Antiphospholipid syndrome: why is it dangerous? The cause of infertility is antiphospholipid syndrome. Phospholipid syndrome symptoms.

In recent decades, cases of “unexplained” infertility or recurrent miscarriage (repeated frozen pregnancies, recurrent miscarriage) have increasingly occurred in medical practice. Some experts associate this state of affairs with a significant deterioration in the state of our environment, with changes in the nutritional structure, with the widespread use of various substitutes and additives in the food industry, the use of synthetic medicines and antibiotics in medicine, a sedentary lifestyle, constant stress and similar factors. It is quite natural that the human immune system cannot help but react to such changes, in which immune disorders, least studied by medicine, are increasingly occurring, leading to damage to the body’s own tissues and cells by the immune processes themselves (the so-called autoimmune diseases).

For example, according to various sources, from 10 to 15 percent of all pregnancies end in miscarriage. It often happens that a woman does not even suspect that she is pregnant, and the very tiny embryo dies before the expected next menstruation begins. There may be several reasons for this. But most often the same things lead to this autoimmune disorders in the mother's body.

Pregnancy- this is a real natural sacrament, completely unique and inimitable. After all, in essence, pregnancy is a process by which nature allows you to create a completely new human body based on the synthesis of cells from the mother and father of the child. At the same time, a child’s body, genetically different from her own, lives and develops in a woman’s body for 9 months, since the child inherits not only the genes of the mother, but also the father.

Normally, the functioning of the immune system assumes that the cells of this system circulate in the body, tracking on the surface of all cells without exception that they encounter on their way, the so-called protein (genetic) code, which is the main factor of tissue compatibility. In the human body, the immune response is determined primarily by proteins included in the so-called HLA system(from English Human Leukocyte Antigens - human leukocyte antigens). Every human body has a genetically determined set of such proteins on the surface of its cells. This set is called fabric type. If two people have similar tissue types, then they talk about histocompatibility. In this case, the proteins can completely match (full tissue compatibility) or partially (partial compatibility). The lower the degree of compatibility, the higher the likelihood of an immune conflict, because these proteins serve as a kind of marker for the immune system, on the basis of which it divides cells into “self” and “foreign”. In order to identify the likelihood of such a conflict, special studies are carried out, for example, HLA typing, i.e. a blood test that reveals the extent to which spouses are similar or distinguishable in their histocompatibility antigens (proteins).

Each person has a unique combination of HLA genes, unique to him and different from any other person, which is initially built on the typed genes of his father and mother (one gene from each parent). If a man and women are similar in terms of tissue compatibility, this leads to the fact that the tissues of the embryo are similar to the tissues of the mother’s body. As a result, the mother’s immune system may not respond sufficiently, and the mechanisms necessary for the formation of the embryo, its implantation and the successful course of pregnancy are not triggered, which leads to the impossibility of implantation of the embryo.

A study called HLA typing is carried out in the first and second grades. This means that the analysis is carried out for two classes of HLA antigens. HLA antigens of the first class are found on the surface of all cells of the human body, and HLA antigens of the second class are present only on the surface of cells that take part in the reactions of the immune system (activated T lymphocytes that destroy damaged foreign cells, for example, due to suppression of infection, and stimulating other cells are B lymphocytes and macrophages, as well as monocytes and dendritic cells). In order to conduct such an analysis, it is necessary to take blood from a vein from both a woman and a man. In the results of the HLA typing analysis, the laboratory technician indicates those identified during this study matches for this particular male-female pair. If there is a match for two or even more HLA antigens, then very often this can be the cause of miscarriage or early miscarriages, sometimes even 2-3 weeks after conception, so that the woman is not even aware of the fact of conception. Sometimes in such situations they say that nature has special wisdom and has provided a special mechanism that does not allow an organism affected by a hereditary disease or a non-viable organism to arise and develop. Moreover, IVF methods in such situations may also turn out to be ineffective. This is due to the fact that each person’s body has genes that determine a predisposition to certain diseases, which most often is not dangerous for our offspring (for example, if the gene is recessive). But if this gene is present in the body of both the father and mother, then the likelihood of having a baby suffering from this serious disease increases many times over.

Sometimes the cells of the immune system are compared to law enforcement officers. If these cells detect “strangers” (this can be bacteria foreign to the body, various viruses, and also their own, modified under the influence of some external factors cells of the body), the immune system immediately produces an immune response. And if the immune system is often forced to fight various kinds of “enemies,” then over time it becomes overactive. In this case, there is a high probability of immunological infertility. Since the human immune system is a very complex and complex mechanism, it can malfunction in various parts of this complex (i.e., depending on where in the human body a particular immune reaction develops). For example, during the period of ovulation, under the influence of hormonal factors, a woman produces special mucus in the cervix, which normally helps sperm penetrate inside and, passing through the uterus and fallopian tubes, reach the egg. However, under the influence of excessive autoimmune reactions, a woman’s body can produce antibodies that lead to “gluing” (aggregation) and death of sperm in cervical canal. In this case, they talk about this type of immunological infertility. Likewise, it is possible to “destruct” sperm upon contact with an egg or reject the embryo during direct implantation in the uterine cavity. The most recent studies show that if present in a woman’s body, they can not only prevent conception, but can also negatively affect the course of pregnancy, lead to delayed fetal development, toxicosis, and even cause spontaneous miscarriage.

And, in general, given that the child’s body is foreign to the mother’s immune system, it would die every time, but normally the uterus is a kind of immunologically privileged (for the fetus) place in a woman’s body, since it is in the uterus that During pregnancy, nature has provided special protection that hides the cellular structures of the fetus from the immune system of the mother's body. However, it sometimes happens that in some women this protective system does not turn on, which leads to fetal rejection, i.e. to early miscarriage. Modern medicine has recently begun to study this pathology and methods of its treatment are at the experimental development stage. These include the introduction of lymphocytes from the potential father of the child in order to increase the mother's body's sensitivity to the father's genes even before pregnancy. Another method is intravenous administration of immunoglobulins.

One type of autoimmune disorder is the production of antibodies to a woman’s own tissues, the consequences of which are various disorders in the hemostasis system (i.e. in the blood clotting system). Such antibodies lead to the fact that the blood becomes more viscous and this leads to the formation of blood clots of different sizes (i.e., the formation of thrombosis and thromboembolic conditions occurs). During pregnancy, their effect is manifested in the fact that the fetus cannot develop normally, because microthrombi in the mother's circulatory system prevent its sufficient blood supply. All this can also lead to both delayed development of the fetus and its death.

There are three main types of such antibodies: lupus anticoagulant, anticardiolipin antibodies and antiphospholipid antibodies. Their presence can be detected using a special blood test - hemostasiograms. These autoimmune disorders are treated with special low-molecular-weight heparin regimens or steroids, which suppress this dysfunctional immune system response.

More often antiphospholipid syndrome develops under the influence of severe infections or due to genetic factors, i.e. hereditary predisposition to the formation of thrombosis and thromboembolic conditions. In the second case (i.e. in the case of “bad” heredity), the body has a defective gene (mutation), which leads to disturbances in the blood coagulation system. Men usually feel the consequences of such a gene after forty years (heart attacks, strokes), and women - during pregnancy. Normally, during a singleton pregnancy, the volume of circulating blood in the female body increases by an average of 30-50%, while blood coagulation and viscosity also increase. Here, too, nature has provided a special mechanism that protects a woman from pathological blood loss during childbirth. However, in those women who have a hereditary tendency to thrombophilia (due to mutations in hemostasis genes), the action of this mechanism can lead to the formation of blood clots in the vessels of the placenta, and this in turn can lead to various pregnancy complications (for example, placental insufficiency with fetal growth retardation in combination with hypoxia) up to fetal death at different stages of pregnancy. Also, mutations in hemostasis genes can lead to disruptions in the functioning of the mother’s body (increased blood pressure, edema, antepartum hemorrhage due to placental abruption, etc.).

It should also be noted that in terms of their clinical manifestations, hereditary and acquired propensity to the formation of thrombosis are very similar, but there are also cases when one complements the other, and in such a situation the risk of thromboembolic conditions increases significantly, leading to very serious health consequences person.

How can you recognize the presence of such unfavorable factors during pregnancy? Experts recommend doing detailed study of hemostasis(this type of research is usually called "extended hemostasiogram") in case if:

• close relatives (mother, father, grandparents) have had any thrombosis, heart attack or stroke in the family;
• if the woman herself has ever experienced a systematic increase in blood pressure, migraine-like headaches, heart attack, stroke, varicose veins veins;
• there were pregnancies that were accompanied by such serious complications as recurrent miscarriage, severe gestosis, postpartum hemorrhage);
• unsuccessful IVF attempts.

Such an analysis is done once in a lifetime, and if it detects genetic changes in a woman’s hemostasis, or acquired changes (antiphospholipid syndrome), then in this case a special approach to pregnancy management is required from the obstetrician-gynecologist observing the woman, as well as special attention on the part of a woman to her health, both during pregnancy itself and after the age of forty.

It should also be noted that sometimes the only sign of such disorders is the presence of false-positive tests for the Wasserman reaction. The woman is not worried about anything, but there were cases in her life when this analysis gave positive result in the absence of all other symptoms of syphilis.

Antiphospholipid syndrome and mutations in hemostasis genes a fairly common phenomenon: according to European scientists, hereditary thrombophilia occurs in 10-12% of the population, and in women with recurrent miscarriage - in 48%; for antiphospholipid syndrome, these figures are 5-6% and 52%, respectively.

It is very important for this pathology antithrombotic diet which must be followed not only by pregnant women with antiphospholipid syndrome and mutations in hemostasis genes, but also by those who are just planning a pregnancy. This diet excludes fatty meat, lard, legumes, hard cheeses, full-fat whole milk, leafy vegetables (spinach, celery, parsley) and prescribes foods that help reduce blood clotting. The latter include seafood, root vegetables, berries (seasonal Siberian berries are especially important for our climate zone), dried fruits, seaweed, and ginger.

Antiphospholipid syndrome (APS) is one of the most pressing multidisciplinary problems of 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, devoted to the laboratory method for diagnosing syphilis. When conducting screening studies, it became obvious that a positive Wasserman reaction can be detected in many people without clinical signs of syphilitic infection. This phenomenon is called "biological falsehood" positive reaction Wasserman". It was soon established that the main antigenic component in the Wassermann reaction is a negatively charged phospholipid, called cardiolipin. The introduction of radioimmunological and then enzyme-linked immunosorbent method (ELI) 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: those detected using IPM using cardiolipin, less often other phospholipids; antibodies detected using functional tests (lupus anticoagulant); antibodies that are not diagnosed using standard methods (antibodies to protein C, S, thrombomodulin, heparan sulfate, endothelium, etc.).

As a result of close interest in studying the role of aPL and improving laboratory diagnostic methods, the conclusion was that aPL are a serological marker of a unique symptom complex, including venous and/or arterial thrombosis, various forms of 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 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 aPL synthesis 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. Wherein clinical significance 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 that were elevated in previous determinations normalizes.

An increase in the incidence of aPL has been noted in some inflammatory, autoimmune and infectious diseases, malignant neoplasms, while taking medications (oral contraceptives, psychotropic drugs, etc.). There is evidence of an immunogenetic predisposition to increased aPL synthesis 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 that causes the development of the 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. The clinical significance of aPL depends on whether their presence in the blood serum is associated with the development of 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 in 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 (ratio 5:1).

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 modern ideas, 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, dysfunction of the kidneys, liver, endocrine organs, gastrointestinal tract. The development of certain forms of obstetric pathology tends to be associated with thrombosis of placental vessels ( table 1).

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 the intracerebral arteries is the most common location of arterial thrombosis in APS. Rare manifestations include thrombosis of large arteries, as well as the ascending aorta (with the development of arcaortic 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 the 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 or 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 the 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 AFS. 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 experience 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 causes of 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 occurs 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 ranges from minimal disturbances detected only by echocardiography (slight regurgitation, thickening of the valve leaflets) to heart disease (stenosis or insufficiency of the mitral, less commonly aortic and tricuspid valves). Despite its widespread occurrence, clinically significant pathology leading to heart failure and requiring surgical treatment is rarely observed (in 5% of patients). However, in some cases, very severe damage to the valves can quickly develop with vegetations caused by thrombotic layers, indistinguishable from infective endocarditis. 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. Within the framework of AFS, the development of cardiac blood clots simulating myxoma has been described.

Renal pathology is very diverse. Most patients have only asymptomatic moderate proteinuria (less than 2 g per day), without renal dysfunction, but acute renal failure may develop with severe proteinuria (up to nephrotic syndrome), active urinary sediment and arterial hypertension. Kidney damage is associated mainly 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, there is damage to the liver (Budd-Chiari syndrome, nodular regenerative hyperplasia, portal hypertension), the gastrointestinal tract (gastrointestinal bleeding, splenic infarction, thrombosis of mesenteric vessels), and the musculoskeletal system (aseptic bone necrosis).

To the number characteristic manifestations APS is an obstetric pathology, the frequency of which can reach 80%. Fetal loss can occur at any time during pregnancy, but is somewhat more common in the second and third trimesters. In addition, the synthesis of aPL is associated with other manifestations, including late gestosis, preeclampsia and eclampsia, intrauterine growth retardation, and premature birth. The development of thrombotic complications in newborns of 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 in specific blood coagulation factors, kidney pathology, or an overdose of anticoagulants. Coombs-positive hemolytic anemia is often observed (10%), 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 make it difficult to diagnose APS. In this regard, in 1999, preliminary classification criteria were proposed, according to which the diagnosis of APS is considered reliable when at least one clinical and one laboratory sign is combined.

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 pregnancy due to severe preeclampsia, or eclampsia, or severe placental insufficiency;

  – three or more consecutive cases of spontaneous abortions 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 class IgG 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;
• a positive lupus anticoagulant detected in plasma at least at an interval of at least 6 weeks using 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 when 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 soon discovered 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 served as the basis for the introduction of the term “primary APS” (PAPS). It is believed that approximately half of patients with APS suffer from the primary form of the disease. However, whether PAPS is an independent nosological form is not completely 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 frequencies, which is probably due to the heterogeneity of the syndrome itself. Currently, 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, less often occlusion of other arteries, including coronary ones; the most striking example of this variant of PAF is Sneddon syndrome;
• women with obstetric pathology (repeated spontaneous abortions);

The course of APS, the severity and prevalence of thrombotic complications 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 manifest as acute, recurrent coagulopathy, often in combination with vasculopathy, affecting many vital organs and systems. This served as the basis for identifying the so-called “catastrophic APS” (CAPS). To define this condition, 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 intake of certain medicines. CAPS occurs in approximately 1% of patients with APS, but despite therapy, in 50% of cases it ends in death.

Treatment of APS

Prevention and treatment of APS are challenging. This is due to the heterogeneity of 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 mainly 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 well as with other thrombophilias) is based on the prescription of indirect anticoagulants (warfarin, acenocoumarol) and antiplatelet agents (primarily low doses acetylsalicylic acid– ASK). This is primarily due to the fact that APS is characterized by a high risk of repeated thrombosis, which significantly exceeds that of idiopathic venous thrombosis. It is believed that most patients with APS with thrombosis require prophylactic antiplatelet and/or anticoagulant therapy for a long time, and sometimes for life. In addition, the risk of primary and recurrent 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, oral contraceptives, etc.

In patients with high levels of aPL in the serum, but without clinical signs of APS (including pregnant women without obstetric pathology and medical history), one should limit oneself to the administration of 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 thromboses) 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, it outweighs the benefit of thrombosis prophylaxis. Secondly, in some patients, recurrence of thrombosis is observed after cessation of anticoagulant therapy (especially during the first 6 months after discontinuation). Thirdly, patients with APS may experience pronounced 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 ( table 2).

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 every dose in the morning, before determining the INR. In older people, lower doses of warfarin should be used to achieve the same level of anticoagulation than in younger people. It is necessary to keep in mind that warfarin interacts with a number of medications, which, 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 dietary recommendations should be given, since foods rich in vitamin K (liver, green tea, leafy vegetables - broccoli, spinach, Brussels sprouts, cabbage, turnips, lettuce) contribute 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-dose 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 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.

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

A 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.

In CAPS, the entire arsenal of intensive and anti-inflammatory therapy methods used in critical conditions of patients with rheumatic diseases is used. 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 for treatment of systemic inflammatory response syndrome (widespread necrosis, adult distress syndrome, adrenal insufficiency, etc.). Pulse therapy is usually carried out according to a 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 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 “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 advantages of this type of therapy and due to the high frequency of side effects in the mother (Cushing's syndrome, diabetes, arterial hypertension) and fetus. The use of glucocorticoids is justified only in case of secondary APS against the background of SLE, since it is aimed at treating the underlying disease. Use indirect anticoagulants during pregnancy, they are generally contraindicated due to their teratogenic effects.

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 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 if 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 clinical observation, the primary task of which is to assess the risk of recurrent thrombosis and their prevention. It is necessary to control 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 prognostically unfavorable factors with regard to mortality in APS are arterial thrombosis, a high frequency of thrombotic complications and thrombocytopenia, and among laboratory markers - the presence of 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 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

Thank you

The site provides background information for informational purposes only. Diagnosis and treatment of diseases must be carried out under the supervision of a specialist. All drugs have contraindications. Consultation with a specialist is required!

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 us to judge the risk of relapse with a high degree of reliability. 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 (APS) is also called Huge's syndrome or anticardiolipin antibody syndrome. This disease was first identified and described in 1986 in patients suffering from systemic lupus erythematosus. Currently, antiphospholipid syndrome is classified as thrombophilias– a group of diseases characterized by increased formation of blood clots.

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 the membranes of platelets, blood vessel cells 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 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.

The listed antiphospholipid antibodies cause damage to the membranes of the cells of the vascular wall, as a result of which the coagulation system is activated, a large number of blood clots are formed, with the help of which the body tries to “patch” vascular defects. Further due to large quantity blood clots, thrombosis occurs, that is, the lumen of the vessels becomes clogged, as a result of which blood cannot circulate freely through them. As a result of thrombosis, starvation occurs of cells that do not receive oxygen and nutrients, which results in the death of the cellular structures of any organ or tissue. It is the death of organ cells or tissues that gives the characteristic clinical manifestations of antiphospholipid syndrome, which can be different depending on which organ has been destroyed due to thrombosis of its vessels.

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 of 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 as a sharp deterioration in 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 impaired cerebral circulation(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 placental abruption, 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 any localization) or infectious disease (AIDS, syphilis, hepatitis C, etc.), 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 disease that a person has, 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)

Let's look at the signs of catastrophic APS and other forms of the disease separately. This approach seems rational, since the clinical manifestations of various types of antiphospholipid syndrome are the same, and only catastrophic APS has differences.

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 disease, 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. A characteristic feature of antiphospholipid syndrome is 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, most often blood clots are localized in the deep veins of the lower extremities, and somewhat less often - 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 femoral head. Thrombosis of large arteries – the abdominal aorta, ascending aorta, etc. – develops relatively rarely.

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 thrombosis of cerebral vessels in APS resemble the clinical picture of multiple sclerosis. In some cases, cerebral thrombosis causes temporary blindness or optic neuropathy.

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 into the 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 ( high blood pressure in the hepatic portal vein system).

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 of the femoral head develop.

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

Catastrophic antiphospholipid syndrome is a type of disease in which there is a rapid, fatal increase in the dysfunction of various organs due to repeated frequent episodes of massive thrombosis. In this case, respiratory distress syndrome, brain and brain disorders develop within a few days or weeks. cardiac circulation, stupor, disorientation in time and space, renal, cardiac, pituitary or adrenal failure, which, if untreated, lead to death in 60% of cases. Typically, catastrophic antiphospholipid syndrome develops in response to infection or surgery.

Antiphospholipid syndrome in men, women and children

Antiphospholipid syndrome can develop in both children and adults. In children, this disease occurs less frequently than in adults, but is more severe. Antiphospholipid syndrome occurs 5 times more often in women than in men. Clinical manifestations and principles of treatment of the disease are the same in men, women and children.

Antiphospholipid syndrome and pregnancy

What causes APS during pregnancy?

Antiphospholipid syndrome negatively affects the course of pregnancy and childbirth, as it leads to thrombosis of the placental vessels. Due to thrombosis of the placental vessels, various obstetric complications arise, such as intrauterine fetal death, fetoplacental insufficiency, fetal growth retardation, etc. In addition, APS during pregnancy, in addition to obstetric complications, can provoke thrombosis in other organs - that is, manifest itself with symptoms that are characteristic of this disease even outside the gestation period. Thrombosis of other organs also negatively affects the course of pregnancy, since their functioning is disrupted.

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.

Complications of pregnancy occurring against the background of a woman having antiphospholipid syndrome are recorded in approximately 80% of cases if APS is not treated. Most often, APS leads to pregnancy loss due to missed abortion, miscarriage, or premature birth. Moreover, the risk of pregnancy loss correlates with the level of anticardiolipin antibodies in a woman’s blood. That is, the higher the concentration of anticardiolipin antibodies, the higher the risk of pregnancy loss.

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 has no history of thrombosis or pregnancy loss during pregnancy early stages(for example, miscarriages, frozen 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.

Pregnancy management is carried out by a doctor who monitors the condition of the fetus, uteroplacental blood flow and the woman herself. If necessary, the doctor adjusts the dosage of drugs depending on the value of blood clotting indicators. This therapy is mandatory for women with APS during pregnancy. However, in addition to these drugs, the doctor may additionally prescribe other medications that are necessary for each specific woman at the current time (for example, iron supplements, Curantil, etc.).

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 natural ways. 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.

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, Sjogren's disease, periarteritis nodosa, autoimmune thrombocytopenic purpura.

Overproduction of antiphospholipid antibodies can be observed with malignant neoplasms, taking medications (psychotropic drugs, hormonal contraceptives etc.), abolition 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 before planning a pregnancy, they should definitely consult an obstetrician-gynecologist. 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 allow you to avoid the development and recurrence of thrombosis, and also 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.

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

Clinical criteria: 1. Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by imaging or Doppler or morphologically, with the exception of superficial venous thrombosis. Morphological confirmation must be provided without the presence of significant inflammation of the vascular wall. 2. Pathology of pregnancy a) one or more cases of intrauterine death of a morphologically normal fetus after 10 weeks of gestation (normal fetal morphological features documented by ultrasound or direct examination of the fetus), or b) one or more cases of preterm delivery of a morphologically normal fetus before 34 weeks of gestation due to severe preeclampsia or eclampsia, or severe placental insufficiency, or c) three or more consecutive cases of spontaneous abortions before 10 weeks of gestation (exceptions - anatomical defects of the uterus, hormonal disorders, maternal or paternal chromosomal disorders) Laboratory criteria 1. Antibodies to cardiolipin of IgG or IgM isotypes detected in serum in medium or high titers at least 2 times within 12 weeks using a standardized enzyme immunoassay method. 2. Antibodies to b2-glycoprotein I IgG and/or IgM isotype, detected in serum in medium or high titers at least 2 times within 12 weeks, using a standardized enzyme immunoassay method. 3. Plasma lupus anticoagulant, in two or more studies at least 12 weeks apart, determined according to the recommendations of the International Society of Thrombosis and Hemostasis (LA/phospholipid-dependent antibodies study group) a) prolongation of plasma clotting time in phospholipid-dependent coagulation tests: APTT, CBC, prothrombin time, tests with Russell venoms, textarine time b) lack of correction for prolongation of the clotting time of screening tests in tests mixed with donor plasma c) shortening or correction of prolongation of clotting time of screening tests when adding phospholipids e) exclusion of other coagulopathies, such as factor VIII inhibitor or heparin (which prolong phospholipid-dependent blood coagulation tests)

Note. A specific APS is diagnosed if one clinical and one serological criterion is met. APS is excluded if aPL without clinical manifestations or clinical manifestations without aPL are detected for less than 12 weeks or more than 5 years. The presence of congenital or acquired risk factors for thrombosis does not exclude APS. Patients should be stratified by a) presence and b) absence of risk factors for thrombosis. Depending on aPL positivity, it is recommended to divide APS patients into the following categories: 1. detection of more than one laboratory marker (in any combination); IIa. VA only; II century aCL only; only antibodies to b2-glycoprotein I.

A particular aPL profile can be identified as a high or low risk for subsequent thrombosis

Table 2. High and low risk of having various aPLs for subsequent thrombosis

a Studied for systemic lupus erythematosus (SLE) only

Recommendations are graded according to the American College of Chest Physicians (ACCP) system: strength of recommendation is based on risk/benefit ratio: grade 1: “strong” recommendation = “we recommend”; grade 2 “weak” recommendation = “we advise” "The quality of evidence is graded: scientific evidence. High Quality=A; average quality =B; low or very low quality = C, so there are 6 possible recommendation classes: 1A; 1B; 1C; 2A; 2B;2C.

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

Diseases	Clinical manifestations
Systemic vasculitis
Polyarteritis nodosa	LS, distal gangrene of the extremities, skin ulcers, skin necrosis, damage to the central nervous system, kidneys
Thromboangiitis obliterans (Buerger-Winiwarter disease)	Recurrent migrating phlebitis, distal gangrene of the extremities, skin ulcers, skin necrosis, myocardial infarction, mesenteric vascular thrombosis, central nervous system damage
Hemorrhagic vasculitis	Hemorrhagic skin rashes, ulcers and skin necrosis, kidney damage
Temporal arteritis (Horton's disease)	Retinal artery thrombosis, headaches
Nonspecific aortoarteritis (Takayasu disease)	Aortic arch syndrome, heart valve disease
TTP (Moschkowitz disease)	Recurrent thrombosis of vessels of various sizes, thrombocytopenia, hemolytic autoimmune anemia
Hemolytic-uremic syndrome	Recurrent thrombosis of vessels of various sizes, kidney damage, hemolytic anemia, hemorrhages
Cutaneous vasculitis	Skin ulcers and necrosis, livedo-vasculitis
Rheumatic diseases
Acute rheumatic fever	Formation of heart defects, thrombosis of vessels of various locations (usually the central nervous system and extremities) according to the mechanism of cardiogenic thromboembolism
SLE	Thrombosis, hematological disorders, livedo
Scleroderma	Livedo, distal gangrene of the extremities, skin ulcers
Thrombophilia
Hereditary (as a result of mutations in coagulation factors, plasma anticoagulants)	Recurrent thrombosis of vessels of various sizes and locations, skin ulcers
DIC syndrome	Thromboembolic complications, thrombocytopenia, skin ulcers
Infectious diseases
Tuberculosis, viral hepatitis, etc.	Thromboembolism, transverse myelitis, livedo

The differential diagnosis from thromboembolic disease depends on the vascular bed involved (venous, arterial, or both).

For venous occlusions, if only venous thrombosis or PE is determined, the differential diagnosis includes:
acquired and genetic thrombophilias;
fibrinolysis defects;
neoplastic and myeloproliferative diseases;
· nephrotic syndrome.

Persons with venous thrombosis under 45 years of age with first-degree relatives with thrombosis at a young age should be tested for genetic thrombophilia. Today it is clear that aPL research should be carried out in some endocrine diseases: Addison's disease and hypopituitarism (Sheehan syndrome). Although the indication of venous thrombosis is an indicator of thrombophilic status, at the same time, some associated clinical manifestations may be a sign of a systemic disease with a higher risk of venous thrombosis. For example, an indication in the anamnesis of painful ulcers mucous membranes in the mouth and genitals in young patients with venous thrombosis should lead to the diagnosis of Behcet's disease, in which, like APS, vessels of any caliber are affected.

If thrombosis of only the arterial bed is detected, the following diseases are excluded:
· atherosclerosis;
· embolism (with atrial fibrillation, atrial myxoma, endocarditis, cholesterol emboli), myocardial infarction with thrombosis of the ventricles of the heart;
· decompression states (Caesson's disease);
· TTP/hemolytic-uremic syndrome.

Young patients with strokes require special attention, in whom aPL is detected in the blood in more than 18% of cases (Kalashnikova L.A.). Some aPL-positive patients may have clinical manifestations similar to multiple sclerosis, which are a consequence of multiple cerebral infarcts confirmed by neuroimaging (MRI). A similar type of damage to the central nervous system is observed when multiple sclerosis and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These patients should be carefully questioned about the presence of family members with strokes and dementia at a young age. When examining autopsies similar cases multiple deep small cerebral infarctions and diffuse leukoencephalopathy are found. This genetic defect is linked to chromosome 19.

In case of combined thrombosis (arterial and venous), the differential diagnosis includes:
· disorders in the fibrinolysis system (dysfibrinogenemia or plasminogen activator deficiency);
· homocysteinemia;
myeloproliferative diseases, polycythemia;
· paradoxical nocturnal hemoglobinuria;
· blood hyperviscosity, for example, with Waldstrom macroglobulinemia, sickle cell disease, etc.;
· vasculitis;
· paradoxical embolism.

When recurrent occlusions of the microvasculature are combined with thrombocytopenia, the differential diagnosis is made between thrombotic microangiopathies (Table 4).

Table 4. Main clinical and laboratory signs associated with thrombocytopenia in antiphospholipid syndrome and thrombotic microangiopathies

Signs	AFS	CAFS	TPP	ICE
Renal involvement	+ -	+ +	+ -	+ -
CNS involvement	+ -	+ +	++	+ -
Multiple organ failure	+ -	+ +	++	+-
Hemorrhages	- -	± -	+ -	+ +
Antibodies to platelets	+ -	+ -	- -	- -
Coombs' direct reaction is positive	+ -	+ -	- -	- -
Schistocytes	- -	± -	+ +	+ -
Hypofibrinogenemia	- -	± -	- -	+ +
APTT prolongation	+ - *	+ - *	- -	+ + #
PDF	- -	+ -	- -	+ +
Hypocomplementemia	+ -	+ -	- - ≠	- - §
ANF+	+ -	+ -	- - ≠	- - §
aFL+	+ +	+ +	- - ≠	- - §

Note: APS - antiphospholipid syndrome, CAPS - catastrophic APS, TTP - thrombotic thrombocytopenic purpura, DIC - disseminated intravascular coagulation, APTT - activated partial thromboplastin time, FDP - fibrinogen degradation products, ANF - antinuclear factor, aPL - antiphospholipid antibodies.
*negative mixing test (when determining lupus anticoagulant).
# positive mixing test (when determining lupus anticoagulant).
≠ TTP may be associated with SLE.
§ DIC may be associated with CAPS.

The differential diagnosis between APS and thrombotic angiopathies is often difficult. It must be taken into account that minor thrombocytopenia in APS may be associated with platelet activation and consumption; many clinical and laboratory manifestations may be common to SLE and TTP. TTP can develop in patients with SLE and, conversely, aPL can occur in TTP, hemolytic-uremic syndrome and HELLP syndrome, and DIC is observed in CAPS. The study of aPL as a screening test is indicated for patients with thrombocytopenia of unknown origin, especially pregnant women with thrombocytopenia, when the risk of hemorrhage due to thrombocytopenia and the risk of thrombosis due to aPL worsens the outcome of both the fetus and the mother.

Skin manifestations, among which livedo is the most common, can occur in various rheumatic diseases. Moreover, skin necrosis, skin ulcers, changes in skin color from pallor to redness require the exclusion of systemic vasculitis, as well as secondary vasculitis due to infections. Pyoderma gangrenosum is also a common cutaneous manifestation of systemic rheumatic diseases, but there are case reports.

Pathology of the heart valves requires the exclusion of infective endocarditis and chronic rheumatic fever. Tables 5 and 6 show the signs found in these pathologies. As you can see, there are a number of similar signs. Rheumatic fever (RF) and APS are two diseases with similar clinical presentations. The triggering factor in both pathologies is infection. In LC, an infectious agent has been proven - group b-hemolytic streptococcus Streptococcus pyogenes. Molecular mimicry between the microbe and heart tissue molecules explains the etiology of the disease LC; similar mechanisms also occur in APS. The timing of the development of the disease after infection in LC and APS is different. RL is induced in the first three weeks after infection, there is a clear connection with previous streptococcal infection, while with APS most cases develop according to the “hit and run” mechanism, i.e. the development of the disease is delayed in time. The nature of damage to the heart valves is also different. In APS, valve stenosis rarely develops and, unlike rheumatic stenosis, in these patients, according to our data, there was no commissure fusion; the narrowing of the orifice was caused by large thromboendocardial overlaps and deformation of the leaflets.

Table 5. Differential diagnosis of heart valve disease in antiphospholipid syndrome, rheumatic fever and infective endocarditis

Signs	AFS	Rheumatic fever	Infective endocarditis
Fever	+/-	+/-	+
Leukocytosis	-	-	+
SRB	-	-	+
Blood culture	-	-	+
aFL	+	-	-
Echo-KG	Diffuse thickening or local thickening of the middle part of the valve or its base	Limited valve thickening involving the superior portion, notochord thickening and fusion, valve calcification	Limited overlap on the atrial or aortic or atrioventricular surface with valve rupture

Table 6. Similar manifestations of antiphospholipid syndrome and acute rheumatic fever (ARF) (Blank M. et al., 2005)

Signs	ORL	AFS
Heart valve deformation	+	+
Histology	Ashof-Talaev granulomas	Fibrosis (collagen IV)
Treatment	Valve replacement	Valve replacement
Damage to the central nervous system (chorea)	+	+
Infection	+ Streptococcus pyogenes	+ Streptococcus pyogenes and etc.
Molecular mimicry	+	+
Infiltration of tissues by lymphocytes	+, including T, M protein-reactive cells	+, including T, reacting with b2 GP1
HLA	DR7+, DR53, DRB1*04, DQA1*03	DRB4*0103(DR53), DM*0102
Complement deposits	+	+
Expression of adhesion molecules	VCAM-I	a1-integrin
Antibodies	M-protein and myosin, GlcNA, laminin, b2 GP1	b2 GP1 to cardiolipin and prothrombin, annexin-V, M-protein

Obstetric pathology of APS also requires laboratory confirmation and exclusion of other causes of pregnancy loss. These include genetic thrombophilia and inflammatory pathology of the genital organs. APL can be detected in infectious diseases at low or moderate positive levels, and repeated aPL studies after 12 weeks are necessary to exclude a connection with infection.

In conclusion, it should be emphasized that APS is an antibody-induced thrombosis, the basis for the diagnosis of which, along with clinical manifestations, is the mandatory presence of serological markers. Obstetric pathology in APS should be considered as a thrombotic complication. A single study of aPL does not allow verification or exclusion of APS.

Treatment abroad

Get treatment in Korea, Israel, Germany, USA

Get advice on medical tourism

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 the laboratory criteria for the diagnosis of APS, are treated with anticoagulants no different from the management of 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 the two regimens of high-intensity and standard, it was shown that high intensity of hypocoagulation was associated with a high frequency 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 bleeding was much less common than death due to thrombosis.

4. An assessment of the patient's risk of bleeding should be performed prior to the appointment. high degree hypocoagulation or 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. Patients with aPL, but without SLE and without previous thrombosis with aPL profile high risk Long-term use of low-dose aspirin is recommended, 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, oral contraceptives. In a case-control study, the risk of stroke doubled in smoking women with VA, compared with non-smokers; 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 feature of the diagnostic criteria for 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 with a high risk of thrombosis profile, 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 accurate diagnosis CAFS developed a step-by-step approach to the CAFS algorithm. This algorithm included a previous history of APS or constant positivity for aPL, the number of organs involved, time of outcome, the presence of microthrombosis according to biopsy, and other data that could explain the cause of multiple thrombosis.

Evidence-based information is provided in four retrospective studies that analyzed the CAPS registry. The most important conclusions on the treatment of CAPS come down to the following conclusions:
1. High level 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 i.v. in 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 of these factors 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 of unfractionated or low molecular weight heparin in therapeutic doses as fast 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.