RU2712444C1 - Method for prevention of preeclampsia in carriers of f2g20210a mutation with superthreshold increase of prothrombin activity - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to a method of preventing preeclampsia in pregnant women with a factor F2G20210A mutation. Method for preventing preeclampsia in pregnant women with a mutation of factor F2G20210A, consisting in using calcium nadroparin when determining a prothrombin activity index of 171.0 % and higher to 18 weeks gestation, and further administration of preventive doses of calcium nadroparin is determined individually taking into account prothrombin activity, determined in period of 18 weeks and 28 weeks of pregnancy.

EFFECT: method described above is simple to use and enables to reduce preeclampsia (PE) by 46,7 %: from 56,7 % to 10 %: RR: 0,1765; 95CI: 0,0725–0,4291; p=0,0001 and improve pregnancy outcomes.

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Description

The invention relates to medicine, in particular to obstetrics and can be used for the prevention of preeclampsia (PE) in carriers of the F2G20210A mutation with an over-threshold increase in prothrombin activity.

et al. The role of haemostasis in placenta-mediated complications Thromb Res. 2019 Sep; 181 Suppl 1:S10-S14. doi: 10.1016/S0049-3848(19)30359-7.). По результатам серии мета-анализов и систематических обзоров носительство мутации F2G20210A ассоциировано с увеличением риска развития ПЭ в 2,5-7,1 раза (Robertson L, Wu О, Langhorne Р et al. Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006 Jan; 132(2):171-96. http://dx.doi.org/10.1111/j.1365-2141.2005.05847.x.; Gao H, Tao FB. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update. Thromb Res. 2015 Feb; 135(2):339-46. http://dx.doi.org/10.1016/j.thromres.2014.12.001). Очевидно, что описанные микротромбозы сосудов плацентарного ложа при развитии ПЭ у носителей мутации F2G20210A имеют связь с гиперкоагуляционным сдвигом, обусловленным повышением как уровня, так и активности протромбина в плазме крови (Стрижаков А.Н., Волощук И.Н., Тимохина Е.В. и др. Клиническое значение тромбофилии в развитии апоптоза и пролиферации при плацентарной недостаточности. Вопросы гинекологии, акушерства и перинатологии. 2010; 9(4):5-12.; Дробинская А.Н., Надеев А.П., Жукова В.А. и др. Морфология плаценты при наследственной тромбофилии. Архив патологии 2014; 76(3):33-36.; Карпич С.А., Шмелева В.М., Головина О.Г. и др. Оценка протромботического фенотипа у асимптомных носителей мутации G1691A в гене фактора V или/и G20210A в гене протромбина с помощью теста генерации тромбина. Тромбоз, гемостаз и реология. 2018; 75(3):11-16. http://dx.doi.org/10.25555/THR.2018.3.0845.). Поэтому, в настоящее время является актуальным создание простого и эффективного способа профилактики ПЭ у носителей мутации F2G20210A при сверхпороговом повышении активности протромбина, позволяющего снизить частоту наступления ПЭ и улучшить исходы беременности.PE occurs in 1-8% of pregnant women and determines not only maternal and perinatal morbidity, but it is also the second leading cause of maternal mortality worldwide and one of the five leading causes of maternal mortality in developed countries (Ghulmiyah L., Sibai B. Maternal mortality from preeclampsia / eclampsia. Semin. Perinatol. 2012; 36 (1): 56-9; Gris JC, Bouvier S.,

et al. The role of haemostasis in placenta-mediated complications Thromb Res. 2019 Sep; 181 Suppl 1: S10-S14. doi: 10.1016 / S0049-3848 (19) 30359-7.). According to a series of meta-analyzes and systematic reviews, carriage of the F2G20210A mutation is associated with an increase in the risk of developing PE by 2.5-7.1 times (Robertson L, Wu O, Langhorne P et al. Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS ) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol. 2006 Jan; 132 (2): 171-96. Http://dx.doi.org/10.1111/j.1365-2141.2005.05847.x .; Gao H, Tao FB. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update. Thromb Res. 2015 Feb; 135 (2): 339-46. Http://dx.doi.org/ 10.1016 / j.thromres.2014.12.001). It is obvious that the described microthromboses of the vessels of the placental bed during the development of PE in carriers of the F2G20210A mutation are associated with a hypercoagulation shift caused by an increase in both the level and activity of prothrombin in the blood plasma (Strizhakov A.N., Voloshchuk I.N., Timokhina E.V. . and other Clinical significance of thrombophilia in the development of apoptosis and proliferation in placental insufficiency. Issues of gynecology, obstetrics and perinatology. 2010; 9 (4): 5-12 .; Drobinskaya A.N., Nadeev A.P., Zhukova V. A. et al. Morphology of the placenta in hereditary thrombophilia. 2014; 76 (3): 33-36 .; Karpich S.A., Shmeleva V.M., Golovina O.G. et al. Assessment of the prothrombotic phenotype in asymptomatic carriers of the G1691A mutation in the gene for factor V or / and G20210A in prothrombin gene using a thrombin generation test. Thrombosis, hemostasis and rheology. 2018; 75 (3): 11-16. http://dx.doi.org/10.25555/THR.2018.3.0845.). Therefore, it is currently relevant to create a simple and effective method for the prevention of PE in carriers of the F2G20210A mutation with an extra-threshold increase in prothrombin activity, which allows reducing the frequency of onset of PE and improving pregnancy outcomes.

A known method for the prevention of severe pregnancy complications in patients with thrombophilia (RF patent No. RU 2367446 C1, 2009), which consists in the appointment of heparoid VESSEL DUE F at the stage of pregravid preparation at a dose of 1000 units per day until the activity index of lupus anticoagulant decreases by at least 0 ,8. During the first trimester of pregnancy, instead of VESSEL DUE F, clexane is administered at a dose of 0.4 ml / day under the skin of the abdomen daily. From the thirteenth week of pregnancy, VESSEL DUE F therapy is resumed at the same dose - 2 tablets 2 times a day until delivery. The efficacy and tolerability of the treatment of VESSEL DUE F is evaluated by the dynamics of the clinical and laboratory manifestations of the thrombophilic process: the value of the VA activity indicator, platelet count, blood fibrinolytic activity (FA) and the status of the fetoplacental complex according to ultrasound data with dopplerometry of the uterine and umbilical arteries

The disadvantage of this method is the ineffectiveness of prophylaxis of PE in patients in the absence of circulation of lupus anticoagulant in blood plasma. In addition, VESSEL DUE F has not undergone clinical trials in pregnant women, therefore it is impossible to speak with confidence about its complete safety for the fetus and mother (FDA, Health Organizations to Study Safety of Medications Taken During Pregnancy. For Immediate Release. 2009. URL: http : //www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm195934.htm (accessed: 10/19/2019)).

A known method for the prevention of preeclampsia in patients with a burdened obstetric history (RF patent No. RU 2663593 C2, 2018), including during the pregravid preparation and during pregnancy, the appointment of vitamin D administration, characterized in that the patients undergo pre-eclampsia DNA extraction and genotyping the following genes: GC gene, rs2282679; CYP2R1 gene, rs2060793; VDR gene, rs2228570, after which patients with identified genotypes C / C, C / T (VDR gene, rs2228570), and / or C / C, C / T (CYP2R1 gene, rs2060793), and / or C / C, A / C (GC gene, rs2282679) was assigned a dose of vitamin D 4000 IU / day, and for pregnant women with identified T / T genotypes (VDR gene, rs2228570); T / T (CYP2R1 gene, rs2060793) and A / A (GC gene, rs2282679) in the absence of the C / C, C / T A / C genotypes of these or other genes, a dose of vitamin D of 2000 IU / day was prescribed.

Genotyping was carried out at risk for the development of PE, which consisted of women with hypertension, kidney disease, obesity (BMI> 34), and a deficiency of body weight. The known method of using vitamin D during pregravid preparation and during gestation made it possible to improve the course of pregnancy compared to the group in which prophylaxis was not carried out: PE episodes were not registered, premature detachment of the normally located placenta was observed 3 times less often, changes 3 times less placenta in the form of a decrease or increase in its volume and 4 times less often fetal development retardation syndrome.

The disadvantage of this method is its inefficiency, as it does not allow the use of the proposed scheme in patients of medium and low risk of developing PE and insufficient safety. It was determined that prolonged intake of vitamin D in doses of more than 2000 units / day during pregnancy requires a dynamic study of the level of vitamin D in the plasma of venous blood after 8 weeks from the start of the drug. When reaching a venous blood plasma vitamin D level of 30 ng / ml, the dose of vitamin D should be reduced to a prophylactic dose of 1000 ME (Canadian Pediatric Society. Vitamin D supplementation: recommendations for Canadian mothers and infants. Pediatr Child Health. 2007; 12 (7 ): 583-589; Overview of current research on the use of vitamin D during pregnancy and the postpartum period Shirinyan L.V., Gurkina E.Yu., Zazerskaya I.E. Translational medicine. 2015. No. 1. P. 52-56 .)

The closest technical result achieved (prototype) is a method for the prevention of preeclampsia in pregnant women with a factor V mutation Leiden 1691, genotype G / A (RF patent No. RU 2666251 C1, 2018), which consists in the appointment of low molecular weight heparins (NMH) in high prophylactic doses within 14 days in terms of the normalized ratio of APS resistance is less than or equal to 0.49 at a gestational age of 7-8. The known method of using LMWH has reduced the absolute risk of developing PE by 12.9%; a decrease in the relative risk of developing PE by 67.7% compared with the group in which prophylaxis of LMWH was not carried out.

The disadvantage of this method is the inefficiency of its use in patients in the absence of carrier mutation of factor V Leiden 1691, genotype G / A.

The authors propose a simple and highly effective way to prevent PE in pregnant women with the F2G20210A mutation with an extra-threshold increase in prothrombin activity, which allows to reduce the frequency of PE onset and improve pregnancy outcomes.

The technical result of the proposed method is to increase efficiency by reducing the incidence of PE in pregnant women with the F2G20210A mutation with an over-threshold increase in prothrombin activity from 56.7% to 10.0%: RR: 0.1765; 95CI: 0.0725-0.4291; p = 0.0001.

The technical result is achieved by using a pre-gravid period of calcium nadroparin in a prophylactic dose when determining the activity indicator of prothrombin 171.0% and above until the gestational age of 18 weeks. The further administration of prophylactic doses of nadroparin calcium is determined individually, taking into account the indicator of prothrombin activity, determined at 18 weeks and 28 weeks of gestation. With a persisting superthreshold increase in the activity of prothrombin (181.0% and higher) in the period of 18 weeks, prophylactic doses of calcium nadroparin of the patient then receive the entire antenatal period (Fig. 1).

Preventive doses of calcium nadroparin are calculated according to the patient’s body weight:

- 50-90 kg of 0.3 ml (2850 ME anti-XA) 2 times a day

- more than 90 kg of 0.4 ml (3800 ME anti-Xa) 2 times a day

The inventive method is illustrated by a figure in the form of a table, which shows the indicators of the effectiveness of prophylaxis of PE in pregnant women with the F2G20210A mutation with an over-threshold increase in prothrombin activity.

The method is as follows.

To confirm the effectiveness of the proposed method, two groups were created: the main group and the comparison group, which included women with the F2G20210A mutation at the stage of pregnancy planning (pregravid) with a prothrombin activity index of 171.0% and higher.

The main group consisted of 50 women with a F2G20210A mutation and an indicator of prothrombin activity of 171.0% and higher at the pregravid stage, who received prophylaxis with calcium nadroparin in prophylactic doses determined by the patient’s body weight before 18 weeks of gestation. The further administration of prophylactic doses of nadroparin calcium is determined individually, taking into account the indicator of prothrombin activity, determined at 18 weeks and 28 weeks of gestation (Fig. 1).

The appointment of calcium nadroparin is approved for use in pregnant women and is included in the clinical protocol "Prevention of venous thromboembolic complications in obstetrics and gynecology" (Letter of the Ministry of Health of the Russian Federation dated May 27, 2014 No. 15-4 / 10 / 2-3792) based on the recommendations of American College of Obstetricians and Gynecologists (ACOG, 2011), Royal College of Obstetricians and Gynaecologists (RCOG, 2009).

A comparison group consisted of 30 patients with a mutation of the factor F2G20210A and an activity index of prothrombin of 171.0% and higher at the pregravid stage, who did not receive calcium nadroparin prophylaxis.

The effectiveness of prescribing calcium nadroparin for the prevention of PE was assessed by the number of PE cases recorded in the main group relative to the comparison group. Statistical processing of the results showed a decrease in the absolute risk of PE in the main group by 46.7%; including heavy PE by 30.7% (Fig. 2).

Clinical examples

1. Patient K.N.N., 32 years old. It was observed in the city center for family planning and reproduction at a specialized reception for miscarriage. This pregnancy is 5, which was carried out jointly by an obstetrician and a hematologist. A medical abortion history of 5–6 weeks, three undeveloped pregnancies of 9–10 weeks. At the pregravid stage, it was examined by a hematologist, the carrier of the mutation F2G20210A was revealed. When pregnancy occurs in the period of 7-8 weeks, along with the volume of examination regulated by order 572H, an indicator of prothrombin activity was determined, which amounted to 190.6%. The remaining markers of thrombinemia corresponded to gestational age. Preventive doses of calcium nadroparin up to 18 weeks of gestation have been prescribed. In a control study at 18 weeks, a decrease in prothrombin activity to 170.2% was determined, and therefore calcium nadroparin was canceled. During the control study of prothrombin activity in the gestational age of 28 weeks, its increase was determined to 210.7%, preventive doses of calcium nadroparin were prescribed, which the patient received before childbirth. The course of a real pregnancy without gestational and perinatal complications. In the gestational age of 38.5 weeks, spontaneous birth through the natural birth canal. A girl was born, weight 3300 with a rating on the Apgar scale of 8 points. In the postpartum period, thromboprophylaxis of VTEC was performed with calcium nadroparin for 6 weeks.

2. Patient G.T.A., 36 years old. It was observed by a hematologist in the Altai branch of the Federal State Budgetary Institution National Medical Research Center for Hematology. This is the third pregnancy, observation together by an obstetrician and a hematologist. A history of medical abortion was 6 weeks, premature birth was 34 weeks abdominally due to severe preeclampsia by a male fetus weighing 2340 grams. When planning a real pregnancy, she was examined to the extent regulated by order 572-N, including genetic testing for the carriage of genetic forms of thrombophilia and a study of indicators of the hemostasis system. Carriage of the F2G20210A mutation with prothrombin activity of 284.9% was determined. In order to prevent obstetric complications, nadroparin calcium was prescribed in prophylactic doses from the fertile cycle, therapy was continued during pregnancy. At a gestational age of 18 weeks, the prothrombin activity indicator was 162%, and therefore, the patient was recommended to cancel calcium nadroparin. With dynamic monitoring of the activity of prothrombin in the period of 28 weeks, the latter is defined as 164%. There was no reappointment of calcium nadroparin. At 39.2 weeks gestation, the patient was delivered abdominally as planned. A boy was born, weight 3470 with an Apgar score of 7 points. In the postpartum period, thromboprophylaxis of VTEC was performed with calcium nadroparin for 6 weeks.

3. Patient B.O.L., 34 years old. It was observed by a hematologist in the Altai branch of the Federal State Budgetary Institution National Medical Research Center for Hematology. Fourth pregnancy, observation together by an obstetrician and a hematologist. A history of 20 years of age preterm delivery of 27.2 weeks in an abdominal way due to the development of severe preeclampsia. A 890 gram boy was born, who died on the 4th day due to the development of respiratory distress syndrome against the background of deep prematurity. The second pregnancy at the age of 23 years, from 29 weeks of pregnancy an increase in blood pressure figures to 150/100 was recorded, moderate proteinuria in the urine analysis (up to 3 grams per day). In connection with the diagnosis: Moderate preeclampsia, the patient received treatment in a hospital setting: magnesia therapy, heparin prophylaxis with low molecular weight heparins in high prophylactic doses. Given the ineffectiveness of the therapy, increasing proteinuria (more than 3 grams per day), unstable hemodynamics (blood pressure up to 160/110), impaired fetal-placental circulation of type 1B according to Dopplerometry, a delivery by cesarean section was performed at 30 weeks. A girl was born, weight 980 grams, with an Apgar score of 5 points. After birth, hematologist examined, revealed by carrier mutation of the F2G20210A gene. The third pregnancy occurred at the age of 30, proceeded with the clinic of the threat of interruption. During pregnancy, three courses of low molecular weight heparins were carried out in a prophylactic dose of 10-14 days at the “critical time” of pregnancy - 7-8 weeks, 12-13 weeks, 22-23 weeks, which coincided with hospitalization in the department of pathology of pregnant women of the Altai Regional Clinical Hospital. The patient also received prophylactic doses of acetylsalicylic acid (75 mg per day) according to the provisions of the clinical protocol (Hypertensive disorders during pregnancy, childbirth and the postpartum period. Preeclampsia. Eclampsia. Clinical recommendations (treatment protocol) letter of the Ministry of Health of the Russian Federation of June 07, 2016 N 15-4 / 10 / 2-3483). In the period 33-34, the pregnancy ended with an abdominal delivery due to antenatal death of a male fetus, weighing 2190 grams. According to the results of pathological studies, antenatal fetal death occurred due to thrombosis of the umbilical cord vessels. When planning a real pregnancy, an indicator of prothrombin activity was determined, which amounted to 201.0%. From the pregravid period, the patient received prophylactic doses of nadroparin calcium throughout the antenatal period and 6 weeks of the postpartum period. From 12 weeks until birth, the patient received acetylsalicylic acid at a dose of 75 mg per day. The indicator of the level of prothrombin activity, determined in the gestational age of 18 and 28 weeks, was 189.0% and 194.0%, respectively. In pregnancy 38.5, the patient was delivered by elective cesarean section. A boy was born, weight 3400 with a rating on the Apgar scale of 7-8 points.

Thus, the claimed method for the prevention of preeclampsia in pregnant women with the F2G20210A mutation with an extra-threshold increase in prothrombin activity, by initiating prophylaxis with calcium nadroparin in prophylactic doses from the pre-gravity period is highly effective, easy to use, and allows you to reduce the frequency of PE by 46.7%: from 56.7% up to 10.0%: RR: 0.1765; 95CI: 0.0725-0.4291; p = 0.0001 and improve pregnancy outcomes.

Claims (1)

A method for the prevention of preeclampsia in pregnant women with a mutation of the factor F2G20210A, which consists in the use of prophylactic calcium with prophylactic doses of prodrombin in determining the activity indicator of prothrombin 171.0% and above until the gestational age of 18 weeks, and the further administration of prophylactic doses of calcium nadroparin is determined individually an indicator of prothrombin activity, determined at 18 weeks and 28 weeks of gestation.

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