Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is characterized by a specific clinical and laboratory symptom complex, including venous and/or arterial thromboses, various forms of obstetric pathology (primarily habitual miscarriage), thrombocytopenia, as well as other neurological, hematological, cutaneous, cardiovascular syndromes in the presence of antiphospholipid antibodies (aPL) in the circulating blood. aPL include lupus anticoagulant (LA) and antibodies to cardiolipin (aCL), reacting with antigenic determinants of negatively charged membrane phospholipids or phospholipid-binding proteins (beta2-glycoprotein-1, annexin V).

APS occurs alone or in combination with other autoimmune diseases, especially systemic lupus erythematosus (SLE).

APS is defined based on the consensus criteria for the international classification adopted in Sydney in 2006 [ 1 ]. It requires clinical criteria such as vascular (venous or arterial) thrombosis or morbidity during pregnancy, and a laboratory criterion based on persistent antiphospholipid antibodies present on two or more occasions at least 12 weeks apart. Antiphospholipid antibodies accepted in the laboratory criteria include lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β 2 -glycoprotein I (anti-β 2 GPI) IgG and IgM.

Epidemiology

The reported annual incidence of APS was 2.1 per 100,000 people, while the estimated prevalence was 50 per 100,000 population [ 2 ]

According to American authors, the incidence of antiphospholipid syndrome in the population reaches 5%. Among patients with habitual miscarriage, antiphospholipid syndrome is 27-42%, according to other researchers - 30-35%, and without treatment, embryo/fetus death is observed in 85-90% of women with autoantibodies to phospholipids. The incidence of secondary antiphospholipid syndrome in women is 7-9 times higher than in men, which is probably explained by the greater predisposition of women to systemic connective tissue diseases.

The exceptional importance of treating antiphospholipid syndrome is that the main complication of the disease is thrombosis. It is especially important that:

• 22% of women with antiphospholipid syndrome have a history of thrombosis, 6.9% - thrombosis of cerebral vessels;
• 24% of all thrombotic complications occur during pregnancy and the postpartum period.

The risk of thrombotic complications increases during pregnancy and in the postpartum period, as there is a physiological increase in the coagulation potential of the blood against the background of hypervolemia.

Causes antiphospholipid syndrome

Antiphospholipid syndrome may be primary, when there is no evidence of autoimmune disease, or secondary to autoimmune processes such as systemic lupus erythematosus (SLE), in 40% of cases.[ 3 ]

Despite the active study of the mechanisms of APS development, the etiology of this disease remains unclear. It is known that infectious agents can in some cases be triggers for the production of aPL. [ 4 ]

An increase in aPL titers is observed against the background of viral infections [hepatitis C virus, HIV, cytomegalovirus, adenovirus, herpes zoster virus (Herpes zoster), rubella, measles, etc.], bacterial infections (tuberculosis, staphylococcal and streptococcal infections, salmonellosis, chlamydia), spirochetosis (leptospirosis, syphilis, borreliosis), parasitic infections (malaria, leishmaniasis, toxoplasmosis).

Genetic risk factors increase the risk of antiphospholipid antibody-associated thrombosis, such as mutations in coagulation factors. HLA-DR7, DR4, DRw53, DQw7, and C4 null alleles have been reported to be associated with antiphospholipid syndrome.[ 5 ] Family and population studies have shown that the loci most likely involved in susceptibility to developing aPL and APS are HLA-DR4, DR7, DR9, DR13, DR53, DQ6, DQ7, and DQ8, and in particular, those most represented in several ethnic groups appear to be HLA-DR4 and HLA-DRw53.[ 6 ]

One of the first genetic risk factors for antiphospholipid syndrome to be discovered outside the HLA region was a polymorphism of the β2GPI gene. A recent meta-analysis [ 7 ] found an association between the β2GPI Val/Leu247 polymorphism and antiphospholipid syndrome, and functional studies found a correlation between this variant and the production of antibodies against β2GPI. [ 8 ]

Other genes that may play a role in the etiology of APS include genes involved in the inflammatory response, such as Toll-like receptor 4 (TLR4) and Toll-like receptor 2 (TLR2), [ 9 ], [ 10 ] as well as in platelet adhesion, such as integrin subunit alpha 2 (GP Ia) and integrin subunit beta 3 (GP IIIa) [ 11 ], [ 12 ] in patients who have experienced thrombotic events. Other genes include genes involved in the blood coagulation cascade, such as protein C receptor (PROCR) and Z-dependent protein inhibitor (ZPI). [ 13 ], [ 14 ]

A total of 16 genes associated with thrombotic PAPS were found in 22 studies: PF4V1 (platelet factor 4 variant 1), SELP (selectin P), TLR2 (Toll-like receptor 2), TLR4 (Toll-like receptor 4), SERPINE1 (Serpin). family member E 1), B2GP1 (beta-2-glycoprotein I), GP Ia (integrin alpha 2 subunit), GP1BA (platelet glycoprotein Ib alpha subunit), F2R (coagulation factor II receptor), F2RL1 (coagulation factor II receptor-like receptor 1), F2 (coagulation factor II), TFPI (tissue factor pathway inhibitor), F3 (coagulation factor III), VEGFA (vascular endothelial growth factor A), FLT1 (FMS-related tyrosine kinase 1), and TNF (tumor necrosis factor).[ 15 ],[ 16 ]

Pathogenesis

The pathogenesis is based on venous and arterial thromboses (non-inflammatory), which can occur in any part of the vascular bed.

Despite the active study of the pathogenesis of antiphospholipid syndrome, it remains unknown whether the presence of aPL alone leads to the development of thrombosis, why thrombosis does not manifest in some patients with elevated aPL titers, and why catastrophic antiphospholipid syndrome does not develop in all cases. The proposed two-factor hypothesis considers the presence of aPL as a potential risk factor for thrombosis, which is realized in the presence of another thrombophilic factor.

There are primary (genetically determined) and secondary (acquired, symptomatic) forms of thrombophilia, which differ from each other in etiology, the nature of hemostasis disorders, complications and prognosis, requiring a differentiated approach to prevention and treatment, but often occurring with similar clinical manifestations.

Primary (genetically determined) and acquired variants of thrombophilia in patients with venous thrombosis

Primary (genetically determined) thrombophilia: -

• polymorphism G1691A in the gene of blood coagulation factor V (factor V Leiden);
• polymorphism G20210A in the prothrombin gene (blood coagulation factor II);
• homozygous genotype 677TT in the gene encoding methylenetetrahydrofolate reductase;
• deficiency of natural anticoagulants [antithrombin III (AT III), proteins C and S];
• sticky platelet syndrome;
• hyperhomocysteinemia;
• increased activity or amount of coagulation factor VIII;
• rare causes (dysfibrinogenemia, deficiency of factors XII, XI, heparin cofactor II, plasminogen).

Acquired conditions:

• malignant neoplasms;
• surgical interventions;
• trauma (especially fractures of long bones);
• pregnancy and postpartum period;
• taking oral contraceptives, substitution therapy in the postmenopausal period;
• immobilization;
• myeloproliferative diseases (polycythemia vera, thrombocythemia, myeloproliferative changes, essential thrombocythemia);
• hyperhomocysteinemia;
• congestive heart failure;
• nephrotic syndrome (loss of AT III in urine);
• hyperviscosity;
• macroglobulinemia (Waldenstrom's disease);
• myeloma disease;
• antiphospholipid syndrome;
• permanent central venous catheter;
• inflammatory bowel disease;
• obesity.

APS as a variant of hematogenous thrombophilia (the leading criterion is venous thrombosis) is a common form of hematogenous thrombophilia. Its share among phlebothrombosis of various localizations is from 20 to 60%. However, the true prevalence of APS in the population of patients with venous thrombosis remains unclear. Currently, APS is a general medical problem, the study of which has long gone beyond rheumatic diseases, in particular systemic lupus erythematosus (SLE), in which this form of autoimmune hematogenous thrombophilia has been studied most thoroughly. Due to the unpredictability and diversity of clinical manifestations, APS can be called one of the most mysterious forms of hematogenous thrombophilia in the clinic of internal diseases.

Thrombotic conditions in APS can be caused by the following mechanisms.

Suppression of the activity of physiological anticoagulants proteins C and B, AT III (reduction of heparin-dependent activation), leading to thrombinemia.

Suppression of fibrinolysis:

• increase in plasminogen activator inhibitor (PA1);
• inhibition of factor XII-dependent fibrinolysis/

Endothelial cell activation or damage:

• enhancing the procoagulant activity of endothelial cells;
• increased expression of tissue factor and adhesion molecules;
• decreased prostacyclin synthesis;
• increasing the production of von Willebrand factor;
• disruption of the functional activity of thrombomodulin, induction of apoptosis of endothelial cells.

Activation and aggregation of platelets are caused by the interaction of aPL with protein-phospholipid complexes of the membrane surfaces of platelets, increased synthesis of thromboxane, and an increase in the level of platelet activating factor

The ability of anti-endothelial antibodies and antibodies to beta-glycoprotein-1 to react with various antigens of the endothelial cell membrane of intravalvular capillaries and the superficial endocardium with the development of histiocytic-fibroplastic infiltration of the valves, focal fibrosis and calcification, and valve deformation.

In an experimental model of aPL-associated fetal loss, data were obtained confirming the great importance of tumor necrosis factor-a (TNF-a) in this.

Symptoms antiphospholipid syndrome

Clinical manifestations of APS [ 17 ]

Frequent (>20% of cases)

• Venous thromboembolism.
• Thrombocytopenia.
• Miscarriage or loss of the fetus.
• Heart attack or transient ischemic attack.
• Migraine.
• Livedo mesh.

Rare (10-20% of cases)

• Heart valve disease.
• Preeclampsia or eclampsia.
• Premature birth.
• Hemolytic anemia.
• Ischemic heart disease.

Very rare (<10% of cases)

• Epilepsy.
• Dementia.
• Chorea.
• Retinal artery occlusion.
• Pulmonary hypertension.
• Venous ulcer of the leg.
• Gngren.
• Osteonecrosis.
• Nephropathy.
• Mesenteric ischemia.

<1% of cases

• Adrenal bleeding.
• Transverse myelitis.
• Budd-Chiari syndrome.
• Sneddon syndrome.
• Respiratory distress syndrome.
• Addison's syndrome.
• Regenerative nodular hyperplasia of the liver.
• Osteonecrosis.
• Skin necrosis.

Although cardiac manifestations of APS are not included in the diagnostic criteria for this disease, cardiac lesions remain important manifestations of nonthrombotic vasculopathy and can range from asymptomatic valvular lesions to life-threatening myocardial infarction.

Cardiological manifestations of antiphospholipid syndrome

Diagnosis	Frequency of occurrence in APS, %
Valvular pathology Vegetations (pseudoinfective endocarditis) Thickening, fibrosis and calcification of valve leaflets Valvular dysfunction (usually insufficiency)	- More than 1 More than 10 More than 10
Myocardial infarction: thrombosis of large branches of coronary arteries intramyocardial thrombosis restenosis after coronary artery bypass grafting restenosis after percutaneous transluminal coronary angioplasty	More than 1 More than 1
Impaired systolic or diastolic function of the ventricles (chronic ischemic dysfunction)	More than 1
Intracardiac thrombosis	Less than 1
Arterial hypertension	More than 20
Pulmonary hypertension	More than 1

Arterial hypertension in antiphospholipid syndrome

A frequent clinical sign of antiphospholipid syndrome (up to 28-30%). It can be caused by intrarenal ischemia due to thrombotic microangiopathy, thrombosis of large renal vessels, renal infarction, thrombosis of the abdominal aorta. Often, arterial hypertension in APS is labile, in some cases - stable malignant. For clinicians, the combination of arterial hypertension with such a characteristic skin lesion as reticular livedo and thrombosis of cerebral vessels is important, which is called Sneddon syndrome.

Damage to the heart valves is found in 30-80% of patients with both APS in SLE and primary APS. Thickening of the valve leaflets (in the mitral cup) is the most common cardiac manifestation in patients with positive aPL even in the absence of vascular or obstetric pathology in both primary and secondary APS (in SLE). Thickening of the tricuspid valve occurs in about 8% of cases. It is believed that valve lesions are more common in primary APS and are associated with the aPL titer. Valve lesions in APS resemble those in SLE: thickening of the valve leaflets (more than 3 mm), asymmetric nodular growths along the edge of the valve closure or on the atrial surface of the mitral and/or ventricular surface of the aortic valves. Changes may vary from minor to gross valve deformations (much less common), accompanied by attacks of cardiac asthma and severe circulatory failure, requiring surgical treatment. Despite the fact that damage to the heart valves is not included in the list of modern diagnostic criteria for APS, in case of valve disorders, close medical supervision is necessary due to the significant probability of developing strokes and transient ischemic attacks in patients with initially existing hypercoagulation caused by the action of aPL.

An important sign is considered to be calcification of the mitral and aortic valves of the heart, which is considered a marker and a powerful predictor of atherosclerotic lesions of the coronary arteries.

Thrombotic or atherosclerotic occlusion of coronary vessels

The basis of coronary artery disease in APS is arterial thrombosis, which may accompany coronary artery atherosclerosis or, most interestingly, be a manifestation of thrombotic vasculopathy in the absence of inflammatory or atherosclerotic vascular wall disease. The incidence of myocardial infarction in primary APS is quite low, while in secondary APS the prevalence of peripheral artery and coronary artery atherosclerosis exceeds that in the population. APS diagnostics should be performed in young patients with coronary pathology or myocardial infarction, especially in the absence of objective risk factors for coronary heart disease.

Systolic and/or diastolic dysfunction

Studies are few and the true prevalence is unknown. There are reports that in PAFS, the diastolic function of the left or right ventricle is impaired to a greater extent, while in SLE, the systolic function of the left ventricle is impaired. Researchers suggest that the systolic and diastolic dysfunction is based on chronic ischemic cardiomyopathy against the background of thrombotic vasculopathy.

Pulmonary hypertension often develops in connection with pulmonary thromboembolic disease in patients with venous thromboses and often leads to right ventricular failure and pulmonary heart disease. A peculiarity is the tendency to recurrent thromboembolic complications in patients with APS. In patients with primary pulmonary hypertension, along with the determination of genetically determined thrombophilia markers, screening for APS should also be performed due to the possibility of developing thrombosis in the microcirculatory bed.

Intracardiac thrombi can form in any of the heart chambers and clinically mimic cardiac tumors (myxoma).

Forms

The following forms of antiphospholipid syndrome are distinguished:

Primary APS as an independent disease that lasts for a long time without any signs of another predominant pathology. This diagnosis requires a certain alertness from the doctor, since primary APS can transform into SLE over time.

Secondary APS developing within the framework of SLE or another disease.

Catastrophic APS, characterized by widespread thrombosis leading to multiple organ failure, disseminated intravascular coagulation syndrome (DIC syndrome).

Complications and consequences

Catastrophic antiphospholipid syndrome (CAPS) is a rare and potentially life-threatening complication of antiphospholipid syndrome (APS) that requires emergency treatment. This condition occurs in less than 1% of people with APS. [ 18 ]

Diagnostics antiphospholipid syndrome

In 2006, the diagnostic criteria for antiphospholipid syndrome were revised.[ 19 ]

Clinical criteria

Vascular thrombosis

• One (or more) clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. Thrombosis must be documented (angiographic, Doppler, or pathological) with the exception of superficial thromboses. Pathological confirmation must be presented without significant inflammation of the vessel wall.
• Pathology of pregnancy
  • One or more cases of intrauterine death of a morphologically normal fetus after the 10th week of gestation (normal fetal morphology is documented by ultrasound or direct examination of the fetus).
  • One or more cases of premature birth of a morphologically normal fetus before the 34th week of gestation due to severe preeclampsia, or eclampsia, or severe placental insufficiency.
  • Three or more consecutive cases of spontaneous abortions before the 10th week of gestation (excluding anatomical defects of the uterus, hormonal disorders, maternal or paternal chromosomal abnormalities).

Laboratory criteria

• Antibodies to cardiolipin of IgG isotypes and/or IgM isotypes, determined in serum in medium or high titers at least 2 times within 12 weeks using a standardized enzyme immunoassay,
• Antibodies to beta2-glycoprotein-1 IgG isotypes and/or IgM isotypes, determined in serum in medium or high titers at least twice within 12 weeks using a standardized enzyme immunoassay.
• Lupus anticoagulant in plasma in two or more studies at least 12 weeks apart, as defined by the International Society on Thrombosis and Haemostasis (LA/Phospholipid-Dependent Antibody Study Group) guidelines:
• increase in clotting time in phospholipid-dependent coagulation tests (APTT, kaolin clotting time, prothrombin time, tests with Russell's viper venom, textarin time);
• lack of correction for increased clotting time of screening tests when mixed with donor plasma;
• shortening or correction of the increase in clotting time of screening tests with the addition of phospholipids;
• exclusion of other coagulopathies, such as factor VIII inhibitor or heparin (which prolong phospholipid-dependent coagulation tests).

A definite APS is diagnosed in the presence of one clinical or laboratory criterion. In case of detection of aPL without clinical manifestations or clinical signs without laboratory confirmation for a period of less than 12 weeks or more than 5 years, the diagnosis of "APS" should be questioned. The concept of a "seronegative variant" of APS is discussed by various researchers, but this term is not generally accepted. [ 20 ]

Diagnosis of congenital (polymorphism of genes encoding coagulation factor V, methylenetetrahydrofolate reductase, prothrombin, plasminogen, etc.) and acquired risk factors for thrombosis does not exclude the possibility of developing antiphospholipid syndrome.

Depending on the presence of certain APL, APS patients can be divided into the following groups:

• category I - positivity for more than one laboratory marker (in any combination);
• category IIa - only BA-positive;
• category IIb - only aCL-positive;
• Category IIc - positive only for antibodies to beta1-glycoprotein-1.

When interviewing patients, it is advisable to clarify the presence of thrombosis and obstetric pathology in close relatives, the presence or absence of acquired risk factors for thrombosis (trauma, surgery, long-term flights, taking hormonal contraceptives, etc.), and find out the obstetric anamnesis. Due to the risk of developing APS, it is necessary to be especially vigilant in relation to young and middle-aged patients who developed thromboembolic complications in the absence of possible acquired risk factors for thrombosis and had a tendency to relapse.

Physical examination

Given the diversity of the clinical picture, the patient's examination should be directed towards diagnosing signs of the disease associated with ischemia or thrombosis of various organs and systems, and searching for the underlying disease that contributed to the development of APS.

The main and most frequent (20-30%) clinical symptoms of antiphospholipid syndrome are deep vein thrombosis of the extremities, spontaneous abortions in early pregnancy, thrombocytopenia, reticular li and velo, migraine, acute cerebrovascular accident and transient ischemic attacks, pulmonary embolism, spontaneous abortions in late pregnancy, thickening or dysfunction of the heart valves, hemolytic anemia. According to the Research Institute of Rheumatology, the following occur with a frequency of over 1%: preeclampsia, eclampsia, epilepsy, leg ulcers, transient blindness, myocardial infarction, thrombosis of the arteries of the lower extremities, thrombosis of the veins of the upper extremities, pseudovasculitis lesions, gangrene of the fingers and toes, cardiomyopathy, angina pectoris, vegetations on the valves, kidney damage, multi-infarct dementia, skin necrosis, avascular necrosis of bone, pulmonary hypertension, thrombosis of the subclavian vein, acute encephalopathy, restenosis after aortocoronary bypass grafting (CABG), gastrointestinal tract damage (esophageal and intestinal ischemia), thrombosis of the retinal arteries, splenic infarction, pulmonary microthrombosis, optic neuropathy. More rare manifestations of antiphospholipid syndrome include transient amnesia, cerebral vein thrombosis, cerebral ataxia, intracardiac thrombosis, pancreatic infarction, Addison's disease, liver damage (Budd-Chiari syndrome), retinal vein thrombosis, hemorrhages in the nail bed, and postpartum cardiopulmonary syndrome.

Laboratory diagnostics of APS (International Preliminary Criteria for the Classification of APS, Sydney, 2005) is based on the detection of lupus anticoagulant and determination of aPL titers. In parallel, screening tests are performed on the test and normal plasma (APTT, kaolin plasma clotting time, test with diluted Russell viper venom, prothrombin time with diluted thromboplastin), confirmatory tests with a mixture of the test and normal plasma (persistent hypocoagulation according to screening tests) and the test plasma with excess of compensating phospholipids (normalization of clotting time according to screening tests).

At present, there is no proven association between the values of total antibodies to the beta2-glycoprotein-1 complex with cofactor proteins (phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylcholine, prothrombin, etc.) and the development of APS. Moderate and significant increases in IgG and IgM class ACL and IgG and IgM class beta2-glycoprotein-1 antibodies, determined in two measurements with an interval of at least 6 weeks (they are considered laboratory criteria for APS) are considered clinically significant.

In patients with APS, it is recommended to determine the level of homocysteine, an independent risk factor for the development of atherosclerosis and thrombosis (recurrent venous thrombosis, stroke, myocardial infarction, carotid artery disease). It is also possible to examine for the presence of genetically determined and other acquired thrombophilia in order to determine the risk of thrombosis and its recurrence.

Instrumental methods include:

• Ultrasound Doppler scanning of blood vessels and venography: used for topical diagnosis of venous and arterial thrombosis;
• Doppler echocardiography: allows diagnosing changes in valves in both APS and SLE (Libman-Sachs endocarditis), intracardiac thrombi, the presence and degree of pulmonary hypertension. A significant difference between valve damage and rheumatic valvulitis is the thickening of the valve leaflet in APS, extending to the middle part and the base of the leaflet. Damage to the chords in APS is extremely uncharacteristic;
• radioisotope lung scintigraphy and angiopulmonographic examination: verification of pulmonary embolism and determination of the need for thrombolytic treatment;
• ECG, 24-hour Holter monitoring (confirmation of myocardial ischemia), blood pressure monitoring;
• cardiac catheterization and coronary angiography: indicated for patients to assess the state of coronary blood flow, as well as the presence of atherosclerotic lesions of the coronary arteries;
• Magnetic resonance imaging of the heart and large vessels: an indispensable method for differentiating intracardiac thromboses and cardiac tumors (myxoma). In some cases, it can be an alternative method for studying the viability and perfusion of the myocardium;
• computed tomography, multispiral and electron beam tomography of the heart: diagnosis and quantitative assessment of coronary artery calcification as a marker of coronary atherosclerosis, as well as thrombi in the chambers of the heart.

Treatment antiphospholipid syndrome

Treatment for antiphospholipid syndrome (APS) aims to reduce the risk of developing more blood clots. [ 21 ]

Due to the heterogeneity of the mechanisms of development of antiphospholipid syndrome, at present there are no unified international standards for the treatment and prevention of thrombotic complications that primarily determine the prognosis of this form of hematogenous thrombophilia.

Since the development of APS is based on thrombotic vasculopathy from capillaries to large vessels, manifested by thromboses with a high risk of relapse, all patients with APS, especially with signs of cardiovascular damage, even in the absence of acquired risk factors for thrombosis, should undergo prophylactic anticoagulant treatment of antiphospholipid syndrome. In the development of APS in patients with SLE, glucocorticoids and cytostatic drugs are used in the treatment along with anticoagulant effects. However, long-term treatment with glucocorticoids has procoagulant activity, i.e. increases the risk of thrombosis.

Currently, most authors recommend, in the absence of clinical symptoms in patients with valve pathology caused by APS, to prescribe antiplatelet therapy - low doses of acetylsalicylic acid. In case of thromboembolic complications in patients with damage to valve structures, intracardiac thromboses, pulmonary hypertension, disorders of systolic or diastolic function of the left ventricle, more active measures are needed to form stable hypocoagulation. This can be achieved by long-term administration of vitamin K antagonists. In the presence of combined forms of hematogenous thrombophilia (APS + genetically determined), as well as acquired risk factors for thrombosis, prophylactic anticoagulant treatment can be indefinitely long, often lifelong.

The main drug for prophylactic anticoagulant treatment is warfarin, a coumarin derivative. The dose of warfarin is selected individually, as in other hematogenous thrombophilias, depending on the standardized INR determined by the prothrombin time, taking into account the sensitivity of the thromboplastin used. In case of acute thrombosis, warfarin is prescribed simultaneously with heparin in a minimum dosage until the INR reaches 2.0 one day before the heparin is discontinued. Subsequently, the optimal INR values for APS are 2.0-3.0 in the absence of additional risk factors for thrombosis and 2.5-3.5 - with a high risk of recurrent thrombosis (the presence of acquired and hereditary risk factors for thrombosis). The main problem with long-term use of warfarin is the risk of hemorrhagic complications, which in some cases require dose adjustment of this drug or its discontinuation. Also, with APS, the risk of warfarin necrosis (rebound thrombosis on the 3rd-8th day of starting coumarin use) may increase, which is based on thrombosis of small skin vessels. This severe complication is aggravated in patients with initially impaired activity of natural anticoagulants - proteins C and S, in particular due to the V Leiden polymorphism, which contributed to the resistance of coagulation factor V to activated protein, which once again emphasizes the need for targeted testing for other thrombophilia variants in patients with APS. In case of detection of the above combinations of thrombophilia, it is preferable to focus on the administration of low molecular weight heparins (LMWH).

The main distinguishing feature of LMWH is the predominance of fractions with a molecular weight of less than 5400 Da and the almost complete absence of large-molecular components that prevail in conventional (unfractionated) heparin. LMWH predominantly inhibit factor Xa (anti-Xa activity), rather than thrombin (anti-IIa activity), which is why the antithrombotic effect is due to weak ancoagulant activity. This characteristic of these drugs allows the use of doses that effectively prevent venous thrombosis and thromboembolic complications with minimally expressed hypocoagulation (a limiting factor in long-term treatment of patients with venous thrombosis).

High bioavailability (about 90%) and average duration of antithrombotic effect after a single injection (about 24 hours) allow to limit one or two injections per day and facilitate the use of LMWH in those patients who need long-term thrombosis prevention. The significantly lower affinity of LMWH to the antiheparin factor of platelets determines their less pronounced ability to cause such a formidable complication as heparin-induced thrombotic thrombocytopenia.

• Type I heparin-induced thrombotic thrombocytopenia (a decrease in the number of platelets by no more than 20%) develops within the first hours or days after the administration of heparins, is usually asymptomatic and is not a contraindication for further treatment.
• Type II heparin-induced thrombotic thrombocytopenia is a serious complication caused by an immune reaction in response to the administration of heparin, occurring with serious hemorrhagic complications, requiring immediate discontinuation of heparins and transfer to indirect anticoagulants.

LMWH, like conventional heparins, are not able to penetrate the placenta into the fetus, and this allows them to be used during pregnancy for the prevention and treatment of thrombosis in pregnant women in the complex therapy of gestosis, miscarriage in women with genetically determined thrombophilia, and APS.

Alternative treatments

Several alternative treatments in addition to anticoagulant therapy, such as statins and hydroxychloroquine (HQ), have been described. HQ has some in vitro effects that may help in the treatment of APS, such as reducing blood viscosity and platelet aggregation. In addition, it may have immunological effects, such as inhibiting intracellular Toll-like receptor (TLR) activation, as well as reducing IL-1, IL-2, IL-6, and TNF-α production. [ 22 ] Moreover, HQ reduces endosomal NADPH oxidase 2 (NOX2) activation and expression in human umbilical vein endothelial cells (HUVECs) stimulated with TNFα or serum from preeclamptic women. Finally, it prevents the loss of zonula occludens 1 (ZO-1) protein, thereby reducing TNFα or preeclampsia serum-induced increased HUVEC monolayer permeability.[ 23 ],[ 24 ]

Aminoquinoline drugs, along with anti-inflammatory activity, immunomodulatory, antiproliferative properties, have antithrombotic and hypolipidemic effects, which is important in the treatment of APS both in SLE and in the primary variant. Against the background of taking aminoquinoline drugs, the frequency of SLE exacerbations and disease activity decreases. Hydroxychloroquine (plaquenil) is prescribed at a dose of 200-400 mg / day, in case of liver and kidney dysfunction, the dose should be reduced. The most significant side effects of hydroxychloroquine are associated with visual impairment; accommodation or convergence disorders, diplopia, drug deposition in the cornea, toxic retinal damage. After the start of treatment, ophthalmological monitoring is necessary every 3 months. In addition, clinical and biochemical blood tests should be performed once a month for monitoring.

Biological agents have also found their place in the treatment of SLE. The drug rituximab (chimeric monoclonal antibodies to CD 20 antigen of B cells), previously used to treat lymphomas and rheumatoid arthritis, also proved effective in patients with high activity of SLE in catastrophic APS.

The drugs of choice for the treatment of arterial hypertension and circulatory failure in patients with APS are ACE inhibitors and angiotensin receptor blockers.