Tactics of preparation for pregnancy in patients with antiphospholipid syndrome

If primary antiphospholipid syndrome is suspected based on the anamnesis data: habitual miscarriage, episodes of thrombophilic complications, previous pregnancies with delayed fetal growth, with early onset of toxicosis in the second half of pregnancy, pregnancy complications in the form of detachment of a normally located placenta, in the early stages of pregnancy with detachment of the chorion - a blood test is performed - a hemostasiogram and determination of lupus anticoagulant. When determining the lupus anticoagulant, a number of studies are carried out to confirm the immune or infectious nature of the lupus anticoagulant, since at present we do not have the technical capabilities for differential diagnostics. We conduct studies to exclude infection, to identify infectious causes of the appearance of antiphospholipid antibodies:

• Bacteriological examination of cervical mucus;
• PCR diagnostics from the cervical canal - herpes simplex viruses, cytomegaloviruses, chlamydia, mycoplasma, ureaplasma;
• Virus;
• Assessment of immune status;
• Assessment of interferon status.

In addition to these studies, we determine the spectrum of antibodies to phospholipids: anticardiolipin antibodies, antiphosphatidylserine, antiphosphatidylinositol, antiphosphatidylethanol, antiphosphatidylcholine, antibodies to phosphatidylic acid. Perhaps, for diagnostics this is not so important, but for determining the tactics of management, it can be of significant help. It is known that in the presence of antibodies to cardiolipin, pregnancy losses occur at later stages of pregnancy and due to complications such as intrauterine growth retardation, toxicosis of the second half of pregnancy. And in the presence of antibodies to phosphatidylserine and phosphatidylcholine, early pregnancy losses are most often observed.

Considering that almost all patients with antiphospholipid syndrome have a persistent viral infection, the first stage of preparation for pregnancy is antibacterial (if necessary based on the results of bacteriological examination and PCR data), antiviral and immunomodulatory therapy.

Treatment begins with metabolic therapy complexes, systemic enzyme therapy for at least a month (Wobenzym 5 tablets 3 times a day); normalization of immunogram parameters is carried out (use of T-activin, immunofan); normalization of interferon status by using individually selected interferon inducers. It is advisable to use enterosorbents (enterosgel, recicene RD, etc.).

After therapy, we monitor hemostasis and re-determine the lupus anticoagulant. Very often, after immunomodulatory therapy, AFA activity decreases.

If changes in the hemostasiogram remain after the therapy, it is necessary to use antiplatelet agents and/or anticoagulants, or conduct a course of plasmapheresis. Of the antiplatelet drugs, aspirin is most often and most successfully used - a prostaglandin synthetase inhibitor: it irreversibly inhibits the synthesis of thromboxane A, inhibits the reaction of platelet release, and reduces platelet adhesion.

Aspirin is contraindicated in gastric ulcer, hypertension, hypersensitivity to aspirin. The use of aspirin in the first trimester of pregnancy is debated, since its teratogenicity is not removed from the agenda, although most researchers believe that it can be used in small doses. Due to the peculiarities of aspirin accumulation in the body, it should be stopped 6-10 days before the expected birth, sometimes there may be hemorrhagic complications in the mother and fetus. But if there is a threat of miscarriage against the background of its use, then such a patient may have hemorrhagic complications. Side effects of aspirin include nausea, pain in the epigastric region, erosive and ulcerative lesions of the stomach, allergic reactions (should be used with caution in broncho-obstructive syndrome), bleeding, thrombocytopenia.

The second class of antiplatelet agents are adenylate cyclase activators and phosphadiesterase inhibitors: curantil, trental, nicotinic acid preparations, antispasmodics. Curantil (dipyridamole) is one of the most commonly used antiplatelet agents after aspirin. It is available in the form of tablets or dragees of 25 or 75 mg. Curantil N differs from regular curantil in a more complete and rapid release of the active substance from the drug formula due to a reduction in the content of hydrophobic substances in the tablet shell, which accelerates its dissolution. Excipients that enhance the disintegration of the tablet are also added to the core.

Curantil inhibits the activity of phosphodiesterase and adenosine deaminase, activates adenylate cyclase, which promotes the accumulation of cAMP and adenosine in platelets and smooth muscle cells of the vascular wall, preventing their inactivation. An increase in cAMP content in the smooth muscles of the vascular wall causes their relaxation. With the accumulation of cAMP in platelets, their aggregation, adhesion and release of aggregation activators, coagulation factors and vasoconstrictors are prevented, while calcium is retained in membrane structures. In addition, curantil affects the metabolism of arachidonic acid, increasing the synthesis of prostacyclin in the vascular wall and reducing the synthesis of thromboxane A2 in platelets by suppressing thromboxane synthetase. This also leads to a decrease in platelet adhesion to the vascular endothelium, subendothelium and collagen of the damaged vascular wall, increasing the lifespan of platelets, preventing their aggregation and blocking the release of bioactive substances. The drug also potentiates the antiplatelet and vasodilating effect of the endothelial factor, inhibits the aggregation of erythrocytes and, to a lesser extent, has a fibrinolytic effect due to the release of plasminogen from the vascular wall. Curantil does not increase the tone of the uterus, increases renal blood flow, improves coronary and cerebral blood flow, normalizes acid-base balance, reduces peripheral resistance, and increases myocardial contractility. An important property of Curantil is the absence of an embryotoxic effect.

Curantil improves uteroplacental and fetoplacental blood flow, and also has an immunostimulating effect due to the induction of interferon biosynthesis.

Contraindications to the use of Curantil are acute myocardial infarction, unstable angina, heart failure, severe hypotension, hemorrhagic syndrome. Side effects of Curantil are nausea, vomiting, headache, tachycardia, diarrhea, decreased blood pressure, general weakness. When using the drug, it is necessary to exclude coffee, strong tea and xanthine-containing products from the diet.

The third group of antiplatelet drugs includes membrane stabilizing drugs: rheopolyglucin and other low-molecular dextrans, which, forming a monomolecular layer on the intima and formed elements of the blood, reduce electrostatic tension, the aggregation capacity of platelets 2 hours after administration. The effect lasts for 24 hours. An increase in the BCC is noted, blood viscosity decreases, fibrin is inactivated by precipitation, and the fibrinolytic activity of the blood increases. During pregnancy, it significantly increases blood flow in the placenta.

Contraindications: allergies, thrombocytopenia, anuria.

The drugs do not penetrate the placenta and are therefore safe during pregnancy. Side effects are very rare, but allergy to rheopolyglucin is rarely observed.

Anticoagulants that can be used in obstetric practice are mainly unfractionated and low molecular weight heparin.

Unfractionated heparin is a direct-acting anticoagulant that blocks thrombin biosynthesis, reduces platelet aggregation, inhibits hyaluronidase activity, and to some extent activates the fibrinolytic properties of blood. After subcutaneous administration of the drug, its peak action is observed after 3-4 hours. Heparin does not penetrate the placenta and has no effect on the embryo/fetus. The dose of the drug should be selected strictly individually. Intravenous and subcutaneous administration is possible. The effectiveness of heparin can be monitored by an increase in activated partial thromboplastin time (APTT) by 1.5-2.5 times compared to the norm. Among the side effects of heparin, it is worth noting the development of osteoporosis, which is observed with prolonged use of heparin even in small doses and in older people. According to these authors, the incidence of symptomatic spinal fractures was 2-3%. According to Monreal et al. (1994) found a 15% incidence of spinal fractures in a small study using 10,000 IU heparin for 3-6 months.

Approximately 3% of patients (studies conducted outside pregnancy) who received unfractionated, i.e. regular, heparin had immune, IgG-related thrombocytopenia, which can sometimes be accompanied by extremely severe heparin-induced thromboses. The diagnosis of immune thrombocytopenia is quite difficult to establish, but can be suspected if the platelet count decreases below > 100x10 ⁹ /or < 50% of the initial level 5-15 days after the start of heparin therapy. This complication occurs due to the fact that heparin is affected by the antiheparin factor of platelets - factor 4 (PF4). This is fraught with the formation of antibodies to the heparin + PF4 complex, which leads to immune thrombocytopenia and the development of thromboses.

One of the undesirable side effects of heparin is the depletion of antithrombin III with long-term use of heparin, which can also explain the lack of effect from the use of heparin, causing a state of hypercoagulation and thrombosis. Increasing the dose of heparin does not give an effect, and continuing therapy can be dangerous.

In a large cohort study, the incidence of major bleeding in pregnant women receiving heparin was 2%. The authors note that there may be a prolonged effect of heparin for more than 28 hours after the last injection and the mechanism for this is unclear, because, as a rule, there is no heparin after 6-12 hours. In this regard, it is recommended to stop taking heparin one day before delivery. If delivery occurs during heparin intake, it is necessary to have a 1% solution of protamine sulfate, which is administered slowly intravenously, and if the heparin content in the blood cannot be determined, then more than one dose should not be administered at once, i.e. more than 1 ml. It should also be remembered that when monitoring the effect of heparin by activated partial thromboplastin time (APTT) during pregnancy, the response to heparin by APTT is weakened due to the increased content of factor VIII and fibrinogen. The lack of effect of heparin may mislead the physician because the APTT level may be within the normal range with a significantly elevated heparin level.

Many complications can be avoided by using low-molecular-weight heparin. Low-molecular-weight heparin is obtained by depolymerization of heparin. The change in molecular weight has changed the pharmacodynamics and pharmacokinetics of the drug, they have higher bioavailability (98%, not 30% like heparin), a longer half-life, so they can be administered once a day outside of pregnancy. However, recent studies on the pharmacokinetics of low-molecular-weight heparin have shown that it differs significantly in the same women outside and during pregnancy, due to an increase in the volume of circulating plasma, an increase in the rate of glomerular filtration, and the production of heparinase in the placenta. Low-molecular-weight heparin has a higher clearance rate and a larger dilution volume, so the concentration of low-molecular-weight heparin, having reached a peak, decreases faster, especially at the end of pregnancy. Therefore, it is more advisable to administer low-molecular-weight heparin 2 times a day, every 12 hours. Low molecular weight heparin has a number of advantages over heparin: it does not have antithrombin properties and does not cause hypocoagulation, the antithrombotic effect is mainly associated with its effect on factor Xa and lipoprotein-associated coagulation inhibitor; it promotes activation of fibrinolysis; it is less susceptible to the action of platelet factor 4 and therefore does not cause immune-mediated thrombosis and, apparently, heparin-induced osteoporosis.

Monitoring of the effectiveness of low molecular weight heparin is carried out in the same way as when using heparin, using APTT, AVR, TEG, anti-Xa, and platelet count.

Outside of pregnancy, indirect anticoagulants are used in patients with antiphospholipid syndrome, most often warfarin, a vitamin K antagonist. This drug cannot be used during pregnancy, as it causes malformations (warfarin syndrome, i.e. it penetrates the placenta). Warfarin is most dangerous for the embryo during the 6-12 weeks of pregnancy. Therefore, if a patient with a history of thromboembolic complications took warfarin, on which the pregnancy occurred, then there is no great danger to the embryo in the first weeks of pregnancy. The drug should be discontinued when pregnancy is established and replaced with regular or low molecular weight heparin.

The greatest debate in the literature is caused by the need to use glucocorticoids in patients with antiphospholipid syndrome. They should definitely not be used outside of pregnancy, since the cycle and ovulation are often disrupted. The first experience of using glucocorticoids was published in 1983 (Lubbe W. et al.), in 1985 (Branch D. et al.). The use of prednisolone in a dose of 40-60 mg / day and aspirin in a dose of 70-80 mg / day gave good results - a favorable outcome of 20 women was in 60-80%. According to Pattison and Lubbe (1991), treatment in a larger group of women with prednisolone was successful in 87% of patients. However, side effects of prednisolone were in all women in the form of Cushingoid syndrome, the appearance of acne, some had mild infectious complications. This therapeutic regimen has been used by many researchers and all have noted the side effects of prednisolone therapy, including gestational diabetes, hypertension, infectious complications. However, to cause such complications, glucocorticoid doses must be more than 30 mg per day, used for a long time. At the same time, there is evidence of the absence of adverse effects of glucocorticoids on the mother and newborn when using small doses of 5-10 mg of prednisolone. During pregnancy, an increased ability of maternal plasma to bind glucocorticoids is noted, which limits their transfer through the placenta, due to the high enzymatic activity of the placental barrier and active destruction in the liver, the effect on the fetus is insignificant.

Glucocorticoids have a number of beneficial effects: anti-inflammatory, anti-allergic, anti-shock, etc.

Antiphospholipid antibodies are IgG globulins, penetrate the placenta and have the same effect on the embryo/fetus/placenta as on the mother's body - they cause thrombosis, placental infarction, etc. Anticoagulant therapy protects the mother from thromboembolism, but not the fetus, since they do not penetrate the placenta. Antiplatelet agents penetrate the placenta, but they cannot always prevent hypercoagulation of the plasma link of hemostasis.

Therefore, it is considered appropriate to use glucocorticoids in small doses, combining them with antiplatelet agents and anticoagulants, and when the effect of their combined use in optimal and safe doses is insufficient to remove antiphospholipid antibodies, it is advisable to use plasmapheresis. Antibodies to phospholipids accumulate slowly, and one course of plasmapheresis is enough to remove the pathogenic effect of antiphospholipid antibodies for almost 3 months.

Plasmapheresis

Currently, methods of efferent therapy, in particular plasmapheresis, have been widely used in the treatment of acute conditions and chronic diseases in surgical and therapeutic hospitals, and more recently in obstetric and gynecological practice.

Plasmapheresis was first proposed in 1914 by two independent groups of authors: Yurevich and Rosenberg and Abel et al. (USA), but its clinical application began only in the mid-20th century due to the development of new technologies - centrifugation, plastic bags, lines, and devices for continuous plasmapheresis. The term "plasmapheresis" is based on the Greek root apheresis, which means "removal", "extraction". Currently, therapeutic plasmapheresis is an operation to selectively remove plasma from the patient's peripheral blood for the purpose of therapeutic correction of its protein or cellular composition. Therapeutic plasmapheresis was first used as a means of removing Y-globulin for the treatment of increased blood viscosity in Waldenstrom's disease. Currently, plasmapheresis is used in various pathological conditions - sepsis, massive tissue destruction syndrome, disseminated intravascular coagulation syndrome, exogenous toxicosis, autoimmune diseases, allergic conditions, atopic and infection-dependent bronchial asthma, asthmatic status.

In total, there are about 200 nosological forms in which plasmapheresis is effective. Depending on the composition of the morphological substrate to be removed, efferent methods of therapy can be divided into plasmapheresis - removal of plasma from peripheral blood, and cytapheresis - selective removal of various cellular elements from peripheral blood. Thus, in some cases, granulocytapheresis (leukocytapheresis) is used to correct the cellular composition of the blood in hemoblastoses and thrombocytosis - removal of granulocytes, lymphocytapheresis - lymphocytes, blastocytapheresis - removal of blast cells, myelokaryocytapheresis - separation of bone marrow suspension into cellular elements.

The possibility of removing and reducing the rate of formation of immune complexes, circulating antibodies by the method of therapeutic plasmapheresis was a prerequisite for the use of the procedure in a number of pathological conditions characterized by immune disorders. For this purpose, therapeutic plasmapheresis was carried out to reduce the content of isoantibodies in patients with bone marrow transplantation, with incompatibility in the Rh and ABO systems, lymphocytotactic, antileukocyte antibodies, antibodies against the kidney transplant. In gynecological practice, plasmapheresis has found application in the complex therapy of patients with pelvic peritonitis after septic abortions, gynecological operations. The studies of Abubakirova AM, Baranov I.I. (1993) proved the effectiveness of plasmapheresis in the treatment of pregnant women with gestosis. Fedorova TA successfully used plasmapheresis to treat patients with chronic recurrent salpingo-oophoritis. Tsakhilova SG {1999) used plasmapheresis in the treatment of patients with recurrent viral infection during pregnancy. The few data cited in foreign literature on the use of plasmapheresis during pregnancy concern mainly the treatment of acute fatty liver disease, HELLP syndrome, and thrombotic thrombocytopenic purpura.

The first works on correction of immune disorders in pregnant women refer to the use of plasmapheresis in the therapy of Rh sensitization for the prevention and treatment of hemolytic disease of the fetus and newborn. Based on the results obtained by various authors, one can judge the positive role of plasmapheresis procedures for the correction of hyperimmune disorders in women with a high degree of Rh sensitization. Clinical experience shows that the number of plasmapheresis operations, their systematicity, and the total volume of plasma exfusion are of certain importance. It can be assumed that some temporary depletion of Rh antibody production occurs. Plasmapheresis can significantly reduce the titer of Rh antibodies in the blood of pregnant women, as a result of which the severity of the hemolytic process in the fetus decreases. The prognosis for the fetus is most favorable when manifestations of Rh sensitization occur after 30 weeks of pregnancy. However, during subsequent Rh-conflict pregnancy, the production of antigen-dependent antibodies may increase again, so it is advisable in these cases to systematically conduct plasmapheresis during pregnancy in order to correct the titer of Rh antibodies. Unlike Rh sensitization, the rate of antibody formation in autoimmune processes is significantly lower, which creates prerequisites for the use of therapeutic plasmapheresis in pregnant women with antiphospholipid syndrome more successfully than in Rh sensitization.

The use of plasmapheresis allows to normalize the rheological properties of blood, reduce hypercoagulation, decrease the dose of corticosteroid drugs and heparin, which is especially important if they are poorly tolerated.

The following therapeutic effects of plasmapheresis are distinguished: specific, non-specific and additional.

Specific effects of plasmapheresis include:

• detoxification (elimination of toxic substances, “unblocking” of natural detoxification systems, antioxidant effect - extracorporeal biotransformation of toxic substances);
• reocorrection (reduction of blood viscosity, increase in deformability of blood cells, reduction in aggregation characteristics of blood cells, reduction in total peripheral resistance);
• immunocorrection (elimination of antigens, antibodies, CIC, immunocompetent cells, “unblocking” the immune system, changing the direction of the immune response);
• increased sensitivity to exogenous and medicinal substances;
• diffusion - diffusion of metabolites from organs and tissues. Non-specific effects of plasmapheresis include:
  • hemodynamic reactions;
  • redistribution of blood cells;
  • activation of the endocrine system;
  • stress reactions.

Additional effects are determined by the effect of infusion transfusion and medicinal preparations necessary for the plasmapheresis procedure. The use of transfusion and medicinal programs allows potentiating the therapeutic effect of plasmapheresis along with leveling the negative impact of this procedure.

There are various modifications of plasmapheresis - cascade plasmafiltration, the principle of which consists in the isolation of plasma on the primary filter, from which high-molecular substances (proteins, lipoproteins, circulating immune complexes - CIC) are removed on the secondary filter. In patients with neuroendocrine disorders, diencephalic syndrome, obesity, specific sorption methods developed in recent years are of particular value, in particular LDL-apheresis, allowing the removal of atherogenic low-density lipoproteins, cholesterol, triglycerides. The difference between plasmapheresis and plasmafiltration is the simplicity of the necessary equipment, relative cheapness, no need for careful heparinization of patients, catheterization of large trunk veins.

To perform intermittent discrete plasmapheresis, refrigerated centrifuges "R-70", "R-80", "Juan" - France, plastic bags and containers "Gemakon-500", "Gemakon-500/300" with citrate preservative - glugicir, devices of the company "Gemonetik", "Dideko", "Baxter", PF-01, based on the use of gravity forces, are used.

Plasmapheresis technique

Plasmapheresis can be performed using an intermittent (discrete) or gravity-driven continuous flow method.

The technique of intermittent plasmapheresis is as follows:

1. Puncture of the ulnar vein;
2. Introduction of plasma-substituting crystalloid and colloid solutions. The ratio of the volume of removed plasma to the volume of plasma-substituting solutions should be at least 1:1.2 - outside of pregnancy, during pregnancy 1:2. It is advisable to introduce protein preparations into the plasma substitution program in the II and III trimesters of pregnancy - 100 ml of 10% albumin solution.
3. Blood exfusion (400-500 ml) into plastic containers such as “Gemakon-500/300”.
4. Separation of formed elements of blood from plasma, carried out in a refrigerated centrifuge in soft centrifugation modes at a speed of 3500-5000 rpm.
5. Separation of plasma into a satellite bag;
6. Reinfusion of blood cells diluted with saline solution.

It is advisable to repeat the procedure 2-3 times, which allows removing 600-900 ml of plasma in 1 session (excluding the hemopreservative). The course of treatment consists of 3 plasmapheresis sessions. Indications for a repeated course of plasmapheresis are the results of clinical and laboratory examination of each patient.

Unlike intermittent plasmapheresis, continuous plasmapheresis requires catheterization of two veins. One venous access is required for the introduction of infusion media, the other - for connection to the blood separator. The patient's blood enters the centrifuge rotor, where it is separated, plasma is removed through some lines, and formed elements are removed through others, which are mixed with plasma-substituting solutions, which are returned to the patient's bloodstream through the second vein. Continuous procedure is ensured by constant operation of the rotor. During the procedure, 5-10 thousand heparin are administered intravenously to prevent thrombus formation. Continuous plasmapheresis uses a special system of lines, collecting bags (containers), an anticoagulant solution containing sodium citrate and dextrose, crystalloid, colloidal and protein solutions. In order to compensate for the deficit in the BCC, infusion media of various directions of action are introduced individually in each case, taking into account the indications.

Contraindications to plasmapheresis

1. Pronounced organic changes in the cardiovascular system;
2. Anemia (hemoglobin below 100 g/l);
3. Hypoproteinemia (protein level below 55 g/l);
4. Hypocoagulation;
5. Immunodeficiency states;
6. Allergic reactions to anticoagulants, colloidal and protein preparations.

Relative contraindications are lack of venous access and acute phlebitis of peripheral veins.

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Complications associated with the plasmapheresis procedure

1. Collaptoid conditions, as a rule, are a consequence of inadequate plasma replacement of the volume of removed plasma in patients with hypotension. If collapse occurs, plasma removal must be stopped and infusion therapy with crystalloid, colloid and protein preparations must be performed.
2. Allergic reactions to the introduction of infusion media. In such situations, the introduction of solutions is stopped, the use of antihistamines and corticosteroids is indicated.
3. Anemia and symptoms of angina. It is necessary to carefully consider the contraindications to plasmapheresis in patients with anemia, in case of severe anemia - the introduction of freshly prepared erythrocyte mass and the prescription of antianemic drugs.
4. Disturbances in the electrolyte composition of the blood (hypocalcemia, hypokalemia), which may manifest as cardiac arrhythmia. Monitoring of electrolyte levels and correction of any disturbances that arise are mandatory.

The literature also describes such complications as pulmonary edema and acute cardiac failure in response to the introduction of large volumes of low-molecular solutions in patients with extragenital pathology. The above complications dictate the need for a thorough examination of women before the procedure - determining the indications for its appointment, strict observance of rights, plasmapheresis, the presence of trained and highly qualified personnel

Our experience of using intermittent plasmapheresis in patients with antiphospholipid syndrome indicates normalization of hemostatic, immunological, biochemical parameters, detoxification effect, which gives grounds to use it for optimization of therapy in women with habitual miscarriage. Research in this direction will be conducted in the future, which may allow us to study and expand the possibilities of using efferent therapy methods in obstetric practice.

Thus, at the stage of preparation for pregnancy, antibacterial, antiviral, immunomodulatory therapy and normalization of the hemostasiogram parameters are carried out, after which pregnancy is allowed. From the II phase of the expected fertile cycle, we prescribe 5 mg of prednisolone or 1 tablet of metipred taken in the morning after breakfast to reduce the effect of prednisolone on the adrenal glands.

2 days before the expected menstruation, please take a pregnancy test and, if the test is positive, conduct a hemostasiogram study and determine the level of lupus anticoagulant.

The basis for determining autosensitivity to human chorionic gonadotropin is habitual miscarriage, a history of artificial abortions, the use of gonadotropic drugs to stimulate ovulation; infectious and allergic diseases and complications.

Preparation for pregnancy is carried out similarly to that carried out in case of sensitization to phospholipids. A distinctive feature is the need to correct the luteal phase deficiency, which is observed more often in case of anti-CG sensitization. It is recommended to conduct courses of systemic enzyme therapy. Disorders in the hemostasis system in patients of this category outside pregnancy are observed very rarely, but if they exist, it is advisable to prescribe antiplatelet agents and/or anticoagulants. Glucocorticoids (prednisolone, methylprednisolone) are prescribed in the second phase of the cycle after ovulation, determined by the rectal temperature chart. The dose is selected individually, taking into account the level of antibodies, the burden of the anamnesis, and individual tolerance. As a rule, 5 or 10 mg of prednisolone in the morning after breakfast. Doses of 15 mg were prescribed extremely rarely with very high antibody levels.

Preparation for pregnancy allows to reduce the percentage of complications in the first trimester: the threat of miscarriage, the development of chronic DIC, the duration of antithrombotic therapy, and reduce the doses of glucocorticoids.

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