What medications can cause secondary afs. Antiphospholipid syndrome: why is it dangerous? Laboratory criteria for antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an acquired autoimmune disease in which the immune system produces antibodies (antiphospholipid antibodies, aPL) to phospholipids in the membranes of its own cells or certain blood proteins. In this case, damage to the blood coagulation system, pathology during pregnancy and childbirth, a decrease in the number of platelets, as well as a number of neurological, skin and cardiovascular disorders are observed.

Skin manifestations of antiphospholipid syndrome

The disease belongs to the group of thrombophilic diseases. This means that its main manifestation is recurrent thrombosis of various vessels.

For the first time, information about the role of specific autoantibodies in the development of coagulation system disorders, as well as the characteristic symptoms of the disease, was presented in 1986 by the English rheumatologist G. R. W. Hughes, and in 1994, at an international symposium in London, it was proposed to use the term “syndrome” to refer to the disease Hughes."

The prevalence of antiphospholipid syndrome in the population has not been fully studied: specific antibodies in the blood of healthy people are found, according to various sources, in 1–14% of cases (on average 2–4%), their number increases with age, especially in the presence of chronic diseases. However, the incidence of the disease in young people (even, most likely, in children and adolescents) is significantly higher than in the elderly.

According to modern concepts, antiphospholipid antibodies are a heterogeneous group of immunoglobulins that react with negatively or neutrally charged phospholipids of various structures (for example, antibodies to cardiolipin, antibodies to beta-2-glycoprotein, lupus anticoagulant).

It is noted that women get sick 5 times more often than men, the peak occurs in middle age (about 35 years).

Synonyms: Hughes syndrome, phospholipid syndrome, antiphospholipid antibody syndrome.

Causes and risk factors

The causes of the disease have not yet been established.

It is noted that a transient increase in the level of antiphospholipid antibodies occurs against the background of some viral and bacterial infections:

• hepatitis C;
• infections caused by the Epstein-Barr virus, human immunodeficiency virus, cytomegalovirus, parvovirus B19, adenovirus, Herpes zoster, measles, rubella, and influenza viruses;
• leprosy;
• tuberculosis and diseases caused by other mycobacteria;
• salmonellosis;
• staphylococcal and streptococcal infections;
• Q fever; and etc.

It is not possible to prevent the development of the disease at the current level of medical development.

It is known that in patients with antiphospholipid syndrome, the incidence of various autoimmune diseases is higher than the average in the population. Based on this fact, some researchers suggest a genetic predisposition to the disease. As evidence in this case, statistics are provided according to which 33% of relatives of patients with APS were carriers of antiphospholipid antibodies.

Most often in European and American populations, three point genetic mutations are mentioned that may be related to the formation of the disease: Leiden mutation (coagulation factor V mutation), prothrombin gene mutation G20210A and defect in the 5,10-methylenetetrahydrofolate reductase gene C677T.

Forms of the disease

The following subtypes of antiphospholipid syndrome are distinguished:

• antiphospholipid syndrome (develops against the background of any disease, more often autoimmune, identified in 1985);
• primary antiphospholipid syndrome (described in 1988);
• catastrophic (CAFS, described in 1992);
• seronegative (SNAFS, separated into a separate group in 2000);
• probable APS, or pre-antiphospholipid syndrome (described in 2005).

In 2007, new varieties of the syndrome were identified:

• microangiopathic;
• recurrent catastrophic;
• cross.

In connection with other pathological conditions, antiphospholipid syndrome is classified as follows:

• primary (is an independent disease, not associated with other pathologies);
• secondary (develops against the background of concomitant systemic lupus erythematosus or other autoimmune diseases, lupus-like syndrome, infections, malignant neoplasms, vasculitis, pharmacotherapy with certain drugs).

Symptoms

The clinical picture associated with the circulation of antiphospholipid antibodies in the systemic circulation varies from asymptomatic carriage of antibodies to life-threatening manifestations. In fact, any organ can be involved in the clinical picture of antiphospholipid syndrome.

The main manifestations of antiphospholipid syndrome are recurrent thrombosis of various vessels.

Antibodies can adversely affect the regulatory processes of the coagulation system, causing their pathological changes. The influence of aPL on the main stages of fetal development has also been established: difficulty in implantation (fixation) of a fertilized egg in the uterine cavity, disturbances in the placental blood flow system, and the development of placental insufficiency.

The main conditions, the appearance of which may indicate the presence of antiphospholipid syndrome:

• recurrent thrombosis (especially deep veins of the lower extremities and arteries of the brain, heart);
• repeated pulmonary embolisms;
• transient ischemic disorders of cerebral circulation;
• stroke;
• episyndrome;
• choreiform hyperkinesis;
• multiple neuritis;
• migraine;
• transverse myelitis;
• sensorineural hearing loss;
• transient vision loss;
• paresthesia (feeling of numbness, crawling);
• muscle weakness;
• dizziness, headaches (even unbearable);
• intellectual disabilities;
• myocardial infarction;
• damage to the valvular apparatus of the heart;
• chronic ischemic cardiomyopathy;
• intracardiac thrombosis;
• arterial and pulmonary hypertension;
• infarctions of the liver, spleen, intestines or gall bladder;
• pancreatitis;
• ascites;
• kidney infarction;
• acute renal failure;
• proteinuria, hematuria;
• nephrotic syndrome;
• skin lesions (livedo reticularis - occurs in more than 20% of patients, postthrombophlebitic ulcers, gangrene of fingers and toes, multiple hemorrhages of varying intensity, purple toe syndrome);
• obstetric pathology, incidence rate - 80% (fetal loss, more often in the second and third trimesters, late gestosis, preeclampsia and eclampsia, intrauterine growth retardation, premature birth);
• thrombocytopenia from 50 to 100 x 10 9 /l.

Diagnostics

Due to the wide range of different symptoms that the disease can present, making a diagnosis is often difficult.

In order to improve the accuracy of diagnosing antiphospholipid syndrome, classification criteria were formulated in 1999, according to which the diagnosis is considered confirmed when (at least) one clinical and one laboratory sign is combined.

It is noted that women suffer from antiphospholipid syndrome 5 times more often than men, the peak occurs in middle age (about 35 years).

Clinical criteria (based on medical history) are vascular thrombosis (one or more episodes of thrombosis of vessels of any caliber in any tissue or organ, and thrombosis must be confirmed instrumentally or morphologically) and pregnancy pathology (one of the listed options or a combination of them):

• one or more cases of intrauterine death of a normal fetus after the 10th week of pregnancy;
• one or more cases of premature birth of a normal fetus before 34 weeks of gestation due to severe preeclampsia, or eclampsia, or severe placental insufficiency;
• three or more consecutive cases of spontaneous termination of a normal pregnancy (in the absence of anatomical defects, hormonal disorders and chromosomal abnormalities on the part of either parent) before the 10th week of gestation.

Laboratory criteria:

• antibodies to cardiolipin of the IgG or IgM isotype, detected in serum in medium or high concentrations at least 2 times after at least 12 weeks using a standardized enzyme-linked immunosorbent assay (ELISA);
• antibodies to beta-2-glycoprotein-1 of the IgG and (or) IgM isotype, detected in serum in medium or high concentrations at least 2 times after at least 12 weeks using a standardized method (ELISA);
• lupus anticoagulant in plasma on two or more study occasions at least 12 weeks apart, determined according to international guidelines.

Antiphospholipid syndrome is considered confirmed if one clinical and one laboratory criterion is met. The disease is excluded if antiphospholipid antibodies without clinical manifestations or clinical manifestations without aPL are detected for less than 12 weeks or more than 5 years.

Treatment

There are no generally accepted international standards for treating the disease; drugs with immunosuppressive effects have not shown sufficient effectiveness.

Pharmacotherapy of antiphospholipid syndrome is aimed mainly at the prevention of thrombosis, using:

• indirect anticoagulants;
• antiplatelet agents;
• lipid-lowering drugs;
• aminoquinoline drugs;
• antihypertensive drugs (if necessary).

Possible complications and consequences

The main danger for patients with antiphospholipid syndrome is thrombotic complications, which unpredictably affect any organ, resulting in acute disturbances in organ blood flow.

For women of childbearing age, in addition, significant complications are:

• miscarriage;
• intrauterine growth retardation as a consequence of impaired placental blood flow and chronic hypoxia;
• placental abruption;
• gestosis, preeclampsia, eclampsia.

According to various sources, antiphospholipid antibodies in the blood of healthy people occur in 1–14% of cases (on average 2–4%), their number increases with age, especially in the presence of chronic diseases.

Forecast

Unfavorable prognostic factors for mortality in APS are thrombosis of arterial vessels, a high incidence of thrombotic complications and thrombocytopenia, and laboratory markers include the presence of a lupus anticoagulant. The course of the disease, severity and prevalence of thrombotic complications are unpredictable.

Prevention

It is not possible to prevent the development of the disease at the current level of medical development. Nevertheless, constant follow-up allows one to assess the risk of developing thrombotic complications, often prevent them and promptly detect concomitant pathology.

Video from YouTube on the topic of the article:

In case of antiphospholipid syndrome (APS), in women with recurrent miscarriage, intrauterine death of the fetus, or a delay in its development in the blood, antibodies produced by the pregnant woman’s body to its own phospholipids are determined - special chemical structures from which the walls and other parts of cells are built. These antibodies (AFA) become the cause of the formation of blood clots during the formation of placental vessels, which can lead to intrauterine growth retardation or fetal death, placental abruption, and the development of pregnancy complications. Also, lupus anticoagulant (a substance detected in the blood during systemic lupus erythematosus 1) is detected in the blood of women suffering from APS.

Complications of APS are miscarriage and premature birth, gestosis (complications of pregnancy, manifested by increased blood pressure, the appearance of protein in the urine, edema), fetal-placental insufficiency (in this condition, the fetus lacks oxygen).

With APS, the incidence of complications during pregnancy and childbirth is 80%. Antiphospholipid antibodies to various elements of the reproductive system are found in 3% of clinically healthy women, with miscarriage - in 7-14% of women, with a history of two or more spontaneous abortions - in every third patient.

Manifestations of antiphospholipid syndrome

At primary APS Only specific changes in the blood are detected.

At secondary APS complications of pregnancy or infertility are observed in patients with autoimmune diseases, such as systemic lupus erythematosus, autoimmune thyroiditis (inflammation of the thyroid gland), rheumatism, etc.

Primary and secondary APS have similar clinical manifestations: recurrent miscarriage, non-developing pregnancies in the first and second trimesters, intrauterine fetal death, premature birth, severe forms of preeclampsia, fetoplacental insufficiency, severe complications of the postpartum period, thrombocytopenia (decreased platelet count). In all cases, the precursor to the death of the fetal egg is the development of a chronic form of DIC syndrome.

Observations show that without treatment, fetal death occurs in 90-95% of women with AFA.

Among patients with recurrent miscarriage, APS is detected in 27-42%. The frequency of this condition among the entire population is 5%.

Preparing for pregnancy with antiphospholipid syndrome

It is especially important to prepare for pregnancy for women who have a history of undeveloped pregnancies, spontaneous abortions (7-9 weeks), early and late toxicosis, chorionic detachment (placenta). In these cases, an examination is carried out for genital infections (by enzyme immunoassay - ELISA, polymerase chain reaction - PCR), a study of hemostasis - indicators of the blood coagulation system (hemostasiogram), exclude the presence of lupus anticoagulant (LA), AFA, evaluate the immune system using special tests.

Thus, preparation for pregnancy includes the following stages:

1. Assessment of the state of the reproductive system of spouses. Correction of endocrine disorders (hormonal therapy).
2. Examination of a couple in order to identify an infectious agent using PCR (detection of pathogen DNA) and serodiagnosis (detection of antibodies to a given pathogen), reflecting the degree of activity of the process. Treatment of identified infections using chemotherapy and enzyme drugs (BOBEIZYM, PHLOGENZYM), immunoglobulins (IMMUNOVENIAN).
3. Study of the state of the immune system, its correction with the help of medications (RIDOSTIN, VIFERON, KIPFERON); lymphocytotherapy (injection of the woman’s husband’s lymphocytes); control and correction of the microcirculatory hemostasis system (CURANTIL, FRAXIPARIN, INFUL).
4. Identification of autoimmune processes and influence on them (glucocorticoids and alternative drugs are used for this: enzymes, interferon inducers).
5. Correction of energy metabolism of both spouses: metabolic therapy to reduce oxygen deficiency in tissues - tissue hypoxia (INOSIE-F, LIMONTAR, KORILIP, metabolic complexes).
6. Psychocorrection - elimination of anxiety, fear, irritability; antidepressants are used, MAGNE-B6(this drug improves metabolic processes, including in the brain). Application of various methods of psychotherapy.
7. If there are diseases of various organs in spouses planning a pregnancy, it is necessary to consult a specialist with subsequent assessment of the degree of damage to the diseased organ, the adaptive capabilities of the body and the prognosis of fetal development with the exception of genetic abnormalities.

Most often, in the presence of APS, a chronic viral or bacterial infection is detected. Therefore, the first stage of preparation for pregnancy is antibacterial, antiviral and immunocorrective therapy. At the same time, other drugs are prescribed.

The indicators of the hemostatic system (coagulation system) in pregnant women with APS differ significantly from the indicators in women with a physiological course of pregnancy. Already in the first trimester of pregnancy, platelet hyperfunction develops, often resistant to therapy. In the second trimester, this pathology can worsen and lead to an increase in hypercoagulation (increased blood clotting) and activation of intravascular thrombus formation. Signs of developing DIC syndrome appear in the blood. These indicators are detected using a blood test - coagulogram. In the third trimester of pregnancy, hypercoagulation phenomena increase, and they can be kept within limits close to normal only with active treatment under the control of blood coagulation parameters. Similar studies are carried out in these patients also during childbirth and the postpartum period.

The second stage of preparation begins with a re-examination after treatment. It includes control of hemostasis, lupus anticoagulant (LA), LPA. When there are changes in hemostasis, antiplatelet agents are used - drugs that prevent the formation of blood clots (ASPIRIN, CURANTIL, TRENTAL, REOPOLIGLUKIN, INFUCOL), anticoagulants (GE-PARIN, FRAXIPARIN, FRAGMIN).

When a planned pregnancy occurs (after examination and treatment), dynamic control of the formation of the fetal-placental complex is carried out, prevention of fetoplacental insufficiency and correction of placental function when it changes (ACTOVEGIN, INSTENON).

Tactics of pregnancy management with antiphospholipid syndrome

From the first trimester, the most important period for fetal development in conditions of autoimmune pathology, hemostasis is monitored every 2-3 weeks. From the early stages, in the cycle of planned conception, treatment with hormones is prescribed - glucocorticoids, which have anti-allergic, anti-inflammatory, anti-shock effects. Combination of glucocorticoids (METIPRED,DEXA-METAZONE, PREDNISOLONE etc.) with antiplatelet agents and anticoagulants deprives the activity of AFA and removes it from the body. Thanks to this, hypercoagulation is reduced and blood clotting is normalized.

All patients with APS have a chronic viral infection (herpes simplex virus, papillomavirus, cytomegalovirus, Coxsackie virus, etc.). Due to the peculiarities of pregnancy, the use of glucocorticoids even in minimal doses may activate this infection. Therefore, during pregnancy, it is recommended to carry out 3 courses of preventive therapy, which consists of intravenous administration IMMUNOGLOBULI-NA in a dose of 25 ml (1.25 g) or OKTAGAMA 50 ml (2.5 g) every other day, three doses in total; suppositories with VIFERON. Small doses of immunoglobulin do not suppress the production of immunoglobulins, but stimulate the body's defenses.

Immunoglobulin is reintroduced after 2-3 months and before childbirth. The administration of immunoglobulin is necessary to prevent the exacerbation of a viral infection and to suppress the production of autoantibodies. At the same time, protection (passive immunity) is formed in the pregnant woman’s body from chronic infection and autoantibodies circulating in the blood, and indirectly, the fetus is protected from them.

When immunoglobulin is administered, there may be complications in the form of allergic reactions, headaches, and sometimes cold-like symptoms occur (runny nose, etc.). To prevent these complications, it is necessary to check the immune, interferon status by determining the immunoglobulins of the IgG, IgM, and IgA classes in the blood (IgM and IgA antibodies are produced when an infectious agent first enters the body and during an exacerbation of the infectious process, IgG remains in the body after an infection). When IgA levels are low, administering immunoglobulin is dangerous due to possible allergic reactions. In order to prevent such complications, a woman is given antihistamines before the administration of immunoglobulins, after which she is prescribed plenty of fluids, tea, juices, and for symptoms similar to colds, antipyretics. These drugs should not be administered on an empty stomach; the patient should eat food shortly before the procedure.

In recent years, studies have appeared in which infusion therapy with solutions of hydroxyethyl starches (HES), leading to an improvement in blood microcirculation in the vessels, is recognized as one of the promising areas in the treatment of APS. Clinical studies of hydroxyethyl starch solutions of the second generation (INFUKOL-GEC) Many clinics in the Russian Federation have shown their effectiveness and safety.

It is known that thrombosis and ischemia of placental vessels (the appearance of areas where there is no blood circulation) in pregnant women with the presence of APS begins in the early stages of pregnancy, therefore treatment and prevention of placental insufficiency is carried out from the first trimester of pregnancy under control -lem of hemostasis. From 6-8 weeks of pregnancy, a gradual prescription of antiplatelet agents and anticoagulants is used against the background of glucocorticoid therapy (CURANTIL, THEONICOL, ASPIRIN, HEPARIN, FRAXIPARIN). In case of changes in hemostasis (hyperfunction of platelets, etc.) and resistance to antiplatelet agents, a course is prescribed in combination with this therapy INFUCOLA every other day intravenously.

Pregnant women with APS are at risk for developing fetoplacental insufficiency. They require careful monitoring of the state of blood circulation in the placenta, fetal-placental blood flow, which is possible during ultrasonic Dopplerometry. This study is carried out in the 2nd and 3rd trimesters of pregnancy, starting from 16 weeks, with an interval of 4-6 weeks. This makes it possible to timely diagnose the developmental features of the placenta, its condition, impaired blood flow in it, and also evaluate the effectiveness of the therapy, which is important when identifying fetal malnutrition and placental insufficiency.

To prevent fetal pathology, women with APS are prescribed therapy that improves metabolism from early pregnancy. This complex (which cannot be replaced by taking regular multivitamins for pregnant women) includes drugs and vitamins that normalize redox and metabolic processes at the cellular level of the body. During pregnancy, it is recommended to use a course of such therapy 3-4 times lasting 14 days (2 regimens of 7 days each). While taking these medications, multivitamins are discontinued, and between courses it is recommended to continue taking multivitamins.

To prevent placental insufficiency in women with APS, it is also recommended in the second trimester of pregnancy, from 16-18 weeks. AKTOVEGINA orally in the form of tablets or intravenously. If signs of fetal-placental insufficiency appear, drugs such as TROXEVAZIN, ESSENTIALE, LIMONTAR, COGITUM. If there is a suspicion of fetal developmental delay (hypotrophy), a course of special therapy is carried out (INFESOL and other drugs).

The tactics for managing pregnant women with APS, outlined in this article, have been tested in practice and have shown high efficiency: in 90-95% of women, pregnancy ends in a timely and safe manner, provided that the patients complete all the necessary studies and prescriptions.

Newborns in women with APS are examined only if the course of the early neonatal period is complicated (in the maternity hospital). In this case, a study of the immune status is carried out, as well as a hormonal assessment of the child’s condition.

Antiphospholipid syndrome (APS) is a set of clinical and laboratory symptoms caused by the presence in the body of antibodies to phospholipids and phospholipid-binding proteins. Phospholipids are the basis of the cell membrane. Antibodies to them react with these substances and damage cell membranes. As a result, a complex of symptoms develops, including:

• blockage (thrombosis) of veins or arteries;
• miscarriage and other obstetric pathology;
• decreased number of platelets in the blood (thrombocytopenia).

The causes of this condition are unknown. There is some correlation with past infectious diseases. There is a hereditary predisposition to the development of APS. This syndrome may complicate the course of systemic lupus erythematosus or, conversely, precede its development.

Let's talk about how antiphospholipid syndrome and pregnancy are related.

Deep vein thrombosis in a young woman may be a sign of antiphospholipid syndrome.

Quite often, only repeated spontaneous abortions make one suspect this serious disease. Let's look at what symptoms can help diagnose APS before pregnancy. This is necessary to start treatment on time and prevent fetal death.

The most common sign of the disease is. The deep veins of the lower extremities are most often affected. But sometimes the superficial veins, as well as the vessels of the liver, adrenal glands and other organs, are affected. Deep vein thrombosis is accompanied by pain and swelling of the limb, and an increase in its temperature. In this condition, a dangerous complication may develop -. It can manifest itself as a persistent cough, hemoptysis, and shortness of breath. In more severe cases, sharp chest pain, severe shortness of breath, and cyanosis of the skin occur. Pulmonary embolism can lead to the death of the patient.

If a young woman develops a stroke, transient ischemic attack, episodes of severe dizziness, or seizures, it is always necessary to exclude thrombosis of the cerebral arteries caused by APS. In some cases, arterial thrombosis can manifest as migraines or even acute mental disorders.

In patients, the cardiovascular system may be affected. Echocardiography reveals changes in the valves with the formation of growths - vegetations. Signs appear or. The appearance of unmotivated shortness of breath, weakness, edema, and rapid heartbeat in a young woman should also be a reason for an in-depth examination and exclusion of APS.

Skin lesions are quite typical - livedo reticularis, skin ulcers, purpura, redness of the soles and palms (erythema).

A decrease in the number of platelets is detected in the blood of patients. Quite often thrombocytopenia is combined with hemolytic anemia. The tendency to bleed is uncharacteristic and occurs most often with an overdose.

Obstetric pathology in APS

In women, APS can manifest as recurrent miscarriage and spontaneous recurrent spontaneous abortions. After three spontaneous abortions, the risk of early termination of a new pregnancy increases to 45%.

Developmental delay or intrauterine fetal death develops, and phenomena occur. Pregnancy is terminated most often in the second and third trimesters. Without treatment, such a sad outcome is observed in 90–95% of patients. With timely correct therapy, the probability of unfavorable development of pregnancy is up to 30%.

Variants of pregnancy pathology:

• unexplained death of a healthy fetus throughout pregnancy;
• death of a healthy fetus due to preeclampsia, or placental insufficiency before 34 weeks of pregnancy;
• at least three spontaneous abortions before 10 weeks of pregnancy in the absence of chromosomal disorders in the parents, hormonal or anatomical disorders of the genital organs in the mother.

Features of pregnancy

During pregnancy planning, a woman should be thoroughly examined by a rheumatologist, cardiologist and other specialists.

During gestation, monthly ultrasound monitoring of fetal development is necessary. Placental circulation should be assessed using Doppler ultrasound. In the third trimester, it is necessary to regularly conduct cardiotocography so as not to miss the onset of oxygen starvation of the fetus due to placental insufficiency.

Determination of antibodies to phospholipids is carried out at 6 weeks of pregnancy and before the planned birth.

Blood coagulation parameters should be determined regularly, including after childbirth. This will help reduce the risk of thrombotic complications.
If changes indicate increased blood clotting, the dose of heparin received by the patient should be increased.

Heparin, including low molecular weight, requires avoidance of breastfeeding. This is the case when the threat to the health and life of the mother is disproportionately higher than any consequences for the child during artificial feeding.

Treatment of antiphospholipid syndrome during pregnancy

If a woman has been diagnosed with APS before pregnancy, there are no clinical manifestations of the disease, and it is manifested only by laboratory changes, treatment may only include acetylsalicylic acid in a dose of up to 100 mg per day, but the benefits of such therapy have not been definitively established.

Another treatment option for asymptomatic APS is the use of hydroxychloroquine. This drug is especially indicated if a woman has concomitant connective tissue diseases, including systemic lupus erythematosus. If there is a risk of thrombosis in asymptomatic patients (surgery, prolonged immobility), heparin is prescribed in a prophylactic dose.

Important factors in preventing thrombotic complications in asymptomatic patients are smoking cessation and normalization of body weight.

In the absence of pregnancy, the main means of preventing complications of APS is warfarin, which prevents the development of thrombosis. However, it is contraindicated during pregnancy. Its use during this period leads to the development of so-called warfarin embryopathy (damage to the fetus). It manifests itself as a violation of the development of the skeletal system, nasal septum, and neurological disorders.

In women with recurrent miscarriage, treatment with heparin is indicated. Studies have not shown any advantage of low molecular weight heparins over unfractionated heparins. However, low molecular weight heparins are more convenient, but more expensive. Treatment with low molecular weight heparins in combination with low doses of acetylsalicylic acid is prescribed. This therapy increases the chance of pregnancy and the birth of a healthy child by two to three times. The most commonly used drug is Enoxyparin at a dose of 20 mg per day subcutaneously. This drug does not cross the placenta and does not harm the unborn baby.

The use of glucocorticosteroid hormones for this purpose is much less effective. However, many scientists recommend using low doses of glucocorticoids (5-10 mg in terms of prednisolone) in addition to heparin preparations.

Glucocorticosteroids are necessarily used in the development of such complications during pregnancy as catastrophic microangiopathy. At the same time, anticoagulants, plasmapheresis, administration of frozen plasma and human immunoglobulin are prescribed.

Drug therapy is carried out aimed at preventing placental insufficiency.

After childbirth, a woman with APS is prescribed lifelong warfarin therapy.

Veronika Ulanova, director of the Family Source center, talks about how to diagnose and treat antiphospholipid syndrome during pregnancy:

Coagulation defects associated with the presence of "lupus anticoagulants"

Other specified coagulation disorders (D68.8)

Rheumatology

general information

Short description

All-Russian public organization Association of Rheumatologists of Russia

Clinical guidelines "Antiphospholipid syndrome" have undergone public examination, agreed upon and approved on December 17, 2013, at a meeting of the Plenum of the ARR Board, held jointly with the specialized commission of the Ministry of Health of the Russian Federation in the specialty "rheumatology". (President of the ARR, Academician of the Russian Academy of Sciences - E.L. Nasonov)

Antiphospholipid syndrome (APS)- a symptom complex that includes recurrent thrombosis (arterial and/or venous), obstetric pathology (usually fetal loss syndrome) and is associated with the synthesis of antiphospholipid antibodies (aPL): anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA), and/or antibodies to b2-glycoprotein I (anti-b2-GP I). APS is a model of autoimmune thrombosis and is classified as an acquired thrombophilia.

ICD 10 code
D68.8 (in the section other blood coagulation disorders; coagulation defects associated with the presence of “lupus anticoagulants” O00.0 spontaneous during pathological pregnancy)

Diagnostics

Diagnostic criteria

Table 1. Diagnostic criteria for APS

Differential diagnosis

Differential diagnosis of APS depends on the existing clinical manifestations. There are a number of genetically determined and acquired diseases that lead to recurrent pregnancy loss, thromboembolic complications, or both (Table 3).

Table 3. Differential diagnosis of antiphospholipid syndrome

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Treatment

1. Management of patients with arterial and/or venous thrombosis and aPL who do not meet the criterion for reliable APS (serological markers at low levels) does not differ from the management of aPL negative patients with similar thrombotic outcomes ( proof level 1C)
Comments. Data from a systematic review suggest that patients with venous thromboembolism and aPL, even if they do not meet laboratory criteria for the diagnosis of APS, are treated with anticoagulants no different from patients with thrombosis not associated with aPL. Usually, heparins are first prescribed: unfractionated (regular), or low-molecular-weight, or pentasaccharides, followed by a transfer to vitamin K antagonists (VKA) (warfarin).

2. It is recommended that patients with definite APS and first venous thrombosis be prescribed vitamin K antagonists (VKA) with a target international normalized ratio (INR) value of 2.0-3.0 ( level of evidence 1B)
Comments. Two clinical studies showed that high-intensity level (INR>3.0) hypocoagulation was not superior to standard level (INR 2.0-3.0) in preventing recurrent thrombosis and was associated with more frequent hemorrhagic complications. In one of the studies comparing two regimens, high-intensity and standard, it was shown that high intensity of hypocoagulation was associated with a high incidence of bleeding, but also, paradoxically, with more frequent thromboembolic complications, which is apparently associated with frequent fluctuations of INR.

3. Patients with definite APS and arterial thrombosis should receive warfarin with a target INR value of > 3.0 or combined with low doses of aspirin (INR 2.0-3.0). ( Level of evidence not graded due to lack of agreement.) Some panel members believe that only antiplatelet agents (aspirin or clopidogrel) or VKAs with a target INR of 2.0-3.0 would be equally justified in these situations)
Comments. In a retrospective study, it was noted that neither low-dose aspirin nor vitamin K antagonists with standard (moderate-intensive) hypocoagulation were effective for secondary thromboprophylaxis in patients with aPL and arterial thrombosis. Another prospective 2-year study noted no difference in response to either aspirin or anticoagulants in patients with aPL positive and negative strokes. However, this study cannot be extrapolated to the population of patients with stroke and definite APS; aPL levels were examined at the beginning of study entry, which could lead to the inclusion of patients with transiently positive aPL. Differences in the intensity of hypocoagulation have been discussed over the past 10 years. The systemic review concluded: for reliable APS, a high risk of relapse was observed with standard hypocoagulation, recurrence of thrombosis was less common with INR > 3.0. Moreover, death due to hemorrhage was much less common than death due to thrombosis.

4. An assessment of the patient’s risk of bleeding should be performed before prescribing a high degree of hypocoagulation or a combination of anticoagulants and antiplatelet agents

5. Non-SLE patients with one episode of stroke not associated with a cardioembolic mechanism, an aPL profile of low thrombotic risk, and the presence of reversible precipitating factors may separately be considered candidates for antiplatelet agents.

6. Patients with reliable APS and thrombosis should receive long-term (lifelong) antithrombotic therapy ( proof level 1C)

7. For patients with one case of venous thrombosis with a low-risk aPL profile and known transient precipitating factors, anticoagulant therapy can be limited to 3-6 months (Level of evidence not graded)

8. In patients with aPL, but without SLE and without previous thrombosis, a high-risk aPL profile is recommended to take long-term low-dose aspirin, especially in the presence of other risk factors for thrombosis ( level of evidence 2C)
Comments. Primary prophylaxis of thrombosis should be carried out in SLE patients with aPL or with classical cardiovascular risk factors, although the effectiveness of aspirin in these cases is disputed, mainly in patients without SLE

9. For SLE patients with positive VA or persistently positive aCL at moderate or high levels, primary thromboprophylaxis with hydroxychloroquine (HCQ) is recommended ( level of evidence 1B,Some members of the ad hoc committeeb supported a level of evidence of 2B for the use of GC) and low dose aspirin ( level of evidence 2B)
Comments. In addition to its anti-inflammatory effect, HCQ has an antithrombotic effect by inhibiting platelet aggregation and the release of arachidonic acid from activated platelets.

11. Cardiovascular factors should be monitored in all patients with a high-risk aPL profile, regardless of the presence of previous thrombosis, concomitant SLE, or additional APS manifestations (level of evidence not graded)
Comments. Patients with APS often have other additional cardiovascular risk factors such as: hypertension, smoking, hypercholesterolemia, and oral contraceptive use. In a case-control study, the risk of stroke doubled in women with VA who smoked compared with nonsmokers; the use of contraceptives increased the risk of strokes by 7 times. In this study, all women with myocardial infarction were smokers at the time of myocardial infarction.

Obstetric pathology is one of the major aspects of APS and is a criterion sign for the diagnostic criteria of APS. Obstetric pathology of APS includes maternal thrombosis, recurrent spontaneous abortions before 10 weeks of gestation, late undesirable pregnancy outcomes (for example: intrauterine fetal death, preeclampsia, placental insufficiency, intrauterine growth restriction, premature birth). Even with optimal therapy according to current recommendations, adverse outcomes in women with APS still vary between 20-30% of cases.

1. Thromboprophylaxis in asymptomatic aPL-positive women during pregnancy and the postpartum period should be carried out according to a risk-stratified approach. (level of evidence not graded)

2. Hydroxychloroquine is recommended for primary thromboprophylaxis in pregnant asymptomatic aPL-positive women, especially in the setting of connective tissue diseases (level of evidence not graded) (level of evidence not graded).

3. In situations of high risk of thrombosis (perioperative period, prolonged immobilization), prophylactic doses of heparin are recommended for asymptomatic aPL-positive women
Comments. The need for thromboprophylaxis in women with aPL in the absence of a history of thrombotic complications remains controversial among experts. Stopping smoking and reducing body mass index when it is high is one of the important conditions for the prevention of thrombosis in these women. Expert opinion was unanimous about the high risk of thrombosis in this group when taking oral contraceptives. Some experts have suggested combining them with anticoagulants, but the prothrombotic risk may outweigh the positive aspects of contraceptives. Given the risk of adverse effects of anticoagulants, most experts do not agree with the continuation of warfarin in the postpartum period in aPL-positive, but without clinical manifestations of patients. With regard to taking low doses of aspirin, expert opinion is also contradictory. This is based on the conclusions of two randomized studies, where one noted the successful completion of pregnancy in this group of women against the background of low doses of aspirin, the second noted its ineffectiveness in thromboprophylaxis. However, most studies confirm that in aPL the profile of high risk of thrombosis, prophylactic doses of heparin are indicated.

4. Heparins (unfractionated or low molecular weight) with or without low-dose aspirin are recommended for the management of pregnant women with APS (Level of evidence 1c).
Approved by recommendationEULARin the management of pregnant women with SLE and APS. The effectiveness of heparin in women with APS has been proven and much attention has been paid to this in the literature; in fact, it is currently prescribed to pregnant women in whom the cause of the previous loss is unknown. A Cochrane systematic review and meta-analysis concluded that the use of unfractionated heparin and aspirin reduced the rate of pregnancy loss by up to 54% in women with aPL and previous obstetric pathology. There is insufficient information about the superiority of low molecular weight heparins over unfractionated heparin in combination with aspirin. Two small studies have shown the similarity of both heparins in pregnant women with aPL.

5. Secondary prevention of thrombosis in women with APS in the postpartum period is lifelong, with the prescription of vitamin K antagonists and maintaining the level of hypocoagulation from 2.0 to 3.0 for venous thrombosis and above 3.0 for arterial thrombosis. (level of evidence 1B)

6. Catastrophic microangiopathy during pregnancy or the puerperium usually includes effective anticoagulant therapy and IV administration of glucocorticoids (GC) ± plasmapheresis followed by the administration of single-group fresh frozen plasma and IV administration of human immunoglobulin, depending on the clinical situation.

In the postpartum period with resistant forms, there are isolated reports of the effectiveness of genetic engineering therapy (rituximab, complement inhibitors, anti-TNF inhibitors).

Clinical guidelines for catastrophic antiphospholipid syndrome (CAPS).
CAPS is characterized by the involvement of many organs in the pathological process in a short period of time. The histological picture is manifested by the presence of occlusion of small vessels and laboratory markers in the blood are antiphospholipid antibodies (aPL). In terms of pathophysiology, CAPS is a thrombotic microangiopathy characterized by diffuse thrombotic microvasculopathy. And although the incidence of CAPS is 1% of all cases of APS, they usually represent a life-threatening condition in 30-50% of cases with a fatal outcome.

Preliminary classification diagnostic criteria for CAPS with a diagnostic algorithm were developed in 2003. To improve the algorithm and more accurately diagnose CAPS, a step-by-step approach of the CAPS algorithm was developed. This algorithm included a previous history of the presence of APS or constant positivity for aPL, the number of organs involved, the time of outcome, the presence of microthrombosis according to biopsy, and other data that could explain the cause of multiple thromboses.

Evidence-based information is provided by four retrospective studies that analyzed the CAPS registry. The most important conclusions on the treatment of CAPS come down to the following conclusions:
1. A high level of recovery is achieved with a combination of anticoagulants (AC) with GC plus plasma exchange (plasmapheresis (PF) (77.8% versus 55.4% in the absence of such a combination p = 0.083), following anticoagulant therapy plus GC, plus PF and /or IV immunoglobulin (69% versus 54.4% in the absence of such a combination p = 0.089).
2. Isolated use of GCs was associated with low recovery rates (18.2% vs. 58.1% of episodes not treated with GCs).
3. The use of cyclophosphamide (CP) improved the survival of patients with CAPS due to SLE.
4. The mortality rate decreased from 53% in patients with CAPS before 2000 to 33.3% in those who suffered CAPS from 2001 to February 2005 (p = 0.005, odds ratio (OR) 2.25; 95% confidential interval ( CI) 1.27-3.99). The main explanation for this reduction in mortality was the combined use of AA + GC + PF and/or IV immunoglobulin.

Based on the above findings, the inclusion of identification and treatment of any associated risk factors for thrombosis (primarily infections) is recommended in the therapeutic strategy for CAPS, and a combination of AA with GC plus PF and/or intravenous human immunoglobulin is recommended in the treatment of CAPS. When CAPS develops against the background of SLE, intravenous administration of CP may be recommended in the absence of contraindications and, especially, in the presence of other clinical manifestations of SLE.

Data from the CAPS International Register did not provide answers to the controversial and unknown aspects of this APS variant. The first and perhaps most important unknown is why a small number of patients with aPL develop multiple organ failure, called CAPS. In addition, the distribution by age, gender, association with SLE, and aPL profile in patients with classic APS and CAPS is similar. From a pathophysiological point of view, CAPS is a thrombotic microangiopathic condition characterized by diffuse thrombotic microvasculopathy. Similar pathological findings may be present in other conditions such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), malignant hypertension, HELLP syndrome, postpartum renal failure and preeclampsia. Thrombotic microangiopathy, accompanied by the presence of aPL in the blood, is described in all of the above conditions, leading to the concept of “microangiopathic antiphospholipid-associated syndrome” and leading to diagnostic searches. However, the source and pathogenetic potential of aPL in these conditions remains unknown; It is assumed that aPL can cause perturbation and damage to endothelial cells, which leads to a catastrophic outcome. Another important point should be the identification of APS patients at high risk of developing CAPS. Identification and treatment of precipitating factors to prevent the development of catastrophic episodes in patients with aPL is essential. Stopping anticoagulants or a low international normalized ratio (INR) was one such factor in 8% of patients with catastrophic episodes, however, doctors treating patients with APS should be especially careful in clinical situations where anticoagulants should be stopped, such as during surgery. . The debate on this issue continues due to the lack of randomized controlled trials. Questions regarding the most appropriate heparin (fractionated or low molecular weight heparin), the optimal INR value after CAPS, the initial doses of GC and the rate of their reduction, the effective protocol for PF, the types of solutions for plasma exchange, as well as the dose and duration of IV human immunoglobulin are the objects of future research.

The expert commission within the framework of the International Congress on aPL recommended at CAFS:
· Use unfractionated or low molecular weight heparin in therapeutic doses as quickly as possible. After the acute phase, patients with CAPS should continue anticoagulant therapy for life to prevent recurrence of thrombosis. When using VKAs, the level of hypocoagulation remains controversial: moderate-intensive level (INR from 2.0 to 3.0) or high-intensity (above 3.0). Most experts tend to recommend a high degree of hypocoagulation.

· Early connection to GC therapy, but the initial dose is variable.

Autoimmune pathology, which is based on the formation of antibodies to phospholipids, which are the main lipid components of cell membranes. Antiphospholipid syndrome can manifest itself as venous and arterial thrombosis, arterial hypertension, valvular heart defects, obstetric pathology (recurrent miscarriage, intrauterine fetal death, preeclampsia), skin lesions, thrombocytopenia, hemolytic anemia. The main diagnostic markers of antiphospholipid syndrome are antibodies to cardiolipin and lupus anticoagulant. Treatment of antiphospholipid syndrome comes down to the prevention of thrombosis, the prescription of anticoagulants and antiplatelet agents.

General information

Antiphospholipid syndrome (APS) is a complex of disorders caused by an autoimmune reaction to phospholipid structures present on cell membranes. The disease was described in detail by the English rheumatologist Hughes in 1986. There are no data on the true prevalence of antiphospholipid syndrome; It is known that insignificant levels of antibodies to phospholipids in blood serum are found in 2-4% of practically healthy individuals, and high titers - in 0.2%. Antiphospholipid syndrome is diagnosed 5 times more often among young women (20-40 years), although men and children (including newborns) can suffer from the disease. As a multidisciplinary problem, antiphospholipid syndrome (APS) attracts the attention of specialists in the field of rheumatology, obstetrics and gynecology, and cardiology.

Causes

The underlying causes of antiphospholipid syndrome are unknown. Meanwhile, factors predisposing to increased levels of antibodies to phospholipids have been studied and identified. Thus, a transient increase in antiphospholipid antibodies is observed against the background of viral and bacterial infections (hepatitis C, HIV, infectious mononucleosis, malaria, infective endocarditis, etc.). High titers of antibodies to phospholipids are found in patients with systemic lupus erythematosus, rheumatoid arthritis, Sjögren's disease, periarteritis nodosa, and autoimmune thrombocytopenic purpura.

Overproduction of antiphospholipid antibodies can occur with malignant neoplasms, taking medications (psychotropic drugs, hormonal contraceptives, etc.), and discontinuation of anticoagulants. There is information about a genetic predisposition to increased synthesis of antibodies to phospholipids in individuals who carry the HLA DR4, DR7, DRw53 antigens and in relatives of patients with antiphospholipid syndrome. In general, the immunobiological mechanisms of the development of antiphospholipid syndrome require further study and clarification.

Depending on the structure and immunogenicity, “neutral” (phosphatidylcholine, phosphatidylethanolamine) and “negatively charged” (cardiolipin, phosphatidylserine, phosphatidylinositol) phospholipids are distinguished. The class of antiphospholipid antibodies that react with phospholipids includes lupus anticoagulant, antibodies to cardiolipin, beta2-glycoprotein-1-cofactor-dependent antiphospholipids, etc. By interacting with phospholipids of the membranes of vascular endothelial cells, platelets, neutrophils, antibodies cause hemostasis disturbances, expressed in the tendency to hypercoagulation.

Classification

Taking into account the etiopathogenesis and course, the following clinical and laboratory variants of antiphospholipid syndrome are distinguished:

• primary– there is no connection with any underlying disease that can induce the formation of antiphospholipid antibodies;
• secondary- antiphospholipid syndrome develops against the background of another autoimmune pathology;
• catastrophic– acute coagulopathy, occurring with multiple thromboses of internal organs;
• AFL-negative a variant of antiphospholipid syndrome, in which serological markers of the disease (Abs to cardiolipin and lupus anticoagulant) are not detected.

Symptoms of antiphospholipid syndrome

According to modern views, antiphospholipid syndrome is an autoimmune thrombotic vasculopathy. In APS, damage can affect vessels of various sizes and locations (capillaries, large venous and arterial trunks), which causes an extremely diverse range of clinical manifestations, including venous and arterial thrombosis, obstetric pathology, neurological, cardiovascular, skin disorders, thrombocytopenia.

The most common and typical sign of antiphospholipid syndrome is recurrent venous thrombosis: thrombosis of the superficial and deep veins of the lower extremities, hepatic veins, portal vein of the liver, retinal veins. Patients with antiphospholipid syndrome may experience recurrent episodes of pulmonary embolism, pulmonary hypertension, superior vena cava syndrome, Budd-Chiari syndrome, and adrenal insufficiency. Venous thrombosis in antiphospholipid syndrome develops 2 times more often than arterial thrombosis. Among the latter, thrombosis of the cerebral arteries predominates, leading to transient ischemic attacks and ischemic stroke. Other neurological disorders may include migraine, hyperkinesis, seizure syndrome, sensorineural hearing loss, ischemic optic neuropathy, transverse myelitis, dementia, and mental disorders.

Damage to the cardiovascular system in antiphospholipid syndrome is accompanied by the development of myocardial infarction, intracardiac thrombosis, ischemic cardiomyopathy, and arterial hypertension. Quite often, damage to the heart valves is observed - from minor regurgitation, detected by echocardiography, to mitral, aortic, tricuspid stenosis or insufficiency. As part of the diagnosis of antiphospholipid syndrome with cardiac manifestations, differential diagnosis with infective endocarditis and cardiac myxoma is required.

Renal manifestations may include both mild proteinuria and acute renal failure. On the part of the gastrointestinal tract, antiphospholipid syndrome causes hepatomegaly, gastrointestinal bleeding, occlusion of mesenteric vessels, portal hypertension, and splenic infarction. Typical lesions of the skin and soft tissues are represented by livedo reticularis, palmar and plantar erythema, trophic ulcers, gangrene of the fingers; musculoskeletal system - aseptic necrosis of bones (femoral head). Hematological signs of antiphospholipid syndrome are thrombocytopenia, hemolytic anemia, and hemorrhagic complications.

In women, APS is often detected in connection with obstetric pathology: repeated spontaneous abortion at various times, intrauterine growth retardation, placental insufficiency, gestosis, chronic fetal hypoxia, premature birth. When managing pregnancy in women with antiphospholipid syndrome, the obstetrician-gynecologist must take into account all possible risks.

Diagnostics

Antiphospholipid syndrome is diagnosed based on clinical (vascular thrombosis, complicated obstetric history) and laboratory data. The main immunological criteria include the detection of medium or high titers of antibodies to cardiolipin of the IgG/IgM class and lupus anticoagulant in the blood plasma twice within six weeks. The diagnosis is considered reliable when at least one main clinical and laboratory criterion is combined. Additional laboratory signs of antiphospholipid syndrome are false-positive RW, positive Coombs test, increased titer of antinuclear factor, rheumatoid factor, cryoglobulins, and antibodies to DNA. A study of CBC, platelets, biochemical blood test, and coagulogram is also indicated.

Pregnant women with antiphospholipid syndrome need monitoring of blood coagulation parameters, dynamic ultrasound of the fetus and

Treatment of antiphospholipid syndrome

The main goal of treatment for antiphospholipid syndrome is to prevent thromboembolic complications. Regular moments include moderate physical activity, avoidance of long periods of immobility, participation in traumatic sports and long air travel. Women with antiphospholipid syndrome should not be prescribed oral contraceptives, and should always consult an obstetrician-gynecologist before planning pregnancy. Pregnant patients are advised to take small doses of glucocorticoids and antiplatelet agents, administration of immunoglobulin, and heparin injections under the control of hemostasiogram parameters throughout the entire gestation period.

Drug therapy for antiphospholipid syndrome may include the prescription of indirect anticoagulants (warfarin), direct anticoagulants (heparin, nadroparin calcium, enoxaparin sodium), antiplatelet agents (acetylsalicylic acid, dipyridamole, pentoxifylline). Preventive anticoagulant or antiplatelet therapy for most patients with antiphospholipid syndrome is carried out for a long time, and sometimes for life. In the catastrophic form of antiphospholipid syndrome, the administration of high doses of glucocorticoids and anticoagulants, sessions, transfusion of fresh frozen plasma, etc. is indicated.

Forecast

Timely diagnosis and preventive therapy help avoid the development and recurrence of thrombosis, as well as hope for a favorable outcome of pregnancy and childbirth. In case of secondary antiphospholipid syndrome, it is important to monitor the course of the underlying pathology and prevent infections. Unfavorable prognostic factors are the combination of antiphospholipid syndrome with SLE, thrombocytopenia, a rapid increase in the antibody titer to cardiolipin, and persistent arterial hypertension. All patients diagnosed with antiphospholipid syndrome should be under the supervision of a rheumatologist with periodic monitoring of serological markers of the disease and hemostasiogram parameters.