Can antiphospholipid syndrome be cured? Is APS a permanent disease or a temporary condition of the body? What causes APS during pregnancy?

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Antiphospholipid syndrome (APS), or antiphospholipid antibody syndrome (SAFA), is a clinical and laboratory syndrome, the main manifestations of which are the formation of blood clots (thrombosis) in the veins and arteries of various organs and tissues, as well as the pathology of pregnancy. The specific clinical manifestations of antiphospholipid syndrome depend on which particular organ’s vessels are clogged with blood clots. In an organ affected by thrombosis, heart attacks, strokes, tissue necrosis, gangrene, etc. can develop. Unfortunately, today there are no uniform standards for the prevention and treatment of antiphospholipid syndrome due to the fact that there is no clear understanding of the causes of the disease, and there are no laboratory and clinical signs, allowing high degree reliability to judge the risk of relapse. That is why the current treatment of antiphospholipid syndrome is aimed at reducing the activity of the blood coagulation system in order to reduce the risk of repeated thrombosis of organs and tissues. This treatment is based on the use of anticoagulant drugs (Heparins, Warfarin) and antiplatelet agents (Aspirin, etc.), which help prevent repeated thrombosis of various organs and tissues against the background of the disease. Anticoagulants and antiplatelet agents are usually taken for life, since such therapy only prevents thrombosis, but does not cure the disease, thus allowing one to prolong life and maintain its quality at an acceptable level.

Antiphospholipid syndrome - what is it?

Antiphospholipid syndrome is non-inflammatory autoimmune disease with a unique set of clinical and laboratory signs, which is based on the formation of antibodies to certain types of phospholipids, which are structural components of platelet and cell membranes blood vessels And nerve cells. Such antibodies are called antiphospholipid antibodies, and are produced by the body’s own immune system, which mistakes the body’s own structures for foreign ones and seeks to destroy them. It is precisely because the pathogenesis of antiphospholipid syndrome is based on the production of antibodies by the immune system against the structures of the body’s own cells that the disease belongs to the group of autoimmune diseases.

The immune system can produce antibodies to various phospholipids, such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI), cardiolipin (diphosphatidylglycerol), phosphatidylglycerol, beta-2-glycoprotein 1, which are contained in membranes of platelets, cells of the nervous system and blood vessels. Antiphospholipid antibodies “recognize” the phospholipids against which they were produced and attach to them, forming large complexes on cell membranes that activate the blood coagulation system. Antibodies attached to cell membranes act as a kind of irritant for the coagulation system, since they imitate trouble in the vascular wall or on the surface of platelets, which causes activation of the blood or platelet coagulation process, as the body seeks to eliminate the defect in the vessel, to “fix” it. This activation of the coagulation system or platelets leads to the formation of numerous blood clots in the vessels of various organs and systems. Further clinical manifestations of antiphospholipid syndrome depend on which particular organ’s vessels are clogged with blood clots.

Antiphospholipid antibodies in antiphospholipid syndrome are a laboratory sign of the disease and are determined, accordingly, by laboratory methods in blood serum. Some antibodies are determined qualitatively (that is, they establish only the fact whether they are present in the blood or not), others are determined quantitatively (they determine their concentration in the blood).

Antiphospholipid antibodies, which are detected using laboratory tests in blood serum, include the following:

• Lupus anticoagulant. This laboratory indicator is quantitative, that is, the concentration of lupus anticoagulant in the blood is determined. Normally, in healthy people, a lupus anticoagulant may be present in the blood at a concentration of 0.8 - 1.2 a.u. Increasing the indicator above 2.0 c.u. is a sign of antiphospholipid syndrome. The lupus anticoagulant itself is not a separate substance, but is a combination of antiphospholipid antibodies of the IgG and IgM classes to various phospholipids of vascular cells.
• Antibodies to cardiolipin (IgA, IgM, IgG). This indicator is quantitative. In antiphospholipid syndrome, the level of antibodies to cardiolipin in the blood serum is more than 12 U/ml, and normally in a healthy person these antibodies may be present in a concentration of less than 12 U/ml.
• Antibodies to beta-2-glycoprotein (IgA, IgM, IgG). This indicator is quantitative. With antiphospholipid syndrome, the level of antibodies to beta-2-glycoprotein increases by more than 10 U/ml, and normally in a healthy person these antibodies may be present in a concentration of less than 10 U/ml.
• Antibodies to various phospholipids(cardiolipin, cholesterol, phosphatidylcholine). This indicator is qualitative and is determined using the Wasserman reaction. If the Wasserman reaction gives a positive result in the absence of syphilis, then this is a diagnostic sign of antiphospholipid syndrome.

However, despite the wide range of clinical signs of antiphospholipid syndrome, doctors identify the leading symptoms of the disease, which are always present in any person suffering from this pathology. The leading symptoms of antiphospholipid syndrome include venous or arterial thrombosis, pathology of pregnancy(miscarriage, recurrent miscarriages, placental abruption, intrauterine fetal death, etc.) and thrombocytopenia ( low level platelets in the blood). All other manifestations of antiphospholipid syndrome are combined into topical syndromes (neurological, hematological, skin, cardiovascular, etc.) depending on the affected organ.

The most common developments are deep vein thrombosis of the leg, pulmonary embolism, stroke (cerebral vascular thrombosis) and myocardial infarction (vascular thrombosis of the heart muscle). Thrombosis of the veins of the extremities is manifested by pain, swelling, redness of the skin, ulcers on the skin, as well as gangrene in the area of ​​​​clogged vessels. Pulmonary embolism, heart attack and stroke are life-threatening conditions that manifest sharp deterioration condition.

In addition, thrombosis can develop in any veins and arteries, as a result of which in people suffering from antiphospholipid syndrome, the skin is often affected (trophic ulcers, rash-like rashes, as well as blue-violet uneven coloration of the skin) and cerebral circulation is impaired (memory deteriorates , headaches appear, dementia develops). If a woman suffering from antiphospholipid syndrome becomes pregnant, then in 90% of cases it is interrupted due to thrombosis of the placental vessels. With antiphospholipid syndrome, the following pregnancy complications are observed: spontaneous abortion, intrauterine fetal death, premature detachment placenta, premature birth, HELLP syndrome, preeclampsia and eclampsia.

There are two main types of antiphospholipid syndrome – primary and secondary. Secondary antiphospholipid syndrome always develops against the background of some other autoimmune (for example, systemic lupus erythematosus, scleroderma), rheumatic (rheumatoid arthritis, etc.), oncological (malignant tumors of any localization) or infectious disease (AIDS, syphilis, hepatitis C, etc. .d.), or after taking medications (oral contraceptives, psychotropic drugs, Isoniazid, etc.). Primary antiphospholipid syndrome develops in the absence of other diseases, and its exact causes are currently unknown. However, it is assumed that hereditary predisposition, severe chronic long-term infections (AIDS, hepatitis, etc.) and the use of certain medications (Phenytoin, Hydralazine, etc.) play a role in the development of primary antiphospholipid syndrome.

Accordingly, the cause of secondary antiphospholipid syndrome is a person’s existing disease, which provoked an increase in the concentration of antiphospholipid antibodies in the blood with the subsequent development of pathology. And the causes of primary antiphospholipid syndrome are unknown.

Despite the lack of knowledge about the exact causes of antiphospholipid syndrome, doctors and scientists have identified a number of factors that can be attributed to predisposing to the development of APS. That is, conditionally, these predisposing factors can be considered the causes of antiphospholipid syndrome.

Currently, predisposing factors for antiphospholipid syndrome include the following:

• Genetic predisposition;
• Bacterial or viral infections (staphylococcal and streptococcal infections, tuberculosis, AIDS, cytomegalovirus infection, Epstein-Barr viruses, hepatitis B and C, infectious mononucleosis, etc.);
• Autoimmune diseases (systemic lupus erythematosus, systemic scleroderma, periarteritis nodosa, autoimmune thrombocytopenic purpura, etc.);
• Rheumatic diseases (rheumatoid arthritis, etc.);
• Oncological diseases (malignant tumors of any location);
• Some diseases of the central nervous system;
• Long-term use of certain medications (oral contraceptives, psychotropic drugs, interferons, Hydralazine, Isoniazid).

Antiphospholipid syndrome - signs (symptoms, clinic)

If thrombosis affects small vessels, this leads to mild disruption of the functioning of the organ in which the clogged veins and arteries are located. For example, when small vessels of the myocardium are blocked, individual small areas of the heart muscle lose the ability to contract, which causes their dystrophy, but does not provoke a heart attack or other severe damage. But if thrombosis affects the lumen of the main trunks coronary vessels, then a heart attack will occur.

With thrombosis of small vessels, symptoms appear slowly, but the degree of dysfunction of the affected organ steadily progresses. In this case, the symptoms usually resemble some chronic illness, for example, liver cirrhosis, Alzheimer's disease, etc. This is the course of the usual types of antiphospholipid syndrome. But with thrombosis of large vessels, a sharp disruption of the organ’s functioning occurs, which causes a catastrophic course of antiphospholipid syndrome with multiple organ failure, disseminated intravascular coagulation syndrome and other serious life-threatening conditions.

Since thrombosis can affect the vessels of any organ and tissue, manifestations of antiphospholipid syndrome in the central nervous system, cardiovascular system, liver, kidneys, gastrointestinal tract, skin, etc. are currently described. Thrombosis of placental vessels during pregnancy provokes obstetric pathology ( miscarriages, premature birth, placental abruption, etc.). Let us consider the symptoms of antiphospholipid syndrome from various organs.

Firstly, you need to know that thrombosis in APS can be venous and arterial. With venous thrombosis, the blood clots are localized in the veins, and with arterial thrombosis, respectively, in the arteries. Characteristic feature antiphospholipid syndrome are recurrent thrombosis. That is, if treatment is not carried out, then episodes of thrombosis of various organs will be repeated again and again, until failure of any organ occurs, incompatible with life. APS also has one more feature - if the first thrombosis was venous, then all subsequent episodes of thrombosis are also, as a rule, venous. Accordingly, if the first thrombosis was arterial, then all subsequent ones will also involve the arteries.

Most often with APS, venous thrombosis of various organs develops. In this case, blood clots are most often localized in the deep veins lower limbs, and somewhat less frequently - in the veins of the kidneys and liver. Deep vein thrombosis of the legs is manifested by pain, swelling, redness, gangrene or ulcers on the affected limb. Blood clots from the veins of the lower extremities can break off from the walls of blood vessels and reach the pulmonary artery with the blood flow, causing life-threatening complications - pulmonary embolism, pulmonary hypertension, hemorrhages in the lungs. With thrombosis of the inferior or superior vena cava, the syndrome of the corresponding vein develops. Thrombosis of the adrenal vein leads to hemorrhage and necrosis of adrenal tissue and the development of subsequent insufficiency.

Thrombosis of the veins of the kidneys and liver leads to the development of nephrotic syndrome and Budd-Chiari syndrome. Nephrotic syndrome is manifested by the presence of protein in the urine, edema and impaired lipid and protein metabolism. Budd-Chiari syndrome is manifested by obliterating phlebitis and thrombophlebitis of the liver veins, as well as a marked increase in the size of the liver and spleen, ascites, increasing hepatocellular failure over time and sometimes hypokalemia (low potassium levels in the blood) and hypocholesterolemia (low cholesterol levels in the blood).

In APS, thrombosis affects not only the veins, but also the arteries. Moreover, arterial thrombosis develops approximately twice as often as venous thrombosis. Such arterial thromboses are more severe in course compared to venous ones, since they manifest themselves as infarctions or hypoxia of the brain or heart, as well as disorders of peripheral blood flow (blood circulation in the skin, limbs). The most common is thrombosis of intracerebral arteries, which results in strokes, heart attacks, hypoxia and other damage to the central nervous system. Thrombosis of the arteries of the extremities leads to gangrene, aseptic necrosis of the head femur. Thrombosis of large arteries develops relatively rarely - abdominal aorta, ascending aorta, etc.

Damage to the nervous system is one of the most severe manifestations of antiphospholipid syndrome. Caused by thrombosis of cerebral arteries. Manifested by transient ischemic attacks, ischemic strokes, ischemic encephalopathy, convulsions, migraines, chorea, transverse myelitis, sensorineural hearing loss and a number of other neurological or psychiatric symptoms. Sometimes the neurological symptoms of cerebral thrombosis in APS resemble clinical picture multiple sclerosis. In some cases, cerebral thrombosis causes temporary blindness or neuropathy optic nerve.

Transient ischemic attacks are manifested by loss of vision, paresthesia (pins and needles sensation, numbness), motor weakness, dizziness and general amnesia. Often, transient ischemic attacks precede a stroke, appearing several weeks or months before it. Frequent ischemic attacks lead to the development of dementia, memory loss, deterioration of attention and other mental disorders that are similar to Alzheimer's disease or toxic brain damage.

Recurrent microstrokes in APS often occur without clear and noticeable symptoms, and can manifest themselves after some time as seizures and the development of dementia.

Headaches are also one of the most common manifestations of antiphospholipid syndrome when thrombosis is localized in intracerebral arteries. In this case, headaches can have a different character - from migraine to constant.

In addition, a variant of central nervous system damage in APS is Sneddon syndrome, which is manifested by a combination of arterial hypertension, livedo reticularis (blue-violet mesh on the skin) and cerebral vascular thrombosis.

Heart damage in antiphospholipid syndrome manifests itself in a wide range of different nosologies, including infarction, valvular disease, chronic ischemic cardiomyopathy, intracardiac thrombosis, high blood pressure and pulmonary hypertension. In rare cases, thrombosis in APS causes manifestations similar to myxoma (heart tumor). Myocardial infarction develops in approximately 5% of patients with antiphospholipid syndrome, and, as a rule, in men under 50 years of age. Most often, with APS, damage to the heart valves occurs, the severity of which varies from minimal disorders (thickening of the valve leaflets, backflow of some blood) to defects (stenosis, heart valve insufficiency).

Despite the fact that damage to the cardiovascular system in APS develops frequently, it rarely leads to heart failure and severe consequences requiring surgery.

Renal vascular thrombosis leads to various disorders of the functioning of this organ. Thus, the most common symptom of APS is proteinuria (protein in the urine), which is not accompanied by any other symptoms. Also, with APS, the development of renal failure with arterial hypertension is possible. Any disturbances in kidney function in APS are caused by microthrombosis of the glomerular vessels, which causes glomerulosclerosis (replacement of kidney tissue with scar). Microthrombosis of the glomerular vessels of the kidneys is designated by the term “renal thrombotic microangiopathy.”

Thrombosis of liver vessels in APS leads to the development of Budd-Chiari syndrome, liver infarction, ascites (fluid effusion in abdominal cavity), increased activity of AST and ALT in the blood, as well as an increase in the size of the liver due to its hyperplasia and portal hypertension (increased pressure in the portal vein system of the liver).

With APS, in approximately 20% of cases, specific skin lesion due to thrombosis of small vessels and peripheral circulation disorders. Livedo reticularis appears on the skin ( vascular network blue-violet color, localized on the legs, feet, hands, thighs, and clearly visible when cooling), ulcers, gangrene of the fingers and toes develops, as well as multiple hemorrhages in the nail bed, which in appearance resemble a “splinter”. Also, sometimes a rash appears on the skin in the form of pinpoint hemorrhages, which in appearance resembles vasculitis.

Another common manifestation of antiphospholipid syndrome is obstetric pathology, which occurs in 80% of pregnant women suffering from APS. As a rule, APS causes pregnancy loss (miscarriage, frozen pregnancy, premature birth), intrauterine growth retardation, as well as gestosis, preeclampsia and eclampsia.

Relatively rare manifestations of APS are lung complications, such as thrombotic pulmonary hypertension (increased blood pressure in the lungs), pulmonary hemorrhages and capillaritis. Thrombosis of the pulmonary veins and arteries can lead to “shock” lung, a life-critical condition that requires immediate medical intervention.

Also rarely with APS, gastrointestinal bleeding, splenic infarction, thrombosis of the mesenteric vessels of the intestine and aseptic necrosis head of the femur.

With APS, there is almost always thrombocytopenia (the number of platelets in the blood is lower than normal), in which the platelet count ranges from 70 to 100 G/L. This thrombocytopenia does not require treatment. In approximately 10% of cases with APS, Coombs-positive hemolytic anemia or Evans syndrome (a combination of hemolytic anemia and thrombocytopenia) develops.

Symptoms of catastrophic antiphospholipid syndrome

Antiphospholipid syndrome in men, women and children

Antiphospholipid syndrome and pregnancy

What causes APS during pregnancy?

It has now been proven that antiphospholipid syndrome can cause the following obstetric complications:

• Infertility of unknown origin;
• IVF failures;
• Miscarriages in early and late pregnancy;
• Frozen pregnancy;
• Intrauterine fetal death;
• Premature birth;
• Stillbirth;
• Fetal malformations;
• Fetal growth retardation;
• Preeclampsia;
• Eclampsia and preeclampsia;
• Premature placental abruption;
• Thrombosis and thromboembolism.

After pregnancy occurs, the doctor chooses one of the recommended tactics, based on the concentration of antiphospholipid antibodies in the blood and the presence of thrombosis or pregnancy complications in the past. In general, the gold standard for pregnancy management in women with APS is the use of low molecular weight heparins (Clexane, Fraxiparine, Fragmin), as well as Aspirin in low dosages. Glucocorticoid hormones (Dexamethasone, Metipred) are currently not recommended for use in pregnancy management with APS, since they have a minor therapeutic effect, but significantly increase the risk of complications for both the woman and the fetus. The only situations when the use of glucocorticoid hormones is justified is the presence of another autoimmune disease (for example, systemic lupus erythematosus), the activity of which must be constantly suppressed.

• Antiphospholipid syndrome, in which a woman has elevated levels of antiphospholipid antibodies and lupus anticoagulant in her blood, but there has been no history of thrombosis or episodes of early pregnancy loss (for example, miscarriages, missed pregnancies before 10–12 weeks). In this case, during the entire pregnancy (before childbirth), it is recommended to take only Aspirin 75 mg per day.
• Antiphospholipid syndrome, in which a woman has elevated levels of antiphospholipid antibodies and lupus anticoagulant in her blood; there have been no thromboses in the past, but there have been episodes of early pregnancy loss (miscarriages up to 10 - 12 weeks). In this case, throughout pregnancy until childbirth, it is recommended to take Aspirin 75 mg per day, or a combination of Aspirin 75 mg per day + low molecular weight heparin preparations (Clexane, Fraxiparin, Fragmin). Clexane is administered subcutaneously at 5000 - 7000 IU every 12 hours, and Fraxiparine and Fragmin - 0.4 mg once a day.
• Antiphospholipid syndrome, in which a woman has elevated levels of antiphospholipid antibodies and lupus anticoagulant in her blood; there have been no thromboses in the past, but there have been episodes of early pregnancy loss (miscarriages up to 10 - 12 weeks) or intrauterine fetal death, or premature birth due to gestosis or placental insufficiency. In this case, throughout pregnancy, until childbirth, low doses of Aspirin (75 mg per day) + low molecular weight heparin preparations (Clexane, Fraxiparine, Fragmin) should be used. Clexane is administered subcutaneously at 5,000–7,000 IU every 12 hours, and Fraxiparine and Fragmin at 7,500–10,000 IU every 12 hours in the first trimester (up to the 12th week inclusive), and then 10,000 IU every 8–12 hours during second and third trimesters.
• Antiphospholipid syndrome, in which a woman has elevated levels of antiphospholipid antibodies and lupus anticoagulant in her blood, and has had thrombosis and episodes of pregnancy loss at any stage in the past. In this case, low doses of Aspirin (75 mg per day) + low molecular weight heparin preparations (Clexane, Fraxiparin, Fragmin) should be used throughout pregnancy until delivery. Clexane is administered subcutaneously at 5000–7000 IU every 12 hours, and Fraxiparine and Fragmin at 7500–10000 IU every 8–12 hours.

Thus, all women with APS receiving heparins and Aspirin during pregnancy are recommended to administer immunoglobulin prophylactically intravenously at 0.4 g per 1 kg of body weight for five days at the beginning of each month, until childbirth. Immunoglobulin prevents the activation of chronic and the addition of new infections. It is also recommended that women receiving heparin take calcium and vitamin D supplements throughout pregnancy to prevent the development of osteoporosis.

The use of Aspirin is stopped at the 37th week of pregnancy, and heparins are administered until the start of regular pregnancy. labor activity, if childbirth is carried out through natural means. If a planned cesarean section is scheduled, then Aspirin is canceled 10 days, and heparins one day before the date of surgery. If heparins were used before the onset of labor, then such women should not be given epidural anesthesia.

After delivery, treatment carried out during pregnancy is continued for another 1 - 1.5 months. Moreover, they resume using Aspirin and heparins 6–12 hours after birth. Additionally, after childbirth, measures are taken to prevent thrombosis, for which it is recommended to get out of bed as early as possible and move actively, as well as bandage your legs with elastic bandages or put on compression stockings.

After 6 weeks of using heparins and Aspirin after childbirth, further treatment of antiphospholipid syndrome is carried out by a rheumatologist, whose competence is the identification and treatment of this disease. 6 weeks after birth, the rheumatologist stops heparins and aspirin, and prescribes the treatment already necessary for later life.

In some regions of Russia, the practice of prescribing Wobenzym to pregnant women with APS is widespread.

Antiphospholipid syndrome (APS) is one of the most pressing multidisciplinary problems modern medicine and is considered a unique model of autoimmune thrombotic vasculopathy.

The study of APS began about a hundred years ago in the works of A. Wassermann, dedicated to laboratory method diagnosis of syphilis. During screening studies, it became obvious that positive reaction Wasserman's infection can be found in many people without clinical signs of syphilitic infection. This phenomenon is called the “biological false-positive Wasserman reaction.” It was soon established that the main antigenic component in the Wassermann reaction was a negatively charged phospholipid called cardiolipin. The introduction of radioimmunological and then enzyme-linked immunosorbent method (IEM) for the determination of antibodies to cardiolipins (aCL) contributed to a deeper understanding of their role in human diseases. According to modern concepts, antiphospholipid antibodies (aPL) are a heterogeneous population of autoantibodies that interact with negatively charged, less often neutral phospholipids and/or phospholipid-binding serum proteins. Depending on the method of determination, aPL are conventionally divided into three groups: detected using IFM using cardiolipin, less often other phospholipids; antibodies detected by functional tests (lupus anticoagulant); antibodies that are not diagnosed using standard methods (antibodies to protein C, S, thrombomodulin, heparan sulfate, endothelium, etc.).

A consequence of close interest in studying the role of aPL and improving methods laboratory diagnostics it was concluded that aPL are a serological marker of a unique symptom complex, including venous and/or arterial thrombosis, various shapes obstetric pathology, thrombocytopenia, as well as a wide range of neurological, skin, and cardiovascular disorders. Since 1986, this symptom complex began to be designated as antiphospholipid syndrome (APS), and in 1994, at an international symposium on aPL, it was also proposed to use the term “Hughes syndrome” - after the name of the English rheumatologist who made the greatest contribution to the study of this problem.

The true prevalence of APS in the population is still unknown. Since the synthesis of aPL is possible and normal, low levels of antibodies are often found in the blood of healthy people. According to various data, the frequency of detection of aCL in the population varies from 0 to 14%, on average it is 2-4%, while high titers are found quite rarely - in approximately 0.2% of donors. APL is detected somewhat more often in elderly people. However, the clinical significance of aPL in “healthy” individuals (i.e., those without obvious symptoms of the disease) is not entirely clear. Often, with repeated tests, the level of antibodies elevated in previous determinations normalizes.

An increase in the incidence of aPL was noted in some inflammatory, autoimmune and infectious diseases, malignant neoplasms, and while taking medications (oral contraceptives, psychotropic drugs, etc.). There is evidence of an immunogenetic predisposition to increased synthesis of aPL and their more frequent detection in relatives of patients with APS.

It has been proven that aPL is not only a serological marker, but also an important “pathogenetic” mediator, developmental main clinical manifestations of APS. Antiphospholipid antibodies have the ability to influence most of the processes that form the basis of the regulation of hemostasis, the violation of which leads to hypercoagulation. Clinical significance aPL depends on whether their presence in the blood serum is associated with the development characteristic symptoms. Thus, manifestations of APS are observed only in 30% of patients with a positive lupus anticoagulant and in 30-50% of patients with moderate or high levels of aCL. The disease develops mainly at a young age, while APS can be diagnosed in children and even newborns. Like other autoimmune rheumatic diseases, this symptom complex is more common in women than in men (5:1 ratio).

Clinical manifestations

The most common and characteristic manifestations of APS are venous and/or arterial thrombosis and obstetric pathology. With APS, vessels of any size and location can be affected - from capillaries to large venous and arterial trunks. Therefore, the range of clinical manifestations is extremely diverse and depends on the location of thrombosis. According to modern concepts, the basis of APS is a kind of vasculopathy caused by non-inflammatory and/or thrombotic damage to blood vessels and ending with their occlusion. Within the framework of APS, pathology of the central nervous system, cardiovascular system, impaired renal function, liver, endocrine organs, gastrointestinal tract. The development of certain forms of obstetric pathology tends to be associated with placental vascular thrombosis ( ).

Venous thrombosis, especially deep vein thrombosis of the lower extremities, is the most typical manifestation of APS, including at the onset of the disease. Thrombi are usually localized in the deep veins of the lower extremities, but can often occur in the hepatic, portal, superficial and other veins. Repeated pulmonary embolisms are typical, which can lead to the development of pulmonary hypertension. Cases of the development of adrenal insufficiency due to thrombosis of the central vein of the adrenal glands have been described. In general, arterial thrombosis occurs approximately 2 times less frequently than venous thrombosis. They are manifested by ischemia and infarctions of the brain, coronary arteries, and peripheral circulatory disorders. Thrombosis of intracerebral arteries is the most common site of arterial thrombosis in APS. Rare manifestations include thrombosis of large arteries, as well as the ascending aorta (with the development of aortic arch syndrome) and the abdominal aorta. A feature of APS is the high risk of recurrent thrombosis. Moreover, in patients with the first thrombosis in the arterial bed, repeated episodes also develop in the arteries. If the first thrombosis was venous, then repeated thromboses, as a rule, are observed in the venous bed.

Damage to the nervous system is one of the most severe (potentially fatal) manifestations of APS and includes transient ischemic attacks, ischemic stroke, acute ischemic encephalopathy, episyndrome, migraine, chorea, transverse myelitis, sensorineural hearing loss and other neurological and psychiatric symptoms. The leading cause of central nervous system damage is cerebral ischemia due to thrombosis of cerebral arteries, but there are a number of neurological and neuropsychiatric manifestations caused by other mechanisms. Transient ischemic attacks (TIA) are accompanied by loss of vision, paresthesia, motor weakness, dizziness, transient general amnesia and often precede a stroke by many weeks and even months. Recurrent TIA leads to multi-infarct dementia, which is manifested by cognitive impairment, decreased ability to concentrate and memory, and other symptoms nonspecific to APS. Therefore, it is often difficult to differentiate from senile dementia, metabolic (or toxic) brain damage and Alzheimer's disease. Sometimes cerebral ischemia is associated with thromboembolism, the sources of which are the valves and cavities of the heart or internal carotid artery. In general, the incidence of ischemic stroke is higher in patients with damage to the heart valves (especially the left side).

Headaches are traditionally considered one of the most common clinical manifestations of APS. The nature of headaches varies from classic intermittent migraine to constant, unbearable pain. There are a number of other symptoms (Guillain-Barré syndrome, idiopathic intracranial hypertension, transverse myelitis, parkinsonian hypertonicity), the development of which is also associated with the synthesis of aPL. Patients with APS often have veno-occlusive eye diseases. One of the forms of such pathology is transient loss of vision (amaurosis fugax). Another manifestation - optic neuropathy is one of the most common reasons blindness in APS.

Heart damage is represented by a wide range of manifestations, including myocardial infarction, damage to the valvular apparatus of the heart, chronic ischemic cardiomyopathy, intracardiac thrombosis, arterial and pulmonary hypertension. In both adults and children, coronary artery thrombosis is one of the main localizations of arterial occlusion due to overproduction of aPL. Myocardial infarction develops in approximately 5% of aPL-positive patients, and it usually occurs in men under 50 years of age. The most common cardiac symptom of APS is damage to the heart valves. It varies from minimal abnormalities detected only by echocardiography (slight regurgitation, thickening of the valve leaflets) to heart disease (stenosis or insufficiency of the mitral, less commonly, the aortic and tricuspid valves). Despite its wide distribution, clinically significant pathology leading to heart failure and requiring surgical treatment, observed rarely (in 5% of patients). However, in some cases, very severe valve damage with vegetations caused by thrombotic deposits, indistinguishable from infective endocarditis, can quickly develop. Detection of vegetations on the valves, especially if they are combined with hemorrhages in the subungual bed and “tympanic fingers,” creates complex diagnostic problems and the need for a differential diagnosis with infective endocarditis. Within the framework of APS, the development of cardiac thrombi mimicking myxoma has been described.

Renal pathology is very diverse. Most patients experience only asymptomatic moderate proteinuria (less than 2 g per day), without renal dysfunction, but acute renal failure with severe proteinuria (up to nephrotic syndrome), active urinary sediment and arterial hypertension. Renal damage is associated primarily with intraglomerular microthrombosis and is defined as “renal thrombotic microangiopathy.”

Patients with APS have clear and specific skin lesions, primarily livedo reticularis (occurring in more than 20% of patients), postthrombophlebitic ulcers, gangrene of the fingers and toes, multiple hemorrhages in the nail bed and other manifestations caused by vascular thrombosis.

In APS, liver damage occurs (Budd-Chiari syndrome, nodular regenerative hyperplasia, portal hypertension), gastrointestinal tract (gastrointestinal bleeding, splenic infarction, thrombosis of mesenteric vessels), musculoskeletal system (aseptic bone necrosis).

Characteristic manifestations of APS include obstetric pathology, the frequency of which can reach 80%. Fetal loss can occur at any stage of pregnancy, but is somewhat more common in the second and third trimester. In addition, aPL synthesis is associated with other manifestations, including late gestosis, preeclampsia and eclampsia, intrauterine growth retardation, and premature birth. The development of thrombotic complications in newborns from mothers with APS has been described, which indicates the possibility of transplacental transfer of antibodies.

Thrombocytopenia is typical for APS. Typically, the platelet count ranges from 70 to 100 x109/l and does not require special treatment. The development of hemorrhagic complications is rare and, as a rule, is associated with a concomitant defect of specific blood coagulation factors, kidney pathology, or an overdose of anticoagulants. Coombs-positive hemolytic anemia (10%) is often observed; Evans syndrome (a combination of thrombocytopenia and hemolytic anemia) is less common.

Diagnostic criteria

The multi-organ nature of symptoms and the need for special confirmatory laboratory tests in some cases cause difficulties in diagnosing APS. In this regard, in 1999, preliminary classification criteria were proposed, according to which the diagnosis of APS is considered reliable when combined, according to at least, one clinical and one laboratory sign.

Clinical criteria:

• Vascular thrombosis: one or more episodes of thrombosis (arterial, venous, small vessel thrombosis). Thrombosis must be confirmed using instrumental methods or morphologically (morphology - without significant inflammation of the vascular wall).
• Pregnancy pathology can have one of three options:

  One or more cases of intrauterine death of a morphologically normal fetus after 10 weeks of pregnancy;

  One or more episodes of premature birth of a morphologically normal fetus before 34 weeks of gestation due to severe preeclampsia, or eclampsia, or severe placental insufficiency;

  Three or more consecutive cases of spontaneous abortion before 10 weeks of pregnancy (with the exception of anatomical defects of the uterus, hormonal disorders, maternal and paternal chromosomal disorders).

Laboratory criteria:

• positive aCL IgG class or IgM in serum in medium and high titers, determined at least twice, with an interval of at least 6 weeks, using a standardized enzyme immunoassay;
• positive lupus anticoagulant detected in plasma at least 6 weeks apart by a standardized method.

Differential diagnosis

Differential diagnosis of APS is carried out with a wide range of diseases occurring with vascular disorders. It should be remembered that with APS there is a very large number of clinical manifestations that can imitate various diseases: infective endocarditis, heart tumors, multiple sclerosis, hepatitis, nephritis, etc. APS in some cases is combined with systemic vasculitis. It is believed that APS should be suspected in the development of thrombotic disorders (especially multiple, recurrent, with unusual localization), thrombocytopenia, obstetric pathology in young and middle-aged people in the absence of risk factors for the occurrence of these pathological conditions. It should be excluded in cases of unexplained thrombosis in newborns, in cases of skin necrosis during treatment with indirect anticoagulants and in patients with a prolonged activated partial thromboplastin time in a screening study.

APS was first described as a variant of systemic lupus erythematosus (SLE). However, it was very soon established that APS can also develop in other autoimmune rheumatic and non-rheumatic diseases (secondary APS). Moreover, it turned out that the connection between overproduction of aPL and thrombotic disorders is more universal and can be observed in the absence of reliable clinical and serological signs of other diseases. This was the basis for the introduction of the term “primary APS” (PAPS). It is believed that approximately half of patients with APS suffer from primary form diseases. However, is PAFS independent? nosological form It's not entirely clear. Noteworthy is the high incidence of PAPS among men (the ratio of men to women is 2:1), which distinguishes PAPS from other autoimmune rheumatic diseases. Individual clinical manifestations or their combinations occur in patients with PAPS with varying frequency, which is probably due to the heterogeneity of the syndrome itself. At the moment, three groups of patients with PAPS are conventionally distinguished:

• patients with idiopathic deep vein thrombosis of the leg, which is often complicated by thromboembolism, primarily in the pulmonary artery system, leading to the development of pulmonary hypertension;
• young patients (up to 45 years) with idiopathic strokes, transient ischemic attacks, and less often occlusion of other arteries, including coronary ones; most a shining example This variant of PAPS is Sneddon syndrome;
• women with obstetric pathology (repeated spontaneous abortions);

The course of APS, the severity and prevalence of thrombotic complications in it are unpredictable and in most cases do not correlate with changes in aPL levels and disease activity (in secondary APS). In some patients, APS may present as an acute, recurrent coagulopathy, often in combination with a vasculopathy affecting many vital functions. important organs and systems. This served as the basis for identifying the so-called “catastrophic APS” (CAPS). For determining this state The names “acute disseminated coagulopathy-vasculopathy” or “devastating non-inflammatory vasculopathy” have been proposed, which also emphasizes the acute, fulminant nature of this variant of APS. The main triggering factor for CAPS is infection. Less commonly, its development is associated with the abolition of anticoagulants or the use of certain medications. CAPS occurs in approximately 1% of patients with APS, but despite the therapy, it ends in death in 50% of cases.

Treatment of APS

Prevention and treatment of APS are challenging. This is due to the heterogeneity pathogenetic mechanisms, polymorphism of clinical manifestations, as well as the lack of reliable clinical and laboratory indicators to predict the recurrence of thrombotic disorders. There are no generally accepted international standards of treatment, and proposed recommendations are based primarily on the results of open-label drug trials or retrospective analyzes of disease outcomes.

Treatment with glucocorticoids and cytotoxic drugs for APS is usually ineffective, except in situations where the advisability of their use is dictated by the activity of the underlying disease (for example, SLE).

Management of patients with APS (as with other thrombophilias) is based on the prescription of indirect anticoagulants (warfarin, acenocoumarol) and antiplatelet agents (primarily low doses of acetylsalicylic acid - ASA). This is primarily due to the fact that APS is characterized by a high risk of repeated thrombosis, which is significantly higher than that of idiopathic venous thrombosis. It is believed that most patients with APS with thrombosis require preventive antiplatelet and/or anticoagulant therapy for a long time, and sometimes for life. In addition, the risk of primary and repeated thrombosis in APS must be reduced by influencing such correctable risk factors as hyperlipidemia (statins: simvastin - simvastol, simlo; lovastatin - rovacor, cardiostatin; pravastatin - lipostat; atorvastatin - Avas, liprimar; fibrates: bezafibrate - cholestenorm; fenofibrate - nofibal, grofibrate; ciprofibrate - lipanor), arterial hypertension(ACE inhibitors - capoten, sinopril, diroton, moex; b-blockers - atenolol, concor, egilok, betaloc ZOK, dilatrend; calcium antagonists - amlovas, norvasc, normodipine, lacidipine), hyperhomocysteinemia, sedentary lifestyle, smoking, taking oral contraceptives and etc.

In patients with high levels of aPL in the serum, but without clinical signs of APS (including pregnant women without a history of obstetric pathology), one should limit themselves to prescribing small doses of ASA (50-100 mg/day). The most preferred drugs are aspirin cardio, thrombo ACC, which have a number of advantages (convenient dosage and the presence of a shell that is resistant to the action of gastric juice). This form makes it possible to provide not only a reliable antiplatelet effect, but also to reduce the adverse effect on the stomach.

Patients with clinical signs of APS (primarily thrombosis) require more aggressive anticoagulant therapy. Treatment with vitamin K antagonists (warfarin, phenylin, acenocoumarol) is undoubtedly a more effective, but less safe (compared to ASA) method of preventing venous and arterial thrombosis. The use of vitamin K antagonists requires careful clinical and laboratory monitoring. Firstly, this is associated with an increased risk of bleeding, and the risk of developing this complication due to its severity outweighs the benefit of preventing thrombosis. Secondly, in some patients, recurrence of thrombosis is observed after cessation of anticoagulant therapy (especially during the first 6 months after discontinuation). Third, patients with APS may experience significant spontaneous fluctuations in the international normalized ratio (INR), which significantly complicates the use of this indicator for monitoring warfarin treatment. However, all of the above should not be an obstacle to active anticoagulant therapy in those patients for whom it is vitally necessary ( ).

The warfarin treatment regimen consists of prescribing a loading dose (5-10 mg of the drug per day) for the first two days, and then selecting the optimal dosage to ensure maintenance of the target INR. It is advisable to take the entire dose in the morning, before determining the INR. In elderly individuals, lower doses of warfarin should be used to achieve the same level of anticoagulation than in younger individuals. It must be borne in mind that warfarin interacts with a number of drugs that, when administered in combination, both reduce (barbiturates, estrogens, antacids, antifungal and antituberculosis drugs) and enhance its anticoagulant effect (non-steroidal anti-inflammatory drugs, antibiotics, propranolol, ranitidine, etc. .). Certain recommendations regarding diet should be given, since rich in vitamin Food (liver, green tea, leafy vegetables - broccoli, spinach, Brussels sprouts and cabbage, turnips, lettuce) contributes to the development of warfarin resistance. Alcohol is avoided during warfarin therapy.

If warfarin monotherapy is insufficiently effective, combination therapy with indirect anticoagulants and low doses of ASA (and/or dipyridamole) is possible. This treatment is most justified in young people without risk factors for bleeding.

In case of excessive anticoagulation (INR>4) in the absence of bleeding, it is recommended to temporarily discontinue warfarin until the INR returns to the target level. In the case of hypocoagulation, accompanied by bleeding, the administration of vitamin K alone is not enough (due to the delayed onset of action - 12-24 hours after administration); Fresh frozen plasma or (preferably) prothrombin complex concentrate is recommended.

Aminoquinoline drugs (hydroxychloroquine - Plaquenil, chloroquine - Delagil) can provide quite effective prevention of thrombosis (at least in secondary APS due to SLE). Along with the anti-inflammatory effect, hydroxychloroquine has certain antithrombotic (suppresses platelet aggregation and adhesion, reduces thrombus size) and hypolipidemic effects.

The central place in the treatment of acute thrombotic complications in APS is occupied by direct anticoagulants - heparin and especially low-molecular-weight heparin preparations (Fraxiparin, Clexane). The tactics of their use do not differ from the generally accepted ones.

For CAPS, the entire arsenal of intensive and anti-inflammatory therapy methods used for critical conditions in patients with rheumatic diseases. The effectiveness of treatment to a certain extent depends on the ability to eliminate the factors that provoke its development (infection, activity of the underlying disease). The prescription of high doses of glucocorticoids for CAPS is not aimed at treating thrombotic disorders, but is determined by the need to treat the systemic inflammatory response syndrome (widespread necrosis, adult distress syndrome, adrenal insufficiency, etc.). Pulse therapy is usually carried out according to the standard regimen (1000 mg methylprednisolone intravenously per day for 3-5 days), followed by glucocorticoids (prednisolone, methylprednisolone) orally (1-2 mg/kg/day). Intravenous immunoglobulin is administered at a dose of 0.4 g/kg for 4-5 days (it is especially effective for thrombocytopenia).

CAPS is the only absolute indication for plasmapheresis sessions, which should be combined with maximum intensive anticoagulant therapy, the use of fresh frozen plasma and pulse therapy with glucocorticoids and cytostatics. Cyclophosphamide (Cytoxan, Endoxan) (0.5-1 g/day) is indicated for the development of CAPS against the background of exacerbation of SLE and to prevent “rebound syndrome” after plasmapheresis sessions. The use of prostacyclin (5 ng/kg/min for 7 days) is justified, however, due to the possibility of developing “rebound” thrombosis, treatment should be carried out with caution.

The administration of glucocorticoids to women with obstetric pathology is currently not indicated due to the lack of data on the benefits of this type of therapy and due to the high frequency of side effects in the mother (Cushing's syndrome, diabetes, arterial hypertension) and the fetus. The use of glucocorticoids is justified only in case of secondary APS due to SLE, since it is aimed at treating the underlying disease. The use of indirect anticoagulants during pregnancy is generally contraindicated due to their teratogenic effect.

The standard for preventing recurrent fetal losses is small doses of ASA, which are recommended to be taken before, during pregnancy and after the birth of the child (at least for 6 months). During pregnancy, it is advisable to combine small doses of ASA with low molecular weight heparin preparations. When delivering by cesarean section, the administration of low molecular weight heparins is canceled 2-3 days in advance and resumed at postpartum period followed by a transition to taking indirect anticoagulants. Long-term heparin therapy in pregnant women can lead to the development of osteoporosis, therefore, to reduce bone loss, it is necessary to recommend taking calcium carbonate (1500 mg) in combination with vitamin D. It should be borne in mind that treatment with low molecular weight heparin is less likely to cause osteoporosis. One of the limitations to the use of low molecular weight heparins is the risk of developing an epidural hematoma, therefore, if there is a possibility of premature delivery, treatment with low molecular weight heparins is discontinued no later than 36 weeks of pregnancy. The use of intravenous immunoglobulin (0.4 g/kg for 5 days every month) has no advantages over standard treatment with ASA and heparin, and is indicated only when standard therapy is ineffective.

Moderate thrombocytopenia in patients with APS does not require special treatment. In secondary APS, thrombocytopenia is well controlled by glucocorticoids, aminoquinoline drugs and, in some cases, low doses of ASA. Treatment tactics for resistant thrombocytopenia, which poses a risk of bleeding, include the use of glucocorticoids in high doses and intravenous immunoglobulin. If high doses of glucocorticoids are ineffective, splenectomy is the treatment of choice.

In recent years, new antithrombotic agents have been intensively developed, which include heparinoids (heparoid lecheva, emeran, sulodexide - Wessel Due), platelet receptor inhibitors (ticlopidine, tagren, ticlopidine-ratiopharm, clopidogrel, Plavix) and other drugs. Preliminary clinical data indicate the undoubted promise of these drugs.

All patients with APS should be under long-term dispensary observation, priority which is to assess the risk of recurrent thrombosis and their prevention. It is necessary to monitor the activity of the underlying disease (in case of secondary APS), timely detection and treatment of concomitant pathologies, including infectious complications, as well as an impact on correctable risk factors for thrombosis. It has been established that unfavorable prognostic factors for mortality in APS are arterial thrombosis, a high incidence of thrombotic complications and thrombocytopenia, and laboratory markers include the presence of a lupus anticoagulant. The course of APS, the severity and prevalence of thrombotic complications are unpredictable; Unfortunately, there are no universal treatment regimens. The above-mentioned facts, as well as the multiorgan nature of the symptoms, require the unification of doctors of various specialties to solve problems associated with the management of this category of patients.

N. G. Klyukvina, Candidate of Medical Sciences, Associate Professor
MMA im. I. M. Sechenova, Moscow

Antiphospholipid syndrome (APS) is a condition in which the body produces antibodies against its own cells. During pregnancy, such a pathology can cause its termination and other serious complications during this period.

Causes

Antiphospholipid syndrome is detected in 2-4% of all pregnant women. The exact causes of this pathology are still not known. Specific antiphospholipid antibodies are found in a wide variety of conditions, including some infectious diseases. Why in some women this phenomenon leads to the development of pregnancy complications, while in others it goes unnoticed, it is not possible to find out.

APS is considered a hereditary disease. It is known that in women suffering from this pathology, some specific genes of the HLA system are detected much more often. It is these genes that cause the immune system to malfunction. As a result, the body begins to produce aggressive antibodies that destroy its own cells.

Specific antibodies act directly on phospholipids - components cell membranes. The endothelium (inner lining) of blood vessels suffers the most. Developing endothelial dysfunction leads to disruption various processes in the hemostatic system. Blood clotting increases and the risk of thrombosis increases. Thrombosis in the blood vessels of the placenta can lead to miscarriage, placental abruption and other serious complications of pregnancy.

Risk factors for developing APS:

• autoimmune diseases (systemic lupus erythematosus, scleroderma, Sjogren's syndrome and others);
• infectious diseases ( viral hepatitis, HIV, Epstein-Barr virus);
• oncological processes (ovarian tumors, blood cancer);
• taking certain medications ( hormonal agents and others).

Symptoms

Recognizing antiphospholipid syndrome during pregnancy is not easy. The disease does not have specific symptoms that allow the doctor to make a diagnosis after the first examination of the patient. When APS develops, a woman experiences whole line pathological signs associated with the formation of blood clots. Manifestations of the disease will depend on the localization of the process.

Possible symptoms of APS:

• swelling of the legs;
• long-term non-healing ulcers on the lower extremities;
• numbness of the limbs;
• crawling sensation;
• headache;
• dyspnea;
• feeling of lack of air;
• intense chest pain;
• visual impairment;
• decreased memory and attention;
• increased blood pressure.

All these signs only indicate the possible development of thrombosis of one location or another. Thrombosis occurs in a variety of pathologies, and antiphospholipid syndrome is only one of the diseases in this long list. To find out the cause of increased blood clotting, it is necessary to undergo examination by a specialist.

The presence of APS should be assumed in all women with infertility and miscarriage. The formation of aggressive antibodies leads to the fact that the embryo cannot fully attach to the wall of the uterus. Its implantation is disrupted, which ultimately leads to miscarriage. Some women develop infertility due to APS.

Suspicion of APS in women appears in the following situations:

• infertility;
• regressing pregnancy;
• 2 or more spontaneous miscarriages in the early stages (if other causes of abortion are excluded);
• spontaneous miscarriage after 10 weeks;
• intrauterine fetal death (due to premature birth, severe gestosis or placental insufficiency);
• stillbirth;
• cases of thrombosis in women under 45 years of age (heart attack, stroke, cerebrovascular accidents, retinal thrombosis).

In all these situations, it is imperative to go through full examination see a specialist to exclude or confirm antiphospholipid syndrome.

Complications of pregnancy

Antiphospholipid syndrome can cause the following complications during pregnancy:

Spontaneous miscarriage

Termination of pregnancy with APS occurs either in the earliest stages or after 10 weeks. In the first case, the implantation of the embryo is disrupted, which leads to its rejection and death. Miscarriage occurs in the first 2-3 weeks of pregnancy, often before a missed period. The woman may not even know that she was pregnant. If you have been trying for a long time and unsuccessfully to conceive a child, you must undergo testing for APS.

Miscarriage after 10 weeks is associated with impaired blood flow in the developing placenta. The formation of blood clots in the mother-placenta-fetus system leads to chorion detachment, bleeding and miscarriage. Termination of pregnancy in the second trimester may also be associated with antiphospholipid syndrome.

Premature birth

Termination of pregnancy at 22-36 weeks is called premature birth. Antiphospholipid syndrome is one of the common causes of this pathology. About the start of labor ahead of schedule says the following symptoms appear:

• lower abdominal pain;
• pain in the lower back;
• opening and shortening of the cervix;
• discharge of the mucus plug;
• outpouring of water

Premature birth leads to the birth of premature newborn. The shorter the pregnancy, the more difficult it will be for the baby to adapt to existence outside the mother’s womb. Nursing of premature babies takes place in a specialized department. For some time, the newborn is in an incubator - a special device that supports the child’s life. Discharge home is possible only after the baby has fully adapted to the new living conditions.

Placental insufficiency

An increase in blood clotting inevitably leads to the formation of numerous blood clots in the placenta. As a result, blood flow in the mother-placenta-fetus system is disrupted. Placental insufficiency develops - a condition in which the baby suffers quite a lot. A sufficient amount does not enter the fetal blood nutrients, which leads to a delay in its development. Significant developmental delays in the baby can cause serious health problems after birth.

Placental insufficiency inevitably leads to another complication of pregnancy - chronic fetal hypoxia. With this pathology, the baby does not receive a sufficient amount of oxygen necessary for its full development. The first person to suffer from hypoxia is nervous system fetus Prolonged hypoxia can cause cerebral palsy and other diseases of the nervous system.

Preeclampsia

Preeclampsia is a specific pathology that occurs only during pregnancy. It is assumed that the main reason for the development of gestosis in APS is endothelial dysfunction and a natural disruption of the woman’s body’s adaptation to the onset of pregnancy. Increased thrombus formation leads to a sharp rise in blood pressure up to the development of eclampsia. Severe gestosis is one of the causes of premature birth and antenatal fetal death.

Premature abruption of the normally located placenta (PONRP)

PONRP is an extremely serious complication of pregnancy. The formation of blood clots and impaired blood flow in the placenta after 20 weeks can lead to its detachment from the uterine wall and massive bleeding. This condition is dangerous for the life of a woman and her baby. In case of severe blood loss, an emergency caesarean section is performed regardless of the stage of pregnancy.

HELLP syndrome

Rare and extremely dangerous pathology in obstetrics, in which the probability of death of the woman and the fetus is very high. HELLP syndrome occurs in the third trimester, most often after 34 weeks. With this pathology, blood thickening occurs, blood clots form, followed by bleeding. HELLP syndrome is considered an extreme degree of multiple organ failure, which occurs when the body’s adaptation to pregnancy is disrupted.

Signs of HELLP syndrome:

• nausea and vomiting;
• pain in the epigastric region;
• pain in the right quadrant;
• swelling;
• headache;
• jaundice;
• vomiting blood;
• hemorrhages at injection sites.

Symptoms are quite nonspecific and can occur in a wide variety of diseases. As the pathology progresses, severe liver failure, convulsions and coma. HELLP syndrome – direct reading to emergency caesarean section and intensive care.

Diagnostics

APS can be confirmed by detecting the following elements in the blood:

• lupus anticoagulant;
• anticardiolipin antibodies;
• antibodies to phospholipids.

Antiphospholipid syndrome is said to occur if these substances were detected in a woman’s blood two or more times in a row. Studies are carried out at intervals of 6-8 weeks. A single detection of antibodies is not indicative. Such substances can occur transiently, that is, for a short period of time. The transient presence of antibodies does not lead to infertility or the development of pregnancy complications.

Indications for testing:

• examination for infertility;
• preparation for pregnancy after miscarriage or regression;
• suspicion of APS during pregnancy;
• cases of thrombosis in the past (heart attacks, strokes, cerebrovascular accidents);
• complicated heredity (thrombosis in close relatives under the age of 45 years).

Blood for antibody determination is taken from a vein in the morning on an empty stomach. On the eve of the study, it is recommended to refrain from eating for 8-12 hours. You can drink clean water before donating blood.

Principles of treatment

When APS is detected, a pregnant woman should be under the supervision of a gynecologist, therapist and hematologist. If necessary, a vascular surgeon and cardiologist are involved. Throughout pregnancy, the expectant mother should regularly visit the doctor and undergo all examinations at due dates. If the condition worsens or complications develop, drug therapy is carried out.

Indications for hospitalization:

• deterioration of the condition of the woman and fetus during therapy;
• moderate and severe gestosis;
• severe disturbance of blood flow in the placenta;
• bleeding;
• thrombosis of any location.

To treat the consequences of antiphospholipid syndrome, two groups of drugs are used:

• antiplatelet agents;
• anticoagulants.

Antiplatelet agents help reduce platelet aggregation and thereby reduce blood clotting. Prescribed orally for 3 weeks. The dosage is determined by the doctor.

Anticoagulants inhibit the activity of the blood coagulation system and prevent the formation of blood clots. Prescribed subcutaneously in a course of 10 or more days. The dosage of anticoagulants is selected individually.

During therapy, the condition of the fetus must be assessed. Doppler measurements are performed every 3-4 weeks. This method allows you to assess the state of blood flow and notice various disturbances in time. If necessary, correction of placental insufficiency and fetal growth retardation is carried out.

Independent childbirth during a full-term pregnancy is possible if the condition of the woman and the fetus is satisfactory. If complications of APS develop, cesarean section cannot be ruled out. The choice of method and timing of delivery depends on the duration of pregnancy and the severity of the manifestations of antiphospholipid syndrome.

There is no specific prevention of APS. Early examination before planning pregnancy will help reduce the risk of complications. If antiphospholipid antibodies are detected, observation by a doctor and long-term use of medications that reduce blood viscosity are recommended. This approach reduces the likelihood of an unfavorable outcome during pregnancy due to APS.

Antiphospholipid syndrome (APS) is a clinical and laboratory symptom complex that includes venous and/or arterial thrombosis, various forms of obstetric pathology (primarily recurrent miscarriage), thrombocytopenia, as well as various other neurological, skin, cardiovascular and hematological disorders. A characteristic immunological feature of APS is antibodies to phospholipids - a heterogeneous group of antibodies that react with a wide range of phospholipids and phospholipid-binding proteins. APS most often develops in SLE (secondary APS) or in the absence of another leading disease (primary APS).

The true prevalence of APS in the population is still unknown. The frequency of detection of antibodies to phospholipids in the serum of healthy people varies from 0 to 14%, on average 2-4% (in high titers in less than 0.2%). The disease often develops at a young age and can occur in children and even newborns. In elderly people, the development of APS may be associated with malignant neoplasms. In the general population, APS is more often detected in women. However, among patients with primary APS, an increase in the proportion of men is noted.

ETIOLOGY

The causes of APS are not known. An increase in the level (usually transient) of antibodies to phospholipids is observed against the background of a wide range of bacterial and viral infections. However, thrombotic complications in patients with infections develop less frequently than antibodies to phospholipids are detected. There is evidence of an immunogenetic predisposition to overproduction of antibodies to phospholipids. There was an increase in the frequency of detection of antibodies to phospholipids in families of patients with APS; Cases of APS (usually primary) have been described in members of the same family.

PATHOGENESIS

Abs to phospholipids bind to phospholipids in the presence of a cofactor, which is β2-glycoprotein I, a protein that binds to phospholipids and has anticoagulant activity. Antiphospholipid antibodies present in the serum of patients with APS react with Ags formed during the interaction of phospholipid components of the membranes of endothelial and other cells (platelets, neutrophils) and β2-glycoprotein I. As a result of this interaction, the synthesis of anticoagulants (prostacyclin, antithrombin III, Annexin V, etc.) and increased formation of procoagulant (thromboxane, tissue factor, platelet activating factor, etc.) mediators, activation of the endothelium (expression of adhesion molecules) and platelets is induced, and neutrophil degranulation occurs.

Antiphospholipid antibodies detected in the serum of patients with infectious diseases usually react with phospholipids in the absence of β2-glycoprotein I and do not have the properties described above.

CLASSIFICATION

The following clinical and laboratory variants of APS are distinguished.

Primary APS.

Secondary APS.

"Catastrophic" APS.

In some patients, APS manifests itself primarily as venous thrombosis, in others as a stroke, in others as obstetric pathology or thrombocytopenia. The development of APS does not correlate with the activity of the underlying disease. Approximately half of patients with APS suffer from the primary form of the disease. However, the question of the nosological independence of primary APS is not completely clear. Primary APS can sometimes be a variant of the onset of SLE. On the contrary, in some patients with classical SLE at the onset, signs of APS may subsequently come to the fore.

In some patients, APS may present with acute recurrent coagulopathy and vasculopathy, affecting vital organs and resembling disseminated intravascular coagulation or hemolytic uremic syndrome. This condition is called "catastrophic" APS.

CLINICAL PICTURE

Since APS is based on non-inflammatory thrombotic damage to vessels of any size and location, the range of clinical manifestations is extremely diverse.

Venous thrombosis is the most common manifestation of APS. Thrombi are usually localized in the deep veins of the lower extremities, but are often found in the hepatic, portal veins, superficial veins, etc. Repeated pulmonary embolisms from the deep veins of the lower extremities are typical, sometimes leading to pulmonary hypertension. APS (more often primary than secondary) is the second most common cause of Budd-Chiari syndrome. Thrombosis of the central vein of the adrenal glands can lead to adrenal insufficiency.

Arterial thrombosis. Thrombosis of intracerebral arteries, leading to stroke and transient ischemic attacks, is the most common localization of arterial thrombosis in APS. Recurrent ischemic strokes caused by damage to small vessels sometimes occur without significant neurological disorders and can manifest as convulsive syndrome, multi-infarct dementia (resembling Alzheimer's disease), and mental disorders.

A variant of APS is Sneddon syndrome, manifested by recurrent thrombosis of cerebral vessels, livedo reticularis, hypertension and developing in young and middle-aged people. Other neurological disorders include migraine headaches, epileptiform seizures, chorea, and transverse myelitis. Sometimes neurological disorders in APS resemble those in multiple sclerosis.

Heart valve damage is one of the common cardiac manifestations of APS. It varies from minimal disturbances detected only by echocardiography (slight regurgitation, thickening of the valve leaflets) to severe heart defects (stenosis or insufficiency of the mitral, less often the aortic and tricuspid valves). Some patients quickly develop severe valve damage with vegetations caused by thrombotic overlays, similar to valve damage in infective endocarditis. Detection of vegetations on the valves, especially if they are combined with hemorrhages in the nail bed and fingers in the form of “drumsticks”, dictates the need differential diagnosis with infective endocarditis. The development of blood clots in the cardiac cavity, simulating cardiac myxoma, has been described. One of possible localizations arterial thrombosis associated with the synthesis of antibodies to phospholipids are the coronary arteries (in men with SLE this is the most common location).

TO frequent complications APS refers to hypertension. It can be labile and is often associated with livedo reticularis and damage to the cerebral arteries as part of Sneddon syndrome, or stable, malignant, manifested by symptoms of hypertensive encephalopathy. The development of hypertension in APS can be associated with many causes, including renal vascular thrombosis, renal infarction, thrombosis of the abdominal aorta (pseudocoarctation), and intraglomerular thrombosis. A connection has been noted between the hyperproduction of antibodies to phospholipids and the development of fibromuscular dysplasia renal arteries. A rare complication of APS is thrombotic pulmonary hypertension, which is associated with both recurrent pulmonary embolism and local ( in situ) thrombosis of the pulmonary vessels.

Kidney damage in APS is associated with intraglomerular microthrombosis and is referred to as renal thrombotic microangiopathy. Microthrombosis of the glomeruli of the kidneys is considered the cause of the subsequent development of glomerulosclerosis, leading to dysfunction of the organ.

Obstetric pathology is considered one of the most characteristic features APS: recurrent miscarriage, recurrent spontaneous abortions, intrauterine fetal death, preeclampsia. Fetal loss can occur at any stage of pregnancy, but more often in the second and third trimesters.

Skin lesions in APS are characterized by a variety of clinical manifestations (usually livedo reticularis). Less common are skin ulcers and pseudovasculitic lesions (purpura, palmar and plantar erythema, pustules, gangrene of the fingers).

Thrombocytopenia is a typical hematological sign of APS. The development of hemorrhagic complications is rare and, as a rule, is associated with a concomitant defect in blood coagulation factors, kidney pathology, or an overdose of anticoagulants. Hemolytic anemia with a positive Coombs test is often observed; Evans syndrome (a combination of thrombocytopenia and hemolytic anemia) is less common.

LABORATORY RESEARCH

Laboratory diagnosis of APS is based on the determination of lupus anticoagulant using functional tests and antibodies to cardiolipin using ELISA. In general, lupus anticoagulant has higher specificity, and anticardiolipin antibodies have higher sensitivity for diagnosing APS. Lupus anticoagulant and antibodies to cardiolipin are detected in 30-40% and 40-50% of patients with SLE, respectively. In the presence of antibodies to phospholipids, the risk of developing thrombosis is 40%, while in the absence of antibodies it is no higher than 15%. A method has been developed for determining antibodies that react with β2-glycoprotein I, an increase in the level of which correlates better with the development of thrombosis than an increase in the level of antibodies to phospholipids. The course of APS, the severity and prevalence of thrombotic complications in most cases do not depend on the concentration of antibodies to phospholipids.

To make a reliable diagnosis of APS, a combination of at least one clinical and one laboratory criterion is necessary.

APS should be suspected in cases of thrombotic disorders (especially multiple, recurrent, with unusual localization), thrombocytopenia, obstetric pathology in young and middle-aged people, as well as in unexplained thrombosis in newborns, in case of skin necrosis during treatment with indirect anticoagulants and in patients with prolonged aPTT during a screening study. With APS, a large number of pseudo-syndromes are observed, which can imitate vasculitis, infective endocarditis, heart tumors, multiple sclerosis, hepatitis, nephritis, etc.

TREATMENT

Prevention and treatment of APS is a complex task (Table 46-2). This is due to the heterogeneity of the pathogenetic mechanisms underlying APS, the polymorphism of clinical manifestations, and the lack of reliable clinical and laboratory indicators to predict the recurrence of thrombotic disorders. The risk of recurrent thrombosis is especially high in young patients with persistent high levels of antibodies to cardiolipin, lupus anticoagulant and with simultaneous detection of antibodies to cardiolipin and lupus anticoagulant, as well as in the presence of recurrent thrombosis and/or obstetric pathology in the anamnesis, in the presence of other thrombotic risk factors disorders (hypertension, hyperlipidemia, smoking, taking oral contraceptives), with high activity of SLE, with rapid withdrawal of indirect anticoagulants, with a combination of high titers of antibodies to phospholipids with other coagulation disorders.

In addition, there are a number of features in the treatment of APS.

In patients with high levels of antibodies to phospholipids in the serum, but without clinical signs of APS (including pregnant women without a history of obstetric pathology), they are limited to prescribing small doses of acetylsalicylic acid (75 mg/day). These individuals require careful follow-up, since their risk of thrombotic complications is very high. Moderate thrombocytopenia usually does not require treatment or is controlled with small doses of GCs.

Management of patients with definite APS is based on the prescription of vitamin K antagonists (warfarin) and antiplatelet agents (low doses of acetylsalicylic acid), which are widely used for the prevention of thrombosis not associated with APS. In patients with both secondary and primary APS, treatment with warfarin, which maintains the INR at a level of 2-3 (or more), leads to a significant reduction in the incidence of recurrent thrombotic complications. However, the use of warfarin is associated with a high risk of bleeding. It is advisable to prescribe antimalarial drugs, which, along with an anti-inflammatory effect, have antithrombotic (suppress platelet aggregation and adhesion, reduce the size of a blood clot) and lipid-lowering activity.

The use of warfarin during pregnancy is contraindicated, as this leads to the development of warfarin embryopathy, characterized by impaired growth of the epiphyses of the bones and hypoplasia of the nasal septum, as well as neurological disorders. Treatment with heparin (especially low molecular weight heparins in standard doses) in combination with low doses of acetylsalicylic acid in women with recurrent miscarriage can increase the frequency of successful births by approximately 2-3 times and is significantly more effective than glucocorticoid therapy.

Thank you

Diagnosis of APS

Criteria for antiphospholipid syndrome

Sappor diagnostic criteria include clinical and laboratory criteria, all of which must be assessed to make a diagnosis of APS. Both clinical and laboratory criteria for antiphospholipid syndrome are presented in the table:

The diagnosis of antiphospholipid syndrome is made when a person has at least one clinical and one laboratory criterion. In other words, if there are only clinical criteria, but at least one laboratory test is missing, then the diagnosis of APS is not made. Likewise, a diagnosis of APS is not made only if laboratory criteria are present and clinical criteria are absent. The diagnosis of APS is excluded if a person has had antiphospholipid antibodies in the blood for less than 12 weeks or more than 5 years in a row, but there are no clinical criteria, or, conversely, for less than 12 weeks or more than 5 years there have been clinical symptoms, but there are no antibodies to phospholipids in the blood.

Since to determine the laboratory criteria for APS it is necessary to examine the concentration of antiphospholipid antibodies in the blood at least twice, it is impossible to make a diagnosis with a single examination. Only when tests for antiphospholipid antibodies in the blood are taken twice can laboratory criteria be assessed. A laboratory test is considered positive only if the level of antibodies to phospholipids is elevated both times. If one time antiphospholipid antibodies are found to be in an increased concentration, and the second time they are normal, then this is considered a negative laboratory criterion and is not a sign of APS. After all, a temporary increase in the level of antiphospholipid antibodies in the blood is very common, and can be recorded after any infectious disease, even a banal ARVI. This temporary increase in the level of antibodies to phospholipids does not require therapy and goes away on its own within a few weeks.

It should be remembered that when determining the levels of antibodies to phospholipids, it is necessary to detect the concentrations of both IgG and IgM. That is, the level of IgG antibodies to cardiolipin and IgM to cardiolipin, as well as the concentration of IgG antibodies to beta-2-glycoprotein-1 and IgM to beta-2-glycoprotein-1 should be determined.

Once the diagnosis of antiphospholipid syndrome has been confirmed or refuted, there is no need to monitor the levels of antibodies to phospholipids in the blood, since their level can fluctuate depending on a wide variety of reasons, such as, for example, recent stress or acute respiratory viral infection.

Antiphospholipid syndrome should be distinguished from the following diseases that have similar clinical symptoms:

• acquired and genetic thrombophilias;
• fibrinolysis defects;
• malignant tumors of any location, including blood;
• embolism;
• myocardial infarction with thrombosis of the ventricles of the heart;
• decompression sickness;
• thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS).

What tests and how to take them (markers of antiphospholipid syndrome)

To diagnose antiphospholipid syndrome, the following tests must be performed:

• antibodies to phospholipids of types IgG, IgM;
• antibodies to cardiolipin types IgG, IgM;
• antibodies to beta-2-glycoprotein 1 types IgG, IgM;
• lupus anticoagulant (it is optimal for this parameter to be determined in the laboratory using the Russell test with viper venom);
• antithrombin III;
• complete blood count with platelet count;
• coagulogram (APTT, mixed-APTT, TV, INR, kaolin time, fibrinogen);
• Wasserman reaction (the result will be positive for APS).

Treatment of antiphospholipid syndrome

There are two main directions in the treatment of APS - the relief (elimination) of already developed acute thrombosis and the prevention of repeated episodes of thrombosis.

Treatment of acute thrombosis. Therapy for already developed thrombosis is carried out with the combined use of direct (Heparin, Fraxiparin, etc.) and indirect anticoagulants (Warfarin). First, Heparin is administered or low molecular weight heparins(Fraxiparin, Fragmin) to quickly achieve a sharp reduction in blood clotting and dissolution of blood clots. Further, when, while using Heparin, the INR (international normalized ratio, an indicator of blood clotting) is in the range from 2 to 3, the patient is transferred to taking Warfarin. The dosage of Warfarin is also selected so that the INR value fluctuates between 2 and 3.

In case of catastrophic antiphospholipid syndrome, it is carried out urgent treatment in intensive care conditions, for which all available methods intensive and anti-inflammatory therapy, such as:

• Antibacterial therapy that eliminates the source of infection;
• The use of Heparin or low molecular weight heparins (Fraxiparin, Fragmin, Clexane) to reduce the formation of blood clots;
• The use of glucocorticoids (Prednisolone, Dexamethasone, etc.) to relieve the systemic inflammatory process;
• The simultaneous use of glucocorticoids and Cyclophosphamide to relieve a severe systemic inflammatory process;
• Intravenous immunoglobulin for thrombocytopenia (low platelet count in the blood);
• If there is no effect from glucocorticoids, Heparin and immunoglobulin, experimental genetically engineered drugs, such as Rituximab, Eculizumab, are administered;
• Plasmapheresis (carried out only with a very high titer of antiphospholipid antibodies in the blood).

For the prevention of thrombosis APS patients must use medications that reduce blood clotting for life. The choice of drugs is determined by the characteristics of the clinical course of antiphospholipid syndrome. Currently, it is recommended to adhere to the following tactics for the prevention of thrombosis in patients with antiphospholipid syndrome:

• In APS with the presence of antibodies to phospholipids in the blood, but the absence of clinical episodes of thrombosis are limited to prescribing acetylsalicylic acid (Aspirin) in low dosages - 75 - 100 mg per day. Aspirin is taken continuously, for life, or until the treatment tactics for APS are changed. If APS with a high titer of antibodies and the absence of episodes of thrombosis is secondary (for example, against the background of systemic lupus erythematosus), then it is recommended to use Aspirin and Hydroxychloroquine (100 - 200 mg per day) simultaneously.
• In APS with previous episodes of venous thrombosis It is recommended to use Warfarin in dosages that provide an INR value of 2 to 3. In addition to Warfarin, Hydroxychloroquine (100–200 mg per day) can be prescribed.
• In APS with previous episodes of arterial thrombosis It is recommended to use Warfarin in dosages that provide an INR value of 3 to 3.5, in combination with Hydroxychloroquine (100 - 200 mg per day). In addition to Warfarin and Hydroxychloroquine, low-dose Aspirin is prescribed if there is a high risk of thrombosis.
• In APS with several episodes of thrombosis It is recommended to use Warfarin in dosages that provide an INR value of 3 to 3.5, in combination with Hydroxychloroquine (100 - 200 mg per day) and Aspirin in low doses.

Use of glucocorticosteroids(Dexamethasone, Metipred, Prednisolone, etc.) and cytostatics for the prevention of thrombosis in APS are not recommended due to low clinical effectiveness and the risk of complications caused by side effects drugs.

In addition to any of the above treatment regimens may be appointed various drugs in order to correct existing violations. Thus, for moderate thrombocytopenia (the number of platelets in the blood is more than 100 G/l), low doses of glucocorticoids (Metypred, Dexamethasone, Prednisolone) are used. For clinically significant thrombocytopenia, glucocorticoids, Rituximab or immunoglobulin (administered intravenously) are used. If the therapy does not increase the number of platelets in the blood, then surgical removal of the spleen (splenectomy) is performed. In case of kidney pathology against the background of APS, drugs from the group of angiotensin-converting enzyme inhibitors (Captopril, Lisinopril, etc.) are used.

In addition, recently they have been developing new drugs that prevent thrombosis, which include heparinoids (Heparoid Lechiva, Emeran, Wessel Due Ef) and platelet receptor inhibitors (Ticlopidine, Tagren, Clopidogrel, Plavix). Preliminary data indicate that these drugs are also effective in APS, and therefore their introduction into the standards of therapy recommended by the international community may be possible in the near future. Currently, these drugs are used to treat APS, but each doctor prescribes them according to his own regimen.

If surgical interventions are necessary for APS You should continue taking anticoagulants (Warfarin, Heparin) for as long as possible, discontinuing them as little as possible before surgery. Heparins and warfarin should be resumed as soon as possible after surgery. In addition, people with antiphospholipid syndrome should get out of bed and move as early as possible after surgery and wear compression stockings to further prevent the risk of blood clots. Instead of wearing compression garments, you can simply wrap your legs with elastic bandages.

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