines the time of blood coagulation. Normally 24-35 seconds. A reduction in this indicator indicates accelerated coagulation, which is an indicator of DIC. If APTT is more than 35 seconds, then the blood, on the contrary, does not clot well, and there is a high risk of postpartum hemorrhage.

Prothrombin is a factor reflecting the quality of blood coagulation. Normally, its value is 78-142%. If this indicator is higher – this is a sign of accelerated blood coagulation, if lower – a woman is at high risk of large loss of blood during bleeding (for example, after childbirth). Antithrombin III .

Thrombophilia is an increased tendency of the human body to form blood clots. It can be acquired and hereditary (congenital).

The manifestation of the disease in carriers of genetic thrombophilic mutations to a large extent depends on age, gender, environmental factors and other other mutations.

Carriers of the disease allele may not have any clinical symptoms of the disease until external factors appear.

The latter include: pregnancy, the postpartum period, immobilization, surgery, trauma, tumors, hormonal drugs for contraception or replacement therapy.

Thrombophilic conditions in obstetrics are one of the important causes of miscarriage and fetoplacental insufficiency.

In addition, hyperhomocysteinemia and a homozygous state according to MTNFR are risk factors for the development of some congenital malformations (defects in the neural tube of the fetus, cleft lip and palate, some types of congenital heart defects, kidneys, etc.).

Antithrombin III Deficiency

Antithrombin III is a natural anticoagulant, which accounts for 75% of all plasma anticoagulant activity, a glycoprotein with a molecular weight of 58 and a plasma content of 200-125 mg / ml.

The primary structure of antithrombin III consists of 432 amino acids. It blocks prothrombinase – it inactivates the factors CPa, XIa, Xa, IXa, VIIIa, kallikrein and thrombin. In the presence of heparin, the activity of antithrombin III increases by more than 2000 times.

Antithrombin III deficiency is inherited autosomally dominantly. Most carriers of this pathology of heterozygotes, homozygotes die very early from thromboembolic complications. Currently, up to 80 mutations of a gene located on the long arm of chromosome 1 have been described.

The incidence of this pathology varies greatly among different ethnic groups.

Epidemiology In the European population, the frequency of antithrombin III deficiency is 1: 2000-1: 5000. According to some reports, 0,3% in the population. Among patients with thromboembolic complications, the incidence of antithrombin III deficiency is 3-8%.

Hereditary deficiency of antithrombin III can be of 2 types:

  1. Type I – a decrease in the synthesis of antithrombin III as a result of a gene mutation;
  2. Type II – a decrease in the functional activity of antithrombin III during its normal production

Clinical manifestations of hereditary antithrombin III deficiency:

  • deep vein thrombosis of the legs, ileofemoral thrombosis (arterial thrombosis is not characteristic of this pathology);
  • habitual miscarriage;
  • fetal fetal death;
  • thrombophilic complications after taking oral contraceptives

The functional activity of antithrombin III is determined by the ability of the plasma sample to inhibit a known amount of thrombin or factor Xa added to the sample in the presence or absence of heparin.

With low antithrombin III activity, the main coagulation tests are not changed, tests for fibrinolysis and bleeding time are normal, platelet aggregation is normal.

With heparin therapy, there is no characteristic adequate increase in APTT.

Treatment Normally, the antithrombin level is 85-110%. During pregnancy, it is slightly reduced and amounts to 75-100%. The lower limit of the concentration of antithrombin III is variable, so it is necessary to take into account not only the level, but also the clinical situation. However, with a decrease in the level of antithrombin III below 30% of patients die from thrombosis.

The basis of the treatment of antithrombin III deficiency is antithrombotic agents. If there are symptoms of thrombophilia, treatment is necessary, and this is not discussed.

For these purposes, use freshly frozen plasma (as a source of antithrombin III), low molecular weight heparins (enoxaparin sodium, calcium nadroparin, dalteparin sodium).

At a low level of antithrombin III, sodium heparin is not used, since heparin resistance and heparin-induced thrombosis are possible.

During pregnancy, low molecular weight heparins are the drugs of choice, their doses are selected individually under the control of hemostasiograms. The second and third trimesters of pregnancy are recognized as critical when the blood coagulation potential increases, and the level of antithrombin III decreases.

Outside pregnancy, patients may be advised to take long-term vitamin K antagonists (warfarin).

Protein C deficiency

Protein C – a natural anticoagulant dependent on vitamin K glycoprotein, is synthesized in the liver in an inactive form. Activated protein C is a serine protease whose function is to inactivate factors Va and VIIIa, an important regulator of thrombin activity on the surface of the endothelium.

Protein C is activated by the interaction of thrombin with thrombomodulin. This connection accelerates the formation of thrombin in the form of activated protein C. The activity of protein C is enhanced by its cofactor, protein S.

Activated protein C proteolytically inactivates factors Va and VIIIa in the presence of protein S, phospholipid (endothelial surface) and calcium, inhibiting the further activation of thrombin.

Congenital protein C deficiency is caused by a gene mutation. The protein C gene is located on chromosome 2. More than 150 mutations of the gene are known. Very often, protein C deficiency is combined with a factor V mutation.

Protein C deficiency is somewhat more common than antithrombin III deficiency; among patients with thrombosis and thromboembolism, this pathology is noted in about 10% of patients. Protein C deficiency is inherited autosomally dominantly.

The level of protein C in heterozygous carriers is 30-60% of the norm, homozygous practically do not have protein C and die in utero or immediately after birth.

Hereditary protein C deficiency can be of 2 types:

  1. Type I – reduction in the amount of protein C;
  2. Type II – a decrease in the activity of protein C at its normal level

Clinical manifestations of protein C deficiency:

  • habitual loss of pregnancy, stillbirth, fetal loss (up to 27,9%);
  • venous thrombosis and thromboembolism at the age of 20-30 years of any localization;
  • necrosis of the skin, subcutaneous tissue (especially in the treatment of indirect anticoagulants);
  • increased risk of thrombosis with oral contraceptives;
  • practical absence of arterial thrombosis

Protein S Deficiency

Protein S is a non-enzymatic cofactor of protein C in the inactivation of factors Va and VIIIa, has its own anticoagulant activity independent of protein C.

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Protein S, like protein C, is dependent on vitamin K and is synthesized in the liver. In blood circulation, it exists in 2 forms – free S protein and complement associated with the C4 component.

Normally, 60-70% of protein S is associated with the C4 complement component – the regulator of the classical pathway of the complement system. The level of binding of protein S to the C4 component of complement determines the content of free protein S.

Only the free form of protein S serves as a cofactor of activated protein C (APC).

Normally, the plasma protein S level is 80-120%. During pregnancy, the level of both free and bound protein S is reduced to 60-80% and lower in the postoperative period.

Protein S deficiency is inherited autosomally dominantly. Carriers of gene mutations are more often heterozygous; carriers of homozygotes are rare. It was found that the protein S gene is located on chromosome 3.

Up to 70 mutations in the S gene are currently known.

Hereditary protein S deficiency can be of 2 types:

  1. Type I – a decrease in the level of free protein S associated with the C4 component of complement, within normal limits;
  2. Type II – a decrease in the level of free and bound protein S

According to researchers, the pregnancy loss rate is 16,5%. Stillbirths are more often observed than early pregnancy loss.

Treatment Patients with protein C and S deficiency are refractory to sodium heparin and antiplatelet agents.

However, in acute thrombotic complications, the use of sodium heparin and then low molecular weight heparins is justified.

As a source of proteins C and S, freshly frozen plasma is used in combination with heparin sodium. Out of pregnancy with thrombophilia, warfarin is used for a long time.

Mutation of factor V (Leiden mutation, resistance to protein C)

Mutation of factor V has become the most common genetic cause of thrombophilia in the European population. It was first identified and described by a group of scientists working in the city of Leiden (Netherlands). From here she got her name – “Leiden mutation”.

The Leiden mutation of the coagulation factor V gene V is characterized by the replacement of the guanine nucleotide with the adenine nucleotide at position 1691. This leads to the replacement of the arginine amino acid with the glutamine amino acid at position 506 in the protein chain that is the product of this gene.

All three designations are synonymous with the same mutation. With such a replacement, factor V is not cleaved by the natural anticoagulant protein C at position 506, as is normal, but becomes resistant to its action. There is a resistance of factor V to protein C.

Thrombophilic causes of miscarriage

In our body, nothing happens just like that. There are always specific catalysts that trigger certain processes. When the level of antithrombin 3 begins to decrease, the cause of such changes should first be clarified. As a rule, the following factors can provoke a decrease in antithrombin 3 in women during pregnancy, as well as in the rest of the population:

  • significant loss of blood;
  • congenital deficiency of antithrombin 3;
  • liver diseases that reduce its functional activity;
  • frequent surgical interventions in the body;
  • abuse of oral contraceptives;
  • oncological diseases.

In this case, there are two options for the development of the situation, leading to a small amount of antithrombin 3 in the body of a woman:

  • the protein is produced, it has all the properties of an anticoagulant, but it is not enough to fully perform its functions;
  • protein is produced in sufficient quantities, but it is dysfunctional.

People who have a decrease in antithrombin 3 fall into a separate risk group and are under the supervision of doctors throughout the treatment period.

The other extreme is an increase in antithrombin 3, which is especially dangerous during pregnancy. Such a pathology in most cases is due to:

  • vitamin K deficiency in the body;
  • taking anabolic drugs;
  • pancreatic diseases;
  • inflammatory processes in the human body, gaining strength.

In order not to miss such coagulation pathologies, do not neglect scheduled examinations and examinations, even if you feel good enough.

Any disease or malfunction in the work of specific individual body systems has its own external manifestations. When the antithrombin 3 level is lowered during pregnancy or, on the contrary, there is a tendency to increase it, experienced specialists will pay attention to the following symptoms. With a deficiency of antithrombin 3:

  • deep vein thrombosis on the legs;
  • fetal fetal death;
  • repeated cases of not bearing a pregnancy.

An increase in the amount of antithrombin 3 during pregnancy does not always have external manifestations. If the indicators are not critical and do not significantly exceed the permissible norm, minor deviations are corrected by the diet, concomitant treatment. In the case when there is a significant difference with the average statistical standards, additional tests are prescribed, on the basis of which medication is prescribed.

Protein S Deficiency

With a factor V mutation, there is a lifelong risk of thrombosis, which is almost 8 times higher than without a mutation, and with homozygous carriage, it is almost 90 times. Thrombosis often occurs in response to provoking factors, one of which is pregnancy. According to M. Kirferminc et al. (1999), 25-50% of patients with placental abruption carry the Leiden mutation gene.

Diagnosis of the Leiden mutation of factor V is often carried out by determining APTT without activated protein C and c.

Resistance to activated protein C is established by the patient’s plasma ability to withstand APTT prolongation caused by the addition of activated protein C.

The sensitivity of the analysis is 85%, and the specificity is 90%. The accuracy of the study increases when plasma with a deficiency of V factor is added to the test system.

The study can be carried out at least 2-3 weeks after completion of anticoagulant therapy in connection with thrombosis.

In patients with similar obstetric complications, APTT may be altered due to the presence of APS.

In these cases, as well as at the borderline values ​​of APTT, the diagnosis “Leiden mutation” is verified by PCR (DNA testing of the gene encoding the synthesis of the V factor of the blood coagulation system).

Treatment To date, there are no controlled, randomized trials of the effectiveness of treatment of carriers of this mutation.

  • Acute thrombosis during pregnancy – iv heparin in a dose of 10-000 units every 15-000 hours under the control of APTT, course of 8-12 days, taking into account the severity of the condition, then switch to low molecular weight heparin – dalteparin sodium at a dose of 5-10 5000 IU 10 times a day, calcium nadroparin at a dose of 000-2 ml 0,4 times a day; enoxaparin sodium in a dose of 0,6-2 mg 40 times a day.
  • A complication of thrombophilia during pregnancy and a history of thromboembolic complications – iv heparin or low molecular weight heparin in lower doses than in the presence of thromboembolic complications
  • In the absence of thromboembolic complications, but in the presence of mutation and thrombophilia – low molecular weight heparin in prophylactic doses throughout pregnancy.
  • After childbirth – sodium heparin, then warfarin for 2-3 months after birth, since this is the time of greatest risk of thromboembolism
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Mutation of the prothrombin gene G20210A

The mutation of the prothrombin G20210A gene is characterized by the replacement of the guanine nucleotide with the adenine nucleotide at position 20210. A feature of this mutation is that the nucleotide substitution is located in the 3′-untranslated region.

This means that the nucleotide sequence of the altered region is not involved in the coding of the amino acid sequence of the prothrombin gene. Therefore, no chemical changes in prothrombin itself in the presence of this mutation does not occur.

In the presence of this mutation, increased amounts of chemically normal prothrombin are detected. The level of prothrombin can be one and a half to two times higher than normal.

Prothrombin, or factor II, under the influence of factors X and XA passes into the active form, which activates the formation of fibrin from fibrinogen. It is believed that this mutation among hereditary thrombophilia is 10-15%, but occurs in about 1-9% of mutations without thrombophilia. Among patients with deep thrombosis, a prothrombin mutation is detected in 6-7%.

When thrombosis occurs, the G20210A mutation is often found in combination with the Leiden mutation.

A combination of these factors is characterized by very early thrombosis – at the age of 20-25 years – with an increase in thromboembolic complications during pregnancy and after childbirth.

  • The prothrombin gene mutation is diagnosed by PCR.
  • The management and treatment of patients with a prothrombin defect is the same as patients with a factor V mutation.
  • Mutations of the MTNFR C677T gene (hyperhomocysteinemia)

Hyperhomocysteinemia is a multifactorial process involving genetic and non-genetic mechanisms. The causes of hyperhomocysteinemia can be hereditary and acquired. Hereditary factors can be divided into enzyme deficiency and transport deficiency.

Qualitative and quantitative violations

Low antithrombin III levels are quite rare. According to statistics, such people are no more than 1% worldwide. Nevertheless, of all the pathologies of the hematopoietic system, it is the hereditary insufficiency of the anticoagulant that is the most common disorder.

Congenital insufficiency of antithrombin III (a heterozygous form of a pathological gene) is manifested by the development of thrombosis in people aged 20-35 years. Trigger factors are: pregnancy, childbirth, surgery or acute inflammation of the internal organs, taking hormonal contraceptives. With a homozygous form, thromboses will develop immediately after birth, but such a violation is extremely rare.

Acquired antithrombin III deficiency can develop at any time, regardless of a person’s age.

A person is not able to independently determine the existing coagulant deficiency, since there are no symptoms of the violation. The only sign of this pathology will be the formation of thrombosis, but they develop not only with a lack of antithrombin III, but also with other disorders of the hematopoiesis system.

Therefore, quantitative deficiency of antithrombin III and qualitative deficiency of antithrombin III are isolated. The first type of disorder is characterized by a low content of antithrombin III in the blood, and the second type is characterized by its functional inferiority. Moreover, with both of these conditions, thrombosis can develop. To find out what exactly led to the formation of blood clots in the vessels, a qualitative study of antithrombin factor is required.

If antithrombin III is elevated, what does this mean?

An increased level of antithrombin III in the patient’s blood indicates the risk of bleeding and insufficient blood coagulation. This is often the result of the following diseases:

  • acute hepatitis
  • chronic inflammatory processes in the body
  • lack of vitamin K,
  • acute form of pancreatitis,
  • pancreatic malignancy
  • cholestasis.

Women complaining of excessively heavy menstruation, it is advisable to donate blood to understand whether they have an antithrombin rate in the blood or not. As a rule, in such cases, the level of antithrombin III is increased.

The use of anabolic drugs leads to an increase in the level of antithrombin III.

Antithrombin 3 study

A protein with special specificity, which is simply necessary for blood coagulation, is antithrombin 3. Its main function in a woman’s body during pregnancy is the prevention of blood clots. In the event that antithrombin 3 in the blood is lowered, this indicates the risk of blood clots, and with an increased rate, the risk of bleeding increases.

Patients in whom antithrombin 3 is significantly reduced fall into a separate group with an increased risk of thrombosis. A hereditary predisposition to a deficiency of such a protein is extremely rare and in this case, blood clots begin to bother a woman as early as 20-30 years old.

Antithrombin 3 in a small amount in the body of a woman during pregnancy can exist in two forms:

  • normal antithrombin is produced in the body, but its amount is not enough;
  • the production of a sufficient amount of protein is observed, but it is dysfunctional.
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Svetlana Borszavich

General practitioner, cardiologist, with active work in therapy, gastroenterology, cardiology, rheumatology, immunology with allergology.
Fluent in general clinical methods for the diagnosis and treatment of heart disease, as well as electrocardiography, echocardiography, monitoring of cholera on an ECG and daily monitoring of blood pressure.
The treatment complex developed by the author significantly helps with cerebrovascular injuries and metabolic disorders in the brain and vascular diseases: hypertension and complications caused by diabetes.
The author is a member of the European Society of Therapists, a regular participant in scientific conferences and congresses in the field of cardiology and general medicine. She has repeatedly participated in a research program at a private university in Japan in the field of reconstructive medicine.

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