Antiphospholipid syndrome

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

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Epidemiology

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

The exceptional importance of treating an antiphospholipid syndrome is that thrombosis becomes the main complication of the disease. 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.

[10], [11], [12], [13], [14], [15], [16]

Causes of the antiphospholipid syndrome

Causes of antiphospholipid syndrome

Despite the active study of the mechanisms of development of APS, the etiology of this disease remains unclear. It is known that infectious agents can in some cases turn out to be triggers of the production of APL.

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

Currently, it is suggested that genetic predisposition plays a significant role in the synthesis of APL. Hyperproduction of aLL, but not clinical manifestations, is associated with some alleles of the main histocompatibility complex (HLA-DRB1 * 04, HLA-DRBl * 07, HLA-DRBl * 130.1 HLA-DRw53, etc.).

[17], [18], [19], [20]

Pathogenesis

Pathogenesis of antiphospholipid syndrome

At the heart of the pathogenesis are venous and arterial thromboses (non-inflammatory), which can occur on any part of the vascular bed.

Despite the active study of the pathogenesis of the antiphospholipid syndrome, it remains to be seen whether only the presence of APL leads to the development of thromboses, why in some patients with elevated titers of AFL thromboses do not manifest, why not in all cases catastrophic antiphospholipid syndrome develops. The proposed two-factor hypothesis considers the presence of APL as a potential risk factor for thrombosis, which occurs in the presence of another factor of thrombophilia.

The primary (genetically determined) and secondary (acquired, symptomatic) forms of thrombophilia differ in etiology, the nature of hemostasis disorders, complications and prognosis that require a differentiated approach to prevention and treatment, but often occur with similar clinical manifestations.

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

Primary (genetically determined) thrombophilia: -

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

Acquired states:

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

APS as a variant of hematogenous thrombophilia (leading criterion - venous thrombosis) is a common form of hematogenous thrombophilia. Its share among phlebothrombosis of different localization ranges from 20 to 60%. However, the true prevalence of APS in the population of patients with venous thrombosis remains unspecified. 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 is studied most well. In connection with the unpredictability and variety of clinical manifestations, APS can be called one of the most mysterious forms of hematogenic 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 of proteins C and B, AT III (reduction of heparin-dependent activation), leading to thrombinemia.

Suppression of fibrinolysis:

• increased inhibitor of plasminogen activator (PA1);
• oppression factor of XII-dependent fibrinolysis /

Activation or damage of endothelial cells:

• increased prokoagulant activity of endothelial cells;
• amplification of expression of tissue factor and adhesion molecules;
• decreased synthesis of prostacyclin;
• increase in the production of von Willebrand factor;
• violation 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 membrane surfaces of platelets, enhanced synthesis of thromboxane, an increase in the level of platelet activating factor

The ability of antiendothedial antibodies and antibodies to beta-glycoprotein-1 to react with various antigens of the membrane of endothelial cells of intracavitary capillaries and the surface endocardium with the development of histiocytic-fibroplastic infiltration of valves, focal fibrosis and calcification, valve deformation.

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

Symptoms of the antiphospholipid syndrome

Symptoms of antiphospholipid syndrome

Despite the fact that cardiac manifestations of APS are not included in the diagnostic criteria of this disease, heart lesions remain important manifestations of non -rombotic vasculopathy and can vary from low-symptom valvular lesions to life-threatening myocardial infarction.

Cardiological manifestations of antiphospholipid syndrome

Diagnosis	Frequency of occurrence with APS,%
Valvular pathology of Vegetation (pseudoinfectious endocarditis) Thickening, fibrosis and calcification of valve flaps Valvular dysfunction (usually insufficiency)	- More than 1 More than 10 More than 10
Myocardial infarction: thrombosis of large coronary artery branches intramyocardial thrombosis restenosis after aortocoronary shunting restenosis after percutaneous transluminal coronary angioplasty	More than 1 More than 1
Violation of 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, and abdominal aortic thrombosis. Often, hypertension with AFS is labile, in some cases - a stable malignant. For clinicians, it is important to combine arterial hypertension with a characteristic skin lesion, like a reticular livedo, and thrombosis of cerebral vessels, which was called Sneddon syndrome.

Damage to the valvular valves is found in 30-80% of patients with both APS in SLE and primary APS. Thickening of valve flaps (a mitral plate) is the most frequent cardiologic manifestation in patients with positive AFL, even in the absence of vascular or obstetric pathology both in primary AFS and in secondary AFS. The thickening of the tricuspid valve occurs in about 8% of cases. It is believed that valvular lesions are more common with primary AFS and are associated with a titre of AFL. Valvular lesions in AFS resemble those in SLE: thickening of valve flaps (more than 3 mm), asymmetrical knotty overgrowth along the edge of valves or at the atrial surface of the mitral and / or ventricular surface of the aortic valve. Changes can vary from minor to gross deformations of valves (much less often), accompanied by attacks of cardiac asthma and severe circulatory failure requiring surgical treatment. Despite the fact that the defeat of the heart valves is not included in the list of modern diagnostic criteria for ASF, in valvular disorders it is necessary to closely monitor the doctor due to the significant likelihood of stroke and transient ischemic attacks in patients with initially existing hypercoagulability due to the action of APL.

An important feature is calcification of mitral and aortic valves of the heart, which is considered as a marker and a powerful predictor of atherosclerotic lesion of the coronary arteries.

[21], [22], [23], [24], [25], [26], [27], [28], [29], [30]

Thrombotic or atherosclerotic occlusion of coronary vessels

At the heart of the lesion of coronary arteries with APS is arterial thrombosis, which can accompany coronary artery atherosclerosis or, most interestingly, be a manifestation of thrombotic vasculopathy in the absence of inflammatory or atherosclerotic lesion of the vascular wall. The incidence of myocardial infarction with primary AFS is rather low, with secondary AFS prevalence of atherosclerosis of peripheral arteries and coronary arteries exceeds that in the population. Diagnosis of APS should be performed in patients of young age with coronary pathology or myocardial infarction, especially in the absence of objective risk factors for IHD.

Systolic and / or diastolic dysfunction

Studies are few, the true prevalence is unknown. There are reports that with PAPS disrupted more diastolic function of the left or right ventricles, while in SLE - systolic function of the left ventricle. The researchers suggest that at the heart of systolic and diastolic dysfunction is chronic ischemic cardiomyopathy with thrombotic vasculopathy.

Pulmonary hypertension often develops due to pulmonary thromboembolic disease in patients with venous thrombosis and often leads to right ventricular failure and pulmonary heart failure. The peculiarity is the propensity to recurrent course of thromboembolic complications in patients with APS. In patients with primary pulmonary hypertension, along with the definition of genetically determined markers of thrombophilia, screening for AFS should also be carried out in connection with the possibility of developing thrombosis in the microcirculatory bed.

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

Forms

Classification of antiphospholipid syndrome

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 prevailing pathology. This diagnosis requires a certain degree of vigilance from the doctor, since the primary AFS may transform into SLE over time.

Secondary APS, developing in the framework of SLE or another disease.

Catastrophic AFS, characterized by widespread thrombosis leading to multi-organ failure, disseminated intravascular coagulation syndrome (DIC syndrome).

[31], [32], [33], [34], [35], [36]

Diagnostics of the antiphospholipid syndrome

Diagnostic criteria for antiphospholipid syndrome

In 2006, the diagnostic criteria of the antiphospholipid syndrome were revised.

[37], [38], [39], [40]

Clinical criteria

Vascular thrombosis

• One (or more) clinical episode of arterial, venous thrombosis or thrombosis of small vessels in any tissue or organ. Thrombosis should be documented (angiographic or Doppler study or morphologically) with the exception of superficial thrombosis. Morphological confirmation should be presented without significant inflammation of the vascular wall.
• Pathology of pregnancy
  • One or more cases of intrauterine death of a morphologically normal fetus after the 10th week of gestation (normal morphological signs of the fetus are 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 (with the exclusion of anatomical defects of the uterus, hormonal disorders, maternal or paternal chromosomal abnormalities).

[41], [42], [43], [44], [45], [46], [47]

Laboratory criteria

• Antibodies to cardiolipin IgG isotypes and / or IgM isotypes, determined in serum in medium or high titers at least 2 times for 12 weeks using a standardized enzyme-linked immunosorbent assay,
• Antibodies to beta2-glycoprotein-1 IgG isohypes and / or IgM isotypes, determined in serum in medium or high titers at least 2 times for 12 weeks using a standardized enzyme-linked immunosorbent assay.
• Lupus anticoagulant in plasma in two or more studies with an interval of at least 12 weeks, determined according to the recommendations of the International Society of Thrombosis and Hemostasis (BA / phospholipid-dependent antibody research group):
• increased coagulation time in phospholipid-dependent coagulation tests (APTT, kaolin clotting time, prothrombin time, Russell's viper tests, textarin time);
• no correction of the increase in the coagulation time of screening tests when mixed with donor plasma;
• shortening or correction of the increase in the coagulation time of screening tests with the addition of phospholipids;
• Exclusion of other coagulopathies, such as, for example, an inhibitor of factor VIII coagulation or heparin (lengthening phospholipid dependent blood coagulation tests).

A definite APS is diagnosed if there is one clinical or laboratory test. If AFL is detected without clinical manifestations or clinical signs without laboratory confirmation in a period of less than 12 weeks or more than 5 years, the diagnosis of "APS" should be in doubt. The term "seronegative variant" of ASF is discussed by various researchers, but this term is not generally accepted.

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

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

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

Diagnosis of antiphospholipid syndrome

When interviewing patients, it is advisable to clarify the presence of thromboses and obstetric pathology in the immediate family, the presence or absence of acquired risk factors for thrombosis (trauma, surgery, long flights, taking hormonal contraceptives, etc.), to find out obstetric history. In connection with the risk of APS development, it is necessary to be especially wary of patients of young and middle age, in whom thromboembolic complications developed in the absence of possible acquired risk factors for thrombosis, there was a tendency to relapse.

[48], [49], [50], [51], [52], [53]

Physical examination

Considering the variety of the clinical picture, the examination of the patient should be directed to diagnosis of signs of the disease associated with ischemia or thrombosis of various organs and systems, the search for the underlying disease that contributed to the development of APS.

The main and most frequent (20-30%) clinical symptoms of the antiphospholipid syndrome are deep vein thrombosis of the extremities, spontaneous abortions in early pregnancy, thrombocytopenia, mesh and bicycling, migraine, acute cerebrovascular accident and transient ischemic attacks, PE, spontaneous abortions on late pregnancy, thickening or dysfunction of heart valves, hemolytic anemia. According to the Research Institute of Rheumatology, with a frequency of more than 1%, there are: preeclampsia, eclampsia, episyndrome, leg ulcers, transient blindness, myocardial infarction, lower limb arteries thrombosis, upper limb veins thrombosis, pseudovasculitis, gangrene of fingers and toes, cardiomyopathy, angina, vegetation on the valves, kidney damage, multi-infarct dementia, skin necrosis, avascular necrosis of the bones, pulmonary hypertension, subclavian vein thrombosis, acute encephalopathy, restenosis after aortocoronary shunting (CABG), lesion gastrointestinal tract (ischaemia of the esophagus and intestine), thrombosis of retinal arteries, spleen infarction, pulmonary microthrombosis, optic nerve neuropathy. Rare manifestations of antiphospholipid syndrome include transient amnesia, cerebral venous thrombosis, cerebral ataxia, intracardiac thrombosis, pancreatic infarction, Addison's disease, liver damage (Badd-Chiari syndrome), retinal vein thrombosis, nail bed hemorrhage, postpartum cardiopulmonary syndrome.

Laboratory diagnosis of APS (International preliminary criteria for the classification of AFS, Sydney, 2005) is based on the detection of lupous anticoagulant and the determination of titers of AFL. In parallel, screening tests (APTT, kaolin plasma clotting time, Russell's viper poison test, diluted thromboplastin prothrombin time) are carried out in the investigated and normal plasma, confirming tests with mixing of the investigated and normal plasma (persistent hypocoagulation by screening tests) and plasma excess comominating phospholipids (normalization of clotting time according to screening tests).

At present, the association between the values of total antibodies to the complex of beta2-glycoprotein-1 with cofactor proteins (phosphatidylserine, phosphatidylinositol, phosphotidyl-ethanolamine, phosphotidylcholine, prothrombin, etc.) has not been established and the development of APS. Clinically significant are the average and significant increases in tigers of ACL classes IgG and IgM and antibodies to beta2-gaikoprotein-1 classes IgG, and IgM, determined in two dimensions with an interval of not less than 6 weeks (referred to laboratory criteria APS).

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

Instrumental methods include:

• ultrasound Doppler vascular scanning and venography: used for topical diagnosis of venous and arterial thrombosis;
• Doppler echocardiography: allows to diagnose valve changes in both APS and SCR (endocarditis Liebman-Sachs), intracardiac thrombi, the presence and extent of pulmonary hypertension. A significant difference in the defeat of valves from rheumatic valvulitis is the thickening of the valve with AFS, extending to the middle part and to the base of the valve. The defeat of the chords in the APS is extremely uncharacteristic;
• radioisotope lung scintigraphy and angiopulmonography: verification of pulmonary embolism and determination of the need for thrombolysis;
• ECG, daily Holter monitoring (confirmation of myocardial ischemia), monitoring of blood pressure;
• cardiac catheterization and coronary angiography: indicated to patients for evaluation of coronary blood flow condition, as well as presence of atherosclerotic lesion of coronary arteries;
• magnetic resonance imaging of the heart and large vessels: an indispensable method for differentiation inside cardiac thrombosis and heart tumors (myxoma). In some cases, it can be an alternative method of studying the viability and perfusion of the myocardium;
• computed tomography, multispiral and electron beam tomography of the heart: diagnosis and quantification of coronary artery calcification as a marker of coronary atherosclerosis, as well as thrombi in the heart chambers.

Treatment of the antiphospholipid syndrome

Treatment of antiphospholipid syndrome

Due to the heterogeneity of the mechanisms of the development of antiphospholipid syndrome, there are currently no unified international standards for the treatment and prevention of thrombotic complications that determine the first and foremost forecast of this form of hematogenic thrombophilia.

Since the development of ASA is based on thrombotic vasculopathy from capillaries to large vessels, manifesting thromboses with a high risk of recurrence, in all patients with APS, especially with signs of cardiovascular damage, even in the absence of acquired risk factors for thrombosis, it is necessary to conduct preventive anticoagulant treatment of antiphospholipid syndrome . With the development of APS in patients with SLE in the treatment, along with the anticoagulant effect, glucocorticoids and cytostatic drugs are used. However, long-term treatment with glucocorticoids has a pro-coagulant activity, i.e. Increases the risk of thrombosis.

Currently, most authors recommend in the absence of clinical symptoms in patients with valvular pathology due to APS, prescribe a disaggregant treatment - low doses of acetylsalicylic acid. In the case of development of thromboembolic complications in patients with valvular disease, intracardiac thrombosis, pulmonary hypertension, impaired systolic or diastolic function of the left ventricle, more active measures are needed aimed at the formation of persistent hypocoagulation. This can be achieved by the long-term administration of vitamin K antagonists. In the presence of combined forms of hematogenic thrombophilia (APS + genetically determined), as well as acquired risk factors for thrombosis, preventative anticoagulant treatment can be indefinitely long, often lifelong.

The main drug for preventive anticoagulant treatment is warfarin, a derivative of coumarin. The dose of warfarin is selected individually, as well as with other hematogenic thrombophilia, depending on the standardized INR, determined by prothrombin time, taking into account the sensitivity of the thromboplastin used. In the case of acute thrombosis, warfarin is given concomitantly with heparin at the lowest dosage until reaching an INR of 2.0 per day before heparin is discontinued. In the subsequent optimal values of INR with 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 recurrence of thrombosis (the presence of acquired and hereditary risk factors for thrombosis). The main problem with prolonged use of warfarin is the risk of hemorrhagic complications, in some cases requiring correction of the dose of this drug or its withdrawal. Also, with AFS, the risk of developing warfarin necrosis (ricochet thrombosis on the 3-8th day of the application of coumarins) may increase, which is based on thrombosis of small vessels of the skin. This severe complication is aggravated in patients with initially impaired activity of natural anticoagulants - proteins C and S, in particular due to V Leiden polymorphism, which contributed to the resistance of the V coagulation factor to the activated protein, which further emphasizes the need for a targeted examination for the presence of other thrombophilia variants in patients with APS. If these combinations of thrombophilia are detected, it is preferable to focus on the assignment of low molecular weight heparins (LMWH).

The main distinguishing feature of LMWH is the predominance in them of fractions with molecular weight less than 5400 Da and almost complete absence of coarse-molecular components prevailing in usual (unfractionated) heparin. LMWH predominantly inhibits factor Xa (anti-Xa activity) and not thrombin (anti-IIa activity), which is why the antithrombotic effect is due to the background of weak ancemic-agglutination activity. This characteristic of these drugs allows the use of such doses that effectively prevent venous thrombosis and thromboembolic complications with minimal expressed hypocoagulation (the limiting factor of prolonged treatment of patients with venous thrombosis).

High bioavailability (about 90%) and average duration of antithrombotic effect after a single injection (about one day) allow one or two injections per day to be limited and facilitate the use of LMWH precisely for those patients who need prolonged thrombosis prophylaxis. The significantly lower affinity of LMWH for the anti-heparin platelet factor determines their less pronounced ability to cause such a formidable complication as heparin-induced thrombotic thrombocytopenia.

• Type I heparin-induced thrombotic thrombocytopenia (less than 20% platelet count) develops during the first hours or days after the administration of heparins, usually occurs asymptomatically and does not refer to contraindications for further treatment.
• II type of heparin-induced thrombotic thrombocytopenia is a serious complication caused by an immune response in response to the appointment of heparin, which occurs with severe hemorrhagic complications, requiring immediate cancellation of heparins and conversion to indirect anticoagulants.

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

Aminohinolinovye drugs, along with anti-inflammatory activity, immunomodulating, antiproliferative property, have antithrombotic and hypolipidemic effect, which is actual in the treatment of APS both in SLE and in the primary variant. Against the background of reception of aminoquinoline preparations, the frequency of exacerbations of SLE and the activity of the disease decrease. Hydroxychloroquine (plakvenil) is prescribed in a dose of 200-400 mg / day, with violations of the liver and kidneys, the dose should be reduced. The most significant side effects of hydroxychloroquine are associated with impaired vision; disorders of accommodation or convergence, diplopia, the deposition of the drug in the cornea, toxic retinal damage. After the start of treatment every 3 months, ophthalmic control is necessary. In addition, for monitoring, you need to perform clinical and biochemical blood tests once a month.

Biological agents have found their place in the treatment of SLE. Previously used for the treatment of lymphomas and rheumatoid arthritis, rituximab (chimeric monoclonal antibodies against CD 20-antigen of B cells) was also effective in patients with high SLE activity 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.