TRANEXAMIC ACID SOLUTION FOR IV INTRODUCTION

TRANEXAMIC ACID

special instructions

Before starting and during treatment with tranexamic acid, it is necessary to consult an ophthalmologist (determining visual acuity, color vision, condition of the fundus).
If visual impairment occurs during treatment with tranexamic acid, the drug should be discontinued. Tranexamic acid preparations should be used with caution in hematuria caused by diseases of the renal parenchyma, since intravascular fibrin deposition is often observed in these conditions, which can aggravate renal damage. In addition, in cases of massive bleeding of any etiology from the upper urinary tract, antifibrinolytic therapy increases the risk of blood clots in the renal pelvis and (or) ureter and, accordingly, the risk of secondary mechanical obstruction of the urinary tract and the development of anuria.

Although clinical studies have not revealed a significant increase in the incidence of thrombosis, the risk of thrombotic complications cannot be completely excluded. Cases of the development of venous and arterial thrombosis and thromboembolism in patients receiving tranexamic acid have been described. In addition, cases of occlusion of the central retinal artery and central retinal vein have been reported. Several patients developed intracranial thrombosis during treatment with tranexamic acid. Accordingly, in patients with a high risk of developing thrombosis (history of thromboembolic complications, cases of thromboembolism in relatives, verified diagnosis of thrombophilia), tranexamic acid should be used only if absolutely necessary and under strict medical supervision. Before using tranexamic acid, an examination should be performed to identify risk factors for thromboembolic complications.

The presence of blood in cavities, such as the pleural cavity, joint cavities and urinary tract (including the renal pelvis and bladder) can lead to the formation of an “insoluble clot” in them due to extravascular coagulation, and such a clot can be resistant to physiological fibrinolysis. Patients with irregular menstrual bleeding should not be prescribed tranexamic acid until the cause of dysmenorrhea is determined. If the amount of menstrual bleeding is inadequately reduced during treatment with tranexamic acid, alternative treatment should be considered.

The effectiveness and safety of tranexamic acid preparations in the treatment of menorrhagia in patients under 16 years of age have not been established.

Particular caution should be exercised if tranexamic acid is used in women concomitantly taking combined oral contraceptives due to the increased risk of thrombosis (see section "Interaction with other medicinal products").

In patients with DIC who require treatment with tranexamic acid, therapy should be carried out under the close supervision of a physician experienced in treating this disease.

Due to the lack of adequate clinical studies, the simultaneous use of tranexamic acid with anticoagulants should be under the close supervision of a specialist experienced in the treatment of blood clotting disorders.

Tranexamic acid, 50 mg/ml, solution for intravenous administration, 5 ml, 10 pcs.

Tranexamic acid preparations should be used with caution in hematuria caused by diseases of the renal parenchyma, since intravascular fibrin deposition is often observed in these conditions, which can aggravate renal damage. In addition, in cases of massive bleeding of any etiology from the upper urinary tract, antifibrinolytic therapy increases the risk of blood clots in the renal pelvis and/or ureter and, accordingly, secondary mechanical obstruction of the urinary tract and the development of anuria.

Patients with irregular menstrual bleeding should not be prescribed tranexamic acid until the cause of dysmenorrhea is determined. If the amount of menstrual bleeding is inadequately reduced during treatment with tranexamic acid, alternative treatment should be considered.

The effectiveness and safety of tranexamic acid preparations in the treatment of menorrhagia in patients under 16 years of age have not been established.

Tranexamic acid should be used with caution in women concomitantly taking combined oral contraceptives due to the increased risk of thrombosis (see section “Interaction with other drugs”).

In patients with DIC who require treatment with tranexamic acid, therapy should be carried out under the close supervision of a physician experienced in treating this disease.

If vision impairment occurs while taking tranexamic acid, you should stop taking the drug and consult a doctor.

The use of tranexamic acid for the prevention of bleeding in the early postpartum period

Relevance

In recent years, there has been a decrease in the level of maternal mortality in developed countries (over the period 1990–2015, maternal mortality in the world decreased by almost 44%). This is probably due to the active implementation of the principles of evidence-based medicine and modern effective protocols for patient management. Maternal mortality is an important criterion for assessing the quality of obstetric care worldwide [1]. Obstetric hemorrhage continues to be one of the top three causes of maternal morbidity and mortality, along with infectious complications and high blood pressure during pregnancy (preeclampsia and eclampsia) [2]. Early postpartum hemorrhage, occurring in the first 24 hours after birth, accounts for a quarter of all maternal deaths worldwide. In 2021 in Russia, the maternal mortality rate from bleeding during childbirth and the postpartum period was 6.4% [3]. The incidence of hemorrhage in the early postpartum period ranges from 3 to 15% of all births [4–6]. These variations are partly due to the use of different management protocols and diagnostic methods, as well as the lack of a clearly defined time interval of the early postpartum period - in some countries the early postpartum period is considered to be 2 hours after birth, in others - 24 hours. In approximately one in five cases, bleeding progresses into a massive one, which threatens the health and life of the mother, increases the need for resuscitation measures and transfusion of blood components, which, in turn, leads to an increase in financial costs for treatment and rehabilitation of the patient. The incidence of severe maternal morbidity is 0.5–15% of all births, and its main cause is bleeding in the early postpartum period [4, 5, 7]. In Russia, the incidence of bleeding in the placenta and postpartum periods was 10.8% of all births in 2017 and 10.9% in 2021 [8]. During pregnancy, physiological changes occur in a woman’s body in almost all systems, which contributes to better adaptation of the mother’s body to changing conditions as the gestation period increases and the successful course of pregnancy and childbirth.

Features of the blood coagulation system during pregnancy

Changes in the blood coagulation system during pregnancy consist of a constant decrease in fibrinolytic activity and an increase in blood coagulation. These changes are of a pronounced adaptive nature and are aimed primarily at reducing the volume of physiological blood loss during childbirth [9]. Normally, changes in the hemostatic system are proportional to the gestational age: from 6–8 weeks. The volume of circulating blood increases, reaching a maximum by 30 weeks, there is a slight decrease in platelet levels, the content of procoagulants increases, while the activity of fibrinolytic system factors, on the contrary, decreases [10, 11]. By the time of birth, the concentrations of fibrinogen, prothrombin, proconvertin, factor VIII, Hageman factor double, with the exception of factors XI and XIII, the level of antithrombin III, protein C decreases, and the level of protein S is reduced during pregnancy and after childbirth [9, 10]. At the end of the third trimester of pregnancy, an increase in prothrombin time is observed, which indicates an increase in thrombin generation and activation of the extrinsic coagulation pathway. This process increases progressively with increasing gestational age, remains high during childbirth and decreases during the first few days of the postpartum period. By the end of pregnancy, a sharp decrease in fibrinolytic activity is observed [12]. These mechanisms are compensatory and adaptive in nature and are necessary both for the normal formation of the fetoplacental complex and for limiting blood loss during childbirth. In general, the physiological meaning of hypercoagulation during pregnancy is to ensure the immunological tolerance of the mother's body to the growing fetus and preparation for the process of childbirth, when a quick stop of bleeding is necessary after separation of the placenta. Thus, an increase in hemostatic potential during pregnancy provides physiological hemostasis during the separation of the placenta, which, together with the contraction of smooth muscles, stops bleeding from the vessels of the placental site.

Causes of postpartum hemorrhage and possibilities for reducing blood loss

The most common causes of postpartum hemorrhage are: impaired uterine contraction (hypotony or atony), retention of parts of the placenta or blood clots in the uterine cavity, trauma to the birth canal and uterine rupture, and disorders of the blood coagulation system [13]. Risk factors for postpartum hemorrhage are: aggravated hemorrhagic history, a history of antenatal or postpartum hemorrhage, initial disorders in the hemostatic system (von Willebrand disease, thrombocytopenia, thrombocytopathy, chronic disseminated intravascular coagulation syndrome, leukemia, etc.), placenta previa, placenta rotation, prolonged labor (especially with labor induction), uterine fibroids or myomectomy during cesarean section, multiple pregnancy, large fetus or polyhydramnios, multiparous (multiparous - more than 3 births), obesity II-III degree, maternal age over 40 years [5, 14, 15]. However, the majority of women who develop bleeding in the early postpartum period do not have risk factors for bleeding [16, 17]. Considering the above, it is especially important to prevent bleeding in the placenta and postpartum periods for all women, regardless of the presence of risk factors [18, 19]. Today, in order to reduce the amount of blood loss after childbirth, active management of the third stage of labor is widely used, including prophylactic administration of uterotonics immediately after the birth of the child, active traction on the umbilical cord and uterine massage [20]. The use of oxytocin in the third stage of labor reduces the risk of blood loss over 500 ml by 50% and over 1000 ml by 40% [21, 22]. However, as shown by two large randomized controlled trials, active cord traction, as well as uterine massage, does not have a significant effect on the incidence of postpartum hemorrhage [23–25]. Thus, the administration of oxytocin after childbirth is the only effective method of preventing bleeding in the postpartum period. However, in recent years, data have appeared on the advisability of using prohemostatic drugs to prevent bleeding along with the administration of oxytocin [26].

The effectiveness of tranexamic acid

The use of tranexamic acid
is recommended for the treatment of postpartum hemorrhage in cases of persistent bleeding after administration of oxytocin or another uterotonic drug, or in cases of bleeding associated with trauma to the birth canal [15, 18]. Tranexamic acid is an antifibrinolytic agent. It has a local and systemic hemostatic effect for bleeding associated with increased fibrinolysis, as well as anti-inflammatory, antiallergic, anti-infective and antitumor effects due to the suppression of the formation of kinins and other active peptides involved in allergic and inflammatory reactions. The experiment confirmed the intrinsic analgesic activity of tranexamic acid, as well as the super-total potentiating effect on the analgesic activity of opiates. The hemostatic effect is achieved by specifically inhibiting the activation of profibrinolysin (plasminogen) and its conversion to fibrinolysin (plasmin). Antifibrinolytic drugs have been shown to reduce blood loss during surgery and reduce mortality in patients with bleeding after trauma without increasing the risk of complications [18]. Systemic antifibrinolytic agents are widely used in elective surgery to prevent early thrombus breakdown (fibrinolysis) and reduce perioperative blood loss [27]. The use of tranexamic acid has been shown to reduce the need for blood transfusions by 39%, as well as the need for reoperation due to bleeding. The CRASH-2 study showed that tranexamic acid reduced mortality from trauma hemorrhage in high-, middle-, and low-income countries [28]. Significant reductions (26–54% compared with placebo) in mean menstrual blood loss were reported in women with menorrhagia treated with tranexamic acid [29]. These data suggest that the use of tranexamic acid may be effective in preventing not only blood loss during surgery, but also postpartum hemorrhage. In patients bleeding after trauma, coagulation occurs rapidly at the site of damaged blood vessels by accumulating fibrin in a dense network, and the fibrinolytic system dissolves clots to prevent permanent vascular occlusion. Thus, the coagulation and fibrinolytic systems are in a state of dynamic balance. Tranexamic acid, being a powerful antifibrinolytic agent, prolongs the time of dissolution of blood clots and increases the efficiency of the body's own hemostatic mechanisms, therefore reducing the amount of blood loss [30]. During childbirth, when the placenta separates from the uterine wall, mechanical and hemostatic mechanisms to prevent bleeding are simultaneously activated: the uterus contracts, pinching the vessels, platelet activity increases, coagulation factors are massively released, and at the same time, the activity of the fibrinolytic system increases [31]. The administration of oxytocin increases uterine contraction, and the administration of tranexamic acid reduces the activation of fibrinolysis, which ensures more reliable hemostasis. Both coagulation and fibrinolysis processes are involved in the control of postpartum blood loss, which supports the hypothesis that the use of tranexamic acid may be effective in the prevention of bleeding in the early postpartum period. Accordingly, there is a clear theoretical rationale for the use of antifibrinolytic agents to reduce postpartum blood loss [32, 33]. A Cochrane systematic review published in 2011 identified five randomized controlled trials evaluating the use of tranexamic acid to prevent bleeding in the early postpartum period, two of which were included in the meta-analysis, which included a total of 453 women [30]. The authors concluded that tranexamic acid reduces the amount of postpartum hemorrhage, but further study is needed to determine the appropriateness of routine use of tranexamic acid for the prevention of postpartum hemorrhage [30]. Since then, several additional studies have been published. We analyzed 10 published randomized controlled trials evaluating the effectiveness of tranexamic acid in the prevention of bleeding in the early postpartum period after cesarean section [26]. In all studies, women receiving tranexamic acid had less blood loss than women receiving placebo, but there was no increase in adverse outcomes. However, these studies did not evaluate safety in the newborn, although tranexamic acid was administered an average of 10 minutes before delivery. H. Yang et al. (2001) compared the effectiveness of tranexamic acid in preventing bleeding in the early postpartum period during vaginal delivery depending on the dose of the drug. Women in group 1 (n=94) received 1.0 g of tranexamic acid intravenously once, in group 2 (n=92) - 0.5 g of tranexamic acid intravenously, in group 3 (n=92) — 0.5 g of aminomethylbenzoic acid intravenously; in the 4th group (control, n=87), the antifibrinolytic drug was not administered. The researchers concluded that a dose of 1 g of tranexamic acid was more effective in preventing postpartum hemorrhage [34]. In a study by K. Gungorduk et al. (2013) showed that the use of tranexamic acid for the prevention of postpartum hemorrhage during natural childbirth reduces the volume of blood loss, the incidence of anemia and does not increase the incidence of thromboembolic complications. Therefore, tranexamic acid is a promising drug for the prevention of bleeding in the early postpartum period, regardless of the method of delivery [35]. According to a 2021 Cochrane review (two studies including 20,172 women), the use of tranexamic acid already in the treatment of bleeding in the postpartum period reduces the risks of maternal mortality due to bleeding, and the drug is more effective when administered 1 g over 1-3 hours after birth, while when the drug was administered after 3 hours there was no significant difference in the volume of blood loss. The use of tranexamic acid reduces the risk of death after childbirth from all causes and does not affect the incidence of severe maternal morbidity. There was also a reduction in the need for surgical hemostasis in a group of women who received tranexamic acid [36]. The indisputable advantage of tranexamic acid preparations is the possibility of their use not only after childbirth, but also during pregnancy. A drug for hemostatic therapy used in the first and second trimesters of pregnancy must meet a number of requirements: not have embryotoxic and teratogenic effects, act quickly and effectively (since the time factor is very important in case of threatened and incipient abortion), not have a cumulative effect, have a slight systemic effect on hemostasis. The last factor is especially important, since activation of intravascular coagulation, on the one hand, can lead to microthrombosis, which disrupts placentation, especially in conditions of physiological hypercoagulation during pregnancy, and on the other hand, it is unsafe for the mother’s body due to the risk of thrombosis. . Tranexamic acid, being an antifibrinolytic agent, inhibits the action of plasmin activator and plasminogen. This allows the drug to have a hemostatic effect without systemic exposure and a pronounced effect on hemostasis [33, 37, 38]. When using tranexamic acid, the coagulation potential of the blood in pregnant women did not increase; therefore, there was no increase in the incidence of thrombotic complications compared to patients who did not take the drug [39]. During pregnancy, Tranexam is prescribed 500 mg 3-4 times a day until bleeding stops completely. After intravenous administration, it is advisable to switch to oral administration of the drug [40]. An important pharmacological property of tranexamic acid, especially during pregnancy, is its anti-inflammatory effect, which is due to the suppression of the formation of kinins, proinflammatory cytokines (tumor necrosis factor, interleukin 1, interleukin 2) and other active peptides involved in inflammatory and allergic reactions. Thus, tranexamic acid can be used as a hemostatic agent both during pregnancy and after childbirth in the complex treatment of postpartum hemorrhage. When administered intravenously, tranexamic acid reduces mortality among women with early postpartum bleeding, regardless of mode of delivery and without increasing the risk of thromboembolic complications [36].

Conclusion

So, in recent years, data have appeared indicating a decrease in the volume of blood loss after childbirth and during cesarean sections while taking tranexamic acid. In this regard, a number of authors have suggested the possible routine use of the drug to prevent increased blood loss during childbirth and caesarean section [33, 41, 42]. This preventive approach is of particular importance in groups at risk for the development of bleeding (women with thrombocytopenia, uterine fibroids, low placental attachment, etc.) [33, 42]. The prophylactic use of tranexamic acid to prevent bleeding in the early postpartum period continues to be studied. Information about the authors:
Yulia Eduardovna Dobrokhotova - Doctor of Medical Sciences, Professor, Head.
Department of Obstetrics and Gynecology, Faculty of Medicine; Dzhokhadze Lela Sergeevna - candidate of medical sciences, assistant at the Department of Obstetrics and Gynecology, Faculty of Medicine. Federal State Budgetary Educational Institution of Russian National Research University named after. N.I. Pirogov of the Russian Ministry of Health. 117997, Russia, Moscow, st. Ostrovityanova, 1. Contact information:
Dzhokhadze Lela Sergeevna, e-mail: [email protected]
Transparency of financial activities:
none of the authors has a financial interest in the presented materials or methods.
There is no conflict of interest
.
The article was received
on October 23, 2018.
About the authors:
Yulia E. Dobrokhotova - MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology, Medical Faculty;
Lela S. Djokhadze - MD, PhD, Assistant of the Department of Obstetrics and Gynecology, Medical Faculty. Pirogov Russian National Research Medical University. 1, Ostrovityanova str., Moscow, 117997, Russian Federation. Contact information:
Lela S. Djokhadze, e-mail
Financial Disclosure:
no authors have a financial or property interest in any material or method mentioned.
There is no conflict of interests.
Received 10/23/2018.