Antiphospholipid syndrome: treatment

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

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

According to some researchers, the use of prednisolone in conjunction with acetylsalicylic acid improves the outcome of pregnancy 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 with the use of high doses of prednisolone - up to 60 mg / day.

A study conducted by the F. Cowchock (1992) showed the effectiveness of therapy with low doses of acetylsalicylic acid in a combination with sodium heparin in the other group with prednisolone (40 mg / day). The percentage of viable children was approximately the same - about 75%, but in the group taking prednisolone, there were more complications.

It was found that therapy with anticoagulants and antiplatelet agents together (heparin sodium 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 the births of viable children, respectively.

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

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

Thus, in women with classical antiphospholipid syndrome with thrombosis in history, the appointment of heparin therapy from the early stages of pregnancy (from the moment of visualization of the fetal egg) under the control of coagulation tests, as well as acetylsalicylic acid (81-100 mg / day), a combined preparation containing calcium and colcalciferol.

If there is a pre-eclampsia in the history, in addition to anticoagulant, antiaggregant therapy, intravenous immunoglobulins 400 mg / kg are used for 5 days of each month (the method in our country is not used).

When a fetus is lost without vascular thrombosis, an anticoagulant and antiplatelet therapy is used in low, maintenance doses (acetylsalicylic acid to 100 mg / day, heparin sodium at a dose of 10,000 IU / day, low-molecular heparins in preventive doses).

Circulation of ACL even in high titres without thrombosis in anamnesis and miscarriage does not require drug therapy, only observation is shown.

A scheme for managing patients with antiphospholipid syndrome was developed and applied.

• Therapy with glucocorticoids in low doses - 5-15 mg / day in terms of prednisolone.
• Correction of hemostasis disorders with antiplatelet agents and anticoagulants.
• Prophylaxis of placental insufficiency.
• Prevention of the reactivation of viral infection in the carrier of the herpes simplex virus type II and cytomegalovirus.
• Treatment of placental insufficiency.
• Treatment plasmapheresis according to indications.

Currently, the use of large doses of glucocorticoids (40-60 mg / day) is 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 the entire pregnancy and 10-15 days postpartum period, followed by a gradual cancellation.

Particular attention should be paid to correction of hemostasis vascular-platelet, microcirculatory disorders. With hyperfunction of platelets the most pathogenetically justified is the use of dipyridamole (75-150 mg daily). The drug improves utero-placental and fetoplacental blood flow, recursive morphofunctional disorders in the placenta. In addition, dipyridamole is one of the few antiplatelet agents that can be used in the early stages of pregnancy. Control of haemostasis indicators is performed once in 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 when the pathological activity of platelets is combined with hypercoagulability in the plasma link and the appearance of markers of intravascular coagulation, early use of small doses of sodium heparin (5000 ED 2-3 times a day subcutaneously) is pathogenetically substantiated. The duration of heparin therapy determines the severity of hemostasis disorders. The administration of small doses of acetylsalicylic acid (81-100 mg / day) promotes the potentiation of the action of heparin, prevents the development of hypercoagulation. The use of low molecular weight 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 the immune response to the formation of the heparin-anti-heparin platelet factor complex is much less likely to develop.

Low molecular weight heparins contribute less to osteoporosis, even with prolonged use, which makes their use more safe and justified during pregnancy.

In order to prevent osteoporosis appoint calcium preparations - 1500 mg / day calcium carbonate in combination with kolokaltsiferolom.

Low molecular weight heparins are less likely to cause hemorrhagic complications than sodium heparin, and these complications are less dangerous. Infiltration and soreness, hematomas common with injections of sodium heparin, are much less pronounced when using low molecular weight heparins, so patients transfer them more easily, which makes possible the long-term use of drugs.

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

Low molecular weight heparins retained the positive qualities of sodium heparin. It is extremely important that they do not penetrate the placental barrier and they 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 sodium enoxaparin, sodium dalteparin, calcium supraparin. For therapeutic purposes, the use of drugs 2 times a day is justified, since the half-life of these drugs is up to 4 hours, but the effect of the drugs persists up to a day. The use of low molecular weight heparins at low doses does not require such strict hemostasis control as with sodium heparin. Doses of drugs:

• enoxaparin sodium - a prophylactic dose of 20-40 mg once a day, therapeutic - 1 mg / kg of mass (distribution of the daily dose for 1 or 2 subcutaneous injections);
• dalteparin sodium - 2500-5000 IU 1-2 times per day or 50 IU / kg of weight;
• Supraparin calcium - 0,3-0,6 ml (2850-5700 ME) 1-2 times vsutki, therapeutic dose - 0.01 ml (95 IU) / kg 2 times a day. However, the complex therapy of glucocorticoids, immunoglobulins, anticoagulants and antiplatelet agents does not always lead to the desired result due to the possible development of drug intolerance, inadequate efficacy of the doses used, and also 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 contributes to detoxification, correction of rheological properties of blood, immunocorrection, increase of sensitivity to endogenous and medicamentous substances. This creates the prerequisites for its use in patients with antiphospholipid syndrome.

The use of plasmapheresis outside pregnancy can reduce the activity of the autoimmune process, normalize hemostasis disorders before the gestation period, since pregnancy becomes a critical moment for the course of antiphospholipid syndrome in connection with the development of hypercoagulable in these patients.

[1], [2], [3], [4], [5], [6]

Indications for plasmapheresis during pregnancy

• high activity of the autoimmune process;
• hypercoagulability as a manifestation of a chronic syndrome of disseminated intravascular coagulation, not corresponding to the term of pregnancy and not amenable to correction by medicinal agents;
• allergic reactions to the administration of anticoagulants and antiaggregants;
• activation of bacterial-viral infection (chorioamnionitis) during pregnancy in response to used glucocorticoids;
• exacerbation of chronic gastritis and / or peptic ulcer of the stomach, duodenal ulcer, requiring a reduction in the doses of glucocorticoids or the cessation of immunosuppressive therapy.

The procedure for conducting plasmapheresis involves the exfusion of 30% of the volume of circulating plasma in one session, which is 600-900 ml. Plasma replacement is carried out by colloidal and crystalloid solutions. The ratio of the volume of the removed plasma and the volume of plasma-substituting solutions is outside of pregnancy 1: 1, and during pregnancy 1: 1, using a 10% solution of albumin in an amount of 100 ml. Plasmapheresis has become an effective method for treating patients with antiphospholipid syndrome and can be used in conjunction 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 the activation of chronic infection, intravenous drip of normal human immunoglobulin at a dose of 25 ml every other day is administered in triplicate every trimester of pregnancy or 10% solution of immunoglobulin (γ-globulin) at a dose of 5 g at intervals of 1-2 days, .

The examination and medication preparation of patients with antiphospholipid syndrome should be performed before the onset of pregnancy. The examination begins with the collection of anamnesis, paying attention to the loss of pregnancy at different terms of gestation, the development of gestosis, fetal hypotrophy, placental insufficiency, thrombosis of different localization. The next step is to determine the presence of lupus anticoagulant, ACL, and hemostasis control. With a positive sample for lupus anticoagulant and the presence of ACL, the study should be repeated at intervals of 6-8 weeks. During this time, it is necessary to conduct a survey and treatment of sexually transmitted infections, as well as a comprehensive examination, including hormonal profile, GHA, ultrasound, genetic counseling. With repeated positive tests for lupus anticoagulant and the presence of changes in the parameters of the hemostasiogram, 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, if necessary, therapeutic plasmapheresis outside of pregnancy.

Indications for consultation of other specialists

Patients with thrombosis in the history of obstetrician-gynecologists conduct together with vascular surgeons. When vein thrombosis occurs in the postpartum period, the question of replacing direct anticoagulants (heparin sodium) with the indirect (vitamin K antagonist - warfarin) and the duration of antithrombotic treatment is decided in conjunction with the vascular surgeon. In case of cerebral thrombosis, hepatic insufficiency (thrombosis of the hepatic veins - Badd-Chiari syndrome), thrombosis of mesenteric vessels (necrosis of the intestine, peritonitis), nephrotic syndrome, renal failure, thrombosis of the retinal arteries, consultations of neurologist, hepatologist, nephrologist, surgeon, rheumatologist , oculist, etc.

Surgical treatment of antiphospholipid syndrome

The need for surgical treatment occurs with thrombosis during pregnancy and in the postpartum period. The question of the need for surgical treatment, including the setting up of a cava filter for the prevention of pulmonary embolism, is solved together with vascular surgeons.

Management of pregnancy

• From the early stages of gestation, the activity of the autoimmune process is monitored, including the definition of lupus anticoagulant, antiphospholipid antibodies, anticardiolipin antibodies, hemostasis control with individual selection of doses of anticoagulant, antiaggregant and glucocorticoid drugs.
• When conducting anticoagulant therapy in the first 3 weeks, a weekly clinical blood test is necessary to count the number of platelets for the timely diagnosis of thrombocytopenia, and then at least once every 2 weeks.
• Ultrasonic fetometry is performed to control the rate of growth and development of the fetus, from 16 weeks of gestation, fetometry is performed at a 3- to 4-week interval to control fetal growth rates and the amount of amniotic fluid.
• In the second trimester of pregnancy, the examination and treatment of sexually transmitted infections is performed, and the condition of the cervix is monitored.
• In II and III trimesters, hepatic and renal functions are examined: an assessment of the presence of proteinuria, the level of creatinine, urea, enzymes - alanine aminotransferase, aspartate aminotransferase.
• Ultrasound dopplerometry is used for the timely diagnosis and treatment of placental insufficiency, as well as for evaluating the effectiveness of the therapy.
• CTG from the 33rd-34th week of pregnancy serves to assess the condition of the fetus and the timing and method of delivery.
• In labor, careful cardiomonitor control is necessary in connection with chronic fetal hypoxia of the fetus of one degree or another and the possibility of developing acute intrauterine fetal hypoxia in its background, and also because of the increased risk of detachment of the normally located placenta.
• Monitor the condition of the puerperas, since it is in the postpartum period that the risk of thromboembolic complications increases. Glucocorticoid therapy is continued for 2 weeks after delivery with a gradual withdrawal.
• Control of the hemostasis system is carried out immediately before childbirth, during childbirth and on the 3-5th day after childbirth. With severe hypercoagulation, it is necessary to prescribe sodium heparin 10-15 thousand units / day for 10 days, acetylsalicylic acid to 100 mg / day for 1 month. In patients receiving antiaggregants and anticoagulants, lactation is suppressed. With short-term changes in the system of hemostasis, amenable to drug therapy, breast-feeding can be delayed for the duration of treatment while preserving lactation.

Student training

If the patient is diagnosed with an antiphospholipid syndrome, she should be informed of the need for treatment during pregnancy and monitoring of the fetus. When there are signs of venous thrombosis of the vessels of the legs - redness, swelling, tenderness along the veins - it is urgent to see a doctor.

Further management of the patient

Patients with antiphospholipid syndrome with vascular thrombosis need hemostasis control and observation of the vascular surgeon and rheumatologist and after the termination of pregnancy. The question of the appropriateness and duration of therapy with anticoagulants and antiplatelet agents (including acetylsalicylic acid and warfarin) is decided individually.