Pregnancy and childbirth in a woman with homozygous factor V Leiden mutation and thrombosis due to hormonal contraception in a history

Over the last 50 years, hormonal contraception (HC) has played a huge role in providing basic principles for family planning. In addition, a variety of hormonal contraceptives have become a very important component of the successful therapy of numerous gynecological diseases [1]. However, since the introduction of HC up to the present time, despite the improvement in the quality of pills, a decrease in the dose of the estrogen component and an improvement in the quality of the gestagen component, a variety of thrombotic complications and complications of a future pregnancy occur in many patients [2, 3]. At the present time, it has been established that the most important cause is the initial, sometimes latent, disorders of the hemostatic system, predisposing to increased blood clotting and thrombosis. The administration of hormonal contraceptives is often a trigger causing genetic thrombophilia [4].

In women with thrombotic complications developing during the first months of oral contraceptive use, hereditary hemostasis disorders are more often detected than in women whose thrombotic complications occurred with longer-term intake of HC [5]. Factor V Leiden (FV Leiden) mutation was discovered in 1994 by Bertina et al. and is still considered to be the most common cause of thrombophilia, found in 5% of Europeans and in about 50% of patients with thrombosis [6]. According to Bick (2002), the presence of FV Leiden mutation increases the risk of thrombosis in heterozygous carriers by 3-8 times compared with the general population, in homozygous carriers by 50-80 times [7]. In carriers of the heterozygous form of FV Leiden mutation, the risk of venous thromboembolism increases by 20-30 times when using second generation oral contraceptives, and by 50 times when using third generation oral contraceptives, compared with healthy women who do not use oral contraceptives [8, 9].

Clinical case

A 31-year-old patient N with complicated thrombotic history presented to our department for pregnancy planning in March, 2016.

It is known from the history that two years ago (July, 2014) the patient underwent ileofemoral thrombosis during the air flight, while she was taking oral contraceptives “Jess”. After the episode of thrombosis, pills were immediately canceled.

Oral contraceptives were prescribed only for contraception, thrombosis occurred during the third month of taking this medication. In this connection, the patient was hospitalized in the Clinical Hospital № 81 (Moscow), where she underwent conservative anticoagulant therapy: she received warfarin during 8 months, then rivaroxaban 20 mg per day until now.

Gynecological history. Menarche was at the age of 13, menstrual cycle established immediately, the cycle was 26 days; moderate, regular, painless menstruation lasted 4 days.

Obstetric history. No pregnancies.

Family history. Sister had deep vein thrombosis (DVT) at the age of 39 years after the operation on the meniscus, she had no pregnancies. Father had a myocardial infarction with a lethal outcome aged 56. Mother died of breast cancer at the age of 35 years.

In the laboratory of hemostasis pathology of the Sechenov First Moscow State Medical University, the patient N. was performed a detailed examination for the presence of acquired and genetic forms of thrombophilia and disorders in the hemostatic system:

• Factor V gene (Leiden) G1691A mutation, homozygous form
• Fibrinogen gene - 455 G / A polymorphism, heterozygous form
• PAI-1 gene - 675 4G / 5G polymorphism, heterozygous form
• Arg353Gin polymorphism in the gene of factor VII, heterozygous form
• 1298 A / C polymorphism in the gene of methylenetetrahydrofolate reductase (MTHFR), homozygous form
• 66 A / G polymorphism in the methionine synthase reductase gene (MTRR), heterozygous form
• 2756 polymorphism in the gene methionine synthase (MTR), heterozygous form
• 174 G / C polymorphism in the gene interleukin-6 (IL-6), homozygous form
• 31 T / C polymorphism in the interleukin-1b gene (IL-1c), homozygous form
• 5032 C / G polymorphism in the gene CD-46, heterozygous form
• Markers of hemostatic system activation: D-dimer (qualitative) 2-3 μg / ml (normal <0.5 μg / ml), soluble fibrin monomer complex (FMC) positive (normal - negative);
• Impairments in the protein C system (protein C global test): НО = 0.38 (normal > 0.7);

Based on the results of the conducted studies and taking into account the history, patient N had the following conclusions: genetic thrombophilia (homozygous FV Leiden mutation, polymorphisms of folate cycle genes and pro-inflammatory cytokines), activation of the hemostatic system, condition after ileofemoral thrombosis on the left leg (2014) due to the hormonal contraceptives, chronic venous insufficiency of the second stage, class 3 of the CEAP classification, family history of thrombosis.

The patient was recommended to switch from rivaroxaban to enoxaparin sodium at a dose of 0.6 ml twice a day during pregnancy planning period, entire pregnancy, as well as the postpartum period with dose adjustment according to the anti-Xa assay. Also, given the presence of polymorphisms of the folate cycle genes, the patient was prescribed the intake of folic acid and B group vitamins during pregnancy planning period and the first trimester.

When pregnancy occurred, the patient continued to receive a low-molecular-weight heparin, whose dose from the moment of pregnancy was increased to 1.4 ml per day and divided into 3 doses in a constant regime under hemostasiogram control. Once every three months, patient N. was performed an ultrasound duplex scan of the veins of the lower limbs, which showed significant positive dynamics during the period of patient’s observation in our clinic. According to ultrasound and Doppler ultrasound of utero-placental and fetal-placental vessels, there were no disturbances, the fetus was appropriate for gestational age. The patient also underwent screening of the first and second trimester of pregnancy, which did not reveal any abnormalities. Every two weeks, the hemostasis system was monitored (platelet aggregation, anti-Xa activity, protein C global test, FMC, D-dimer, thromboelastography, activated partial thromboplastin time).

At 19 weeks gestation, the dose of enoxaparin sodium was increased to 1.6 ml per day, due to activation of the hemostasis system (D-dimer Ceveron - 1088.1, normal to 250 ng / ml, anti Xa - 0.56), and acetylsalicylic acid in the dosage of 100 mg per day was added to the therapy due to the increased aggregation of thrombocytes (with ADP 80%, with ristomycin 88%, normal up to 80% and 90%, respectively).

At 37 weeks gestation, acetylsalicylic acid was withdrawn. Enoxaparin sodium was canceled a day before the scheduled operative delivery and resumed in 8-12 hours after the operation at a dose of 0.6 ml twice a day for the entire postpartum period.

At a period of 39 weeks and 4 days the patient was delivered by cesarean section. Alive, full-term girl was born, with a body weight 3300 grams, height 51 cm. The Apgar score was 8/9 points. The baby was healthy. The blood loss was 500 ml. The postpartum period was without complications. During the first five days after delivery, the patient received enoxaparin sodium at the dose of 0.4 ml per day, then the dose was increased to 0.6 ml twice a day under dose control (anti-Xa) and efficacy taken into account (D-dimer level). The anti-Xa level was normal within six weeks of the postpartum period, the D-dimer level by the sixth week was appropriate for the indicator of a non-pregnant women.

Discussion

Despite the improvement and widespread use of hormonal contraceptives at present as one of the most reliable methods of contraception, and the method for treating many gynecological diseases, various thrombotic complications still take the first place in the list of side effects in this category of pills. Over the past decade, many studies have been carried out which proved the effect of НС on individual links of the hemostasis system and on the coagulation background in general [10, 11].

Thus, oral contraceptives affect the function of platelets, leading to their hyperactivity, its degree depends on the duration of taking pills. Markers of thrombocyte reactions increase in blood plasma: β-thromboglobulin (β-TG), 4-antiheparin factor of platelets (PF4) and platelet factor 3 (PF3) and thromboxane A2 (ТхА2). Although, according to many authors, moderate activation of platelets is observed in the process of taking HC, but an increase in the duration of taking these pills for more than nine months leads to a progression of platelet aggregation due to initiation of blood clotting through the platelet link [12, 13].

The activation of fibrinolysis is indicated by a decrease in the level of PAI-1 and an increase in the concentration of t-PA and plasminogen. Among the changes in the fibrinolysis system, an increase in PAP and FDP complexes, such as D-dimer, should be noted.

During oral contraceptive use, an increase in the activity of most blood procoagulants, including fibrinogen, vitamin-K dependent clotting factors - prothrombin, VII, IX, X, XII, is also observed. The degree of increase in the levels of these factors directly depends on the dose of estrogens in the pill. An isolated increase in these factors means that there is potential hypercoagulation without signs of activation of intravascular coagulation and thrombosis [14].

During prolonged intake of hormonal contraceptives, there is a decrease in the concentration of natural blood anticoagulants: protein C (PC), protein S (PS), antithrombin III (AT III). It was found that by the third month of taking HC, their level did not change significantly, but by the ninth month there was a significant decrease in anticoagulant components of the hemostasis system [15]. In addition, a decrease in sensitivity to activated protein C (APC) in women taking oral contraceptives is observed. The degree of such acquired resistance to activated protein C (APC-R) is similar to that in the presence of the heterozygous form of FV Leiden mutation. But unlike the genetically caused APC-R, the acquired APC-R is not detected after the withdrawal of this category pills. It is known that the degree of APC-R in women with a heterozygous form of the FV Leiden mutation taking hormonal contraceptives is similar to that for the homozygous form of FV Leiden mutation [16].

The mechanism of action of the FV Leiden mutation is the replacement of the amino acids arginine by glutamine at the position of the 506 gene encoding the factor V. As a result of the FV Leiden mutation, the function of the protein C system, the most important anticoagulation pathway in the body, is impaired [10]. In the context of ordinary life, when compensatory functions of the body persist, phenotypically this mutation may not manifest itself in any way, but in the situation of taking HC the acquired form is added to the genetic APC-R, which immediately creates conditions for its phenotypic realization. Thus, in women with a heterozygous FV Leiden mutation, the risk of thrombosis increases by 34 times in comparison with the control group. If there is a homozygous form, the risk of thrombosis increases by 80-100 times, compared with the control group [11-13].

Conclusion

In the process of studying the patient’s history and examination, many risk factors for the development of thrombosis, such as a thrombotic family history (sister had DVT, father died after myocardial infarction at the age of 56 years old), combined oral contraceptives, and long flight were found. According to laboratory studies, the presence of the genetic form of thrombophilia was confirmed. Thus, there is no doubt that this patient is categorically contraindicated to use hormonal contraceptives, and long-term air travel is possible only if anticoagulant therapy is applied. In case of timely identification of thrombotic family history and genetic form of thrombophilia, as well as the presence of additional risk factors (smoking, obesity, the presence of infectious, oncological diseases, etc.) until oral contraceptives were prescribed, it might have been possible to avoid such severe thrombotic complications.

This clinical case proves once again the importance of timely diagnosing genetic or acquired disorders of the hemostasis system, as well as the proper correction of anticoagulants doses under the control of hemostasiogram during the preparation and management of pregnancy in women at high risk of thrombotic complications.