Antiphospholipid syndrome - Treatment

The following main directions of drug treatment of antiphospholipid syndrome are described in the world literature:

• glucocorticoids in combination with anticoagulants and antiplatelet agents;
• administration of glucocorticoids together with acetylsalicylic acid;
• correction of the hemostasis system with anticoagulants and antiplatelet agents;
• monotherapy with acetylsalicylic acid;
• sodium heparin monotherapy;
• high doses of intravenous immunoglobulins.

According to some researchers, the use of prednisolone together with acetylsalicylic acid improves pregnancy outcomes in patients with antiphospholipid syndrome. Other authors point to a large number of complications from glucocorticoid therapy - steroid ulcers, gestational diabetes mellitus, osteoporosis, etc. It should be noted that the above side effects are observed when using high doses of prednisolone - up to 60 mg/day.

A study conducted by F. Cowchock (1992) demonstrated the effectiveness of low-dose acetylsalicylic acid therapy in combination with sodium heparin in one group and prednisolone (40 mg/day) in another group. The percentage of viable babies born was approximately the same - about 75%, but more complications were noted in the group taking prednisolone.

It has been established that therapy with anticoagulants and antiplatelet agents in combination (sodium heparin at a dose of 10,000 IU/day + acetylsalicylic acid at a dose of 75 mg/day) is more effective than monotherapy with acetylsalicylic acid - 71 and 42% of viable births, respectively.

Without therapy, the birth of viable children is observed in only 6% of cases.

In recent years, foreign authors have attempted to divide patients with antiphospholipid syndrome into groups based on anamnestic data with subsequent prescription of treatment regimens.

Thus, in women with classical antiphospholipid syndrome with a history of thrombosis, it is necessary to prescribe heparin therapy from the early stages of pregnancy (from the moment of visualization of the ovum) under the control of coagulation tests, as well as acetylsalicylic acid (81–100 mg/day), a combination drug containing calcium and cholecalciferol.

In the presence of a history of preeclampsia, in addition to anticoagulant and antiplatelet therapy, intravenous immunoglobulins are used at a dose of 400 mg/kg for 5 days each month (this method is not used in our country).

In case of fetal loss without a history of vascular thrombosis, anticoagulant and antiplatelet therapy is used in low, maintenance doses (acetylsalicylic acid up to 100 mg/day, sodium heparin at a dose of 10,000 IU/day, low molecular weight heparins in prophylactic doses).

Circulation of ACL even in high titers without a history of thrombosis and miscarriage does not require drug therapy; only observation is indicated.

A scheme for managing patients with antiphospholipid syndrome has been developed and is being applied.

• Low-dose glucocorticoid therapy - 5–15 mg/day in terms of prednisolone.
• Correction of hemostatic disorders with antiplatelet agents and anticoagulants.
• Prevention of placental insufficiency.
• Prevention of reactivation of viral infection in carriers of herpes simplex virus type II and cytomegalovirus.
• Treatment of placental insufficiency.
• Therapeutic plasmapheresis according to indications.

Currently, the use of high doses of glucocorticoids (40–60 mg/day) is considered unjustified due to the high risk of side effects. We use glucocorticoid therapy in low and medium doses (5–15 mg in terms of prednisolone) throughout pregnancy and 10–15 days of the postpartum period, followed by gradual withdrawal.

Special attention should be paid to the correction of hemostatic vascular-platelet, microcirculatory disorders. In case of platelet hyperfunction, the most pathogenetically justified is the use of dipyridamole (75-150 mg daily). The drug improves uteroplacental and fetoplacental blood flow, relapses morphofunctional disorders in the placenta. In addition, dipyridamole is one of the few antiplatelet agents allowed for use in early pregnancy. Monitoring of hemostatic parameters is carried out once every 2 weeks, during the selection of therapy - according to indications.

As an alternative, the use of acetylsalicylic acid (81–100 mg/day) is acceptable.

In cases where pathological platelet activity is combined with hypercoagulation in the plasma link and the appearance of markers of intravascular blood coagulation, early use of small doses of sodium heparin (5000 U 2-3 times a day subcutaneously) is pathogenetically justified. The duration of heparin therapy determines the severity of hemostasis disorders. The administration of small doses of acetylsalicylic acid (81-100 mg/day) helps to potentiate the effect of heparin and prevents the development of hypercoagulation. The use of low-molecular heparins remains one of the main methods of pathogenetic treatment of antiphospholipid syndrome.

When using low molecular weight heparins, such a formidable complication as heparin-induced thrombocytopenia, associated with an immune response to the formation of a heparin-antiheparin factor complex of platelets, develops much less frequently.

Low molecular weight heparins are less likely to cause osteoporosis even with long-term use, making their use during pregnancy safer and more justified.

To prevent osteoporosis, calcium preparations are prescribed - 1500 mg/day of calcium carbonate in combination with cholecalciferol.

Low-molecular heparins cause hemorrhagic complications less frequently than sodium heparin, and these complications are less dangerous. Infiltration and pain, hematomas, common with sodium heparin injections, are significantly less pronounced when using low-molecular heparins, so patients tolerate them better, which makes long-term use of the drugs possible.

Unlike conventional sodium heparin, low molecular weight heparins, as a rule, do not stimulate or enhance platelet aggregation, but, on the contrary, weaken it, which makes their use preferable for the prevention of thrombosis.

Low molecular weight heparins have retained the positive properties of sodium heparin. It is extremely important that they do not penetrate the placental barrier and can be used for prevention and treatment in pregnant women without any negative consequences for the fetus and newborn.

The main drugs used in obstetric practice are enoxaparin sodium, dalteparin sodium, and nadroparin calcium. For therapeutic purposes, it is justified to use the drugs 2 times a day, since their half-life is up to 4 hours, but the effect of the drugs lasts for up to 24 hours. The use of low-molecular heparins in low doses does not require such strict hemostasis control as when using sodium heparin. Doses of drugs:

• enoxaparin sodium - prophylactic dose 20-40 mg once a day, therapeutic - 1 mg/kg of body weight (distribution of the daily dose into 1 or 2 subcutaneous injections);
• dalteparin sodium - 2500–5000 IU 1–2 times a day or 50 IU/kg of body weight;
• nadroparin calcium - 0.3-0.6 ml (2850-5700 IU) 1-2 times a day, the therapeutic dose is 0.01 ml (95 IU) / kg 2 times a day. However, combination therapy with glucocorticoids, immunoglobulins, anticoagulants and antiplatelet agents does not always lead to the desired result due to the possible development of drug intolerance, insufficient effectiveness of the doses used, as well as due to the occurrence of side effects. In addition, there is a category of patients resistant to drug therapy.

Plasmapheresis has a number of specific effects. It promotes detoxification, correction of blood rheological properties, immunocorrection, and increased sensitivity to endogenous and medicinal substances. This creates prerequisites for its use in patients with antiphospholipid syndrome.

The use of plasmapheresis outside of pregnancy allows to reduce the activity of the autoimmune process, normalize hemostatic disorders before the gestation period, since pregnancy becomes a critical moment for the course of antiphospholipid syndrome due to the development of hypercoagulation in these patients.

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Indications for plasmapheresis during pregnancy

• high activity of the autoimmune process;
• hypercoagulation as a manifestation of chronic disseminated intravascular coagulation syndrome, which does not correspond to the gestational age and cannot be corrected with medications;
• allergic reactions to the administration of anticoagulants and antiplatelet agents;
• activation of bacterial-viral infection (chorioamnionitis) during pregnancy in response to the glucocorticoids used;
• exacerbation of chronic gastritis and/or gastric ulcer, duodenal ulcer, requiring a reduction in glucocorticoid doses or cessation of immunosuppressive therapy.

The plasmapheresis technique includes exfusion of 30% of the circulating plasma volume in one session, which is 600–900 ml. Plasma substitution is performed with colloidal and crystalloid solutions. The ratio of the volume of plasma removed to the volume of plasma-substituting solutions is 1:1 outside pregnancy, and 1:1.2 during pregnancy using 100 ml of 10% albumin solution. Plasmapheresis has become an effective method of treating patients with antiphospholipid syndrome and can be used in combination with other medications.

In some cases, especially in virus carriers, long-term use of glucocorticoids can cause chorioamnionitis, which adversely affects the course of pregnancy and leads to infection of the fetus. In order to prevent activation of chronic infection, intravenous drip administration of normal human immunoglobulin is used at a dose of 25 ml every other day three times in each trimester of pregnancy or a 10% solution of immunoglobulin (γ-globulin) at a dose of 5 g at intervals of 1–2 days, 2 administrations per course.

Examination and drug preparation of patients with antiphospholipid syndrome should be carried out before pregnancy. The examination begins with collecting anamnesis, paying attention to pregnancy losses at different stages of gestation, development of gestosis, fetal hypotrophy, placental insufficiency, thrombosis of various localizations. The next stage is determination of the presence of lupus anticoagulant, LAC and hemostasis control. In case of a positive test for lupus anticoagulant and the presence of LAC, the examination should be repeated at an interval of 6-8 weeks. During this time, examination and treatment of sexually transmitted infections should be carried out, as well as a comprehensive examination, including a hormonal profile, HSG, ultrasound, genetic counseling. In case of repeated positive tests for lupus anticoagulant and changes in the hemostasiogram parameters, treatment should be started outside of pregnancy. Therapy is selected individually depending on the activity of the autoimmune process, and it includes antiplatelet agents, anticoagulants, glucocorticoids, and, if necessary, therapeutic plasmapheresis outside of pregnancy.

Indications for consultation with other specialists

Obstetricians and gynecologists treat patients with a history of thrombosis together with vascular surgeons. In the event of venous thrombosis in the postpartum period, the question of replacing direct anticoagulants (sodium heparin) with indirect ones (vitamin K antagonist - warfarin) and the duration of antithrombotic treatment is decided together with a vascular surgeon. In the event of thrombosis of cerebral vessels, liver failure (hepatic vein thrombosis - Budd-Chiari syndrome), thrombosis of mesenteric vessels (intestinal necrosis, peritonitis), nephrotic syndrome, renal failure, thrombosis of retinal arteries, consultations with a neurologist, hepatologist, nephrologist, surgeon, rheumatologist, ophthalmologist, etc. are necessary.

Surgical treatment of antiphospholipid syndrome

The need for surgical treatment arises in case of thrombosis during pregnancy and in the postpartum period. The question of the need for surgical treatment, including the installation of a cava filter to prevent pulmonary embolism, is decided jointly with vascular surgeons.

Pregnancy management

• From the early stages of gestation, the activity of the autoimmune process is monitored, including the determination of lupus anticoagulant, antiphospholipid antibodies, anticardiolipin antibodies, and hemostasis control with individual selection of doses of anticoagulant, antiplatelet and glucocorticoid drugs.
• When conducting anticoagulant therapy, a weekly clinical blood test with platelet count is required in the first 3 weeks for timely diagnosis of thrombocytopenia, and then at least once every 2 weeks.
• Ultrasound fetometry is performed to monitor the growth and development rate of the fetus; from 16 weeks of pregnancy, fetometry is performed at 3–4-week intervals to monitor the growth rate of the fetus and the amount of amniotic fluid.
• In the second trimester of pregnancy, examination and treatment of sexually transmitted infections are carried out, and the condition of the cervix is monitored.
• In the second and third trimesters, liver and kidney functions are examined: assessment of the presence of proteinuria, creatinine levels, urea, enzymes - alanine aminotransferase, aspartate aminotransferase.
• Ultrasound Doppler is used for timely diagnosis and treatment of manifestations of placental insufficiency, as well as for assessing the effectiveness of the therapy.
• CTG from the 33rd–34th week of pregnancy is used to assess the condition of the fetus and select the timing and method of delivery.
• During labor, careful cardiac monitoring is necessary due to chronic intrauterine fetal hypoxia of varying degrees of severity and the possibility of developing acute intrauterine fetal hypoxia against its background, as well as due to the increased risk of detachment of a normally located placenta.
• The condition of mothers in labor is monitored, since the risk of thromboembolic complications increases in the postpartum period. Glucocorticoid therapy is continued for 2 weeks after delivery with gradual withdrawal.
• The hemostasis system is monitored immediately before delivery, during delivery, and on the 3rd to 5th day after delivery. In case of severe hypercoagulation, it is necessary to prescribe sodium heparin 10–15 thousand U/day subcutaneously for 10 days, acetylsalicylic acid up to 100 mg/day for 1 month. In patients receiving antiplatelet agents and anticoagulants, lactation is suppressed. In case of short-term changes in the hemostasis system that respond to drug therapy, breastfeeding can be postponed for the duration of treatment while maintaining lactation.

Patient education

If the patient is diagnosed with antiphospholipid syndrome, she should be informed about the need for treatment during pregnancy and monitoring of the fetus. If signs of venous thrombosis of the leg vessels appear - redness, swelling, pain along the veins - you should immediately consult a doctor.

Further management of the patient

Patients with antiphospholipid syndrome with vascular thromboses need hemostasis control and observation by a vascular surgeon and rheumatologist even after the end of pregnancy. The question of the advisability and duration of therapy with anticoagulants and antiplatelet agents (including acetylsalicylic acid and warfarin) is decided individually.