Obstetric hemorrhage is the most common cause of maternal mortality worldwide.1 Recent evidence has linked activation of the fibrinolytic pathway with the onset of severe hemorrhage in different settings including trauma, heart and orthopedic surgery, and obstetrics.2–4
Tranexamic acid (TXA) is a lysine analog that binds to lysine receptors on plasminogen and plasmin, thereby inhibiting plasmin mediated fibrin degradation. Tranexamic acid has a half-life of 2 hours and is cleared mainly by the kidney. The use of TXA has been associated with decreased bleeding complications and mortality in trauma and heart surgery.2,5 Similarly, a recent large multicenter international clinical trial found that TXA decreased bleeding-related mortality in women with established postpartum hemorrhage (defined as more than 500 mL after a vaginal delivery or 1,000 mL after a cesarean delivery).6 Moreover, none of the previous trials reported any significant increase in adverse events related to the use of TXA, including thromboembolic events. Thus, it appears that TXA is a safe and effective agent for the prevention and treatment of hemorrhage.
FIBRINOLYSIS AND HEMORRHAGE
Most data regarding the role of fibrinolysis in hemorrhage come from patients with early-onset traumatic coagulopathy. The latter is a condition present in up to 30% of traumatic hemorrhage before admission to the hospital.7
Early acute traumatic coagulopathy occurs before iatrogenic hemodilution (secondary to administration of fluids) or hypothermia and before massive consumption of clotting factors takes place. Early hypoperfusion results in endothelial upregulation of the receptor thrombomodulin, which interacts with thrombin, leading to activation of the protein C pathway. Protein C is a natural anticoagulant that irreversibly inhibits factors Va and VIIIa and also enhances fibrinolysis through inhibition of plasminogen activator inhibitor 1, resulting in increased unopposed activity of tissue plasminogen activator.8 Increased fibrinolytic activity has also been described in obstetric hemorrhage secondary to uterine atony, placental abruption, and placenta accreta.9 After placental disruption, there is a massive increase in endothelial release of tissue plasminogen activator.4 Similarly, in the immediate postpartum period, a significant increase in serum D-dimer levels points toward an increase in fibrinolytic activity that could play a significant role in postpartum hemorrhage.10 The latter concept provides the basis for a plausible role of antifibrinolytic agents (eg, TXA) for the prevention, treatment, or both of postpartum hemorrhage (Fig. 1).
EVIDENCE FOR THE USE OF TRANEXAMIC ACID OUTSIDE OF PREGNANCY
Antifibrinolytic agents have been used extensively in different medical scenarios. In a recent large randomized clinical trial in trauma, administration of TXA within 3 hours of injury resulted in decreased mortality.5 In this study, TXA was administered initially as a 1-g bolus intravenously (IV) followed by 1 g IV over 8 hours as a continuous infusion. The use of TXA after 3 hours of occurrence of trauma did not improve patients' outcomes or survival. Importantly, there was no evidence that the use of TXA in the setting of trauma resulted in increased risk of thromboembolic complications. Based on this study, many trauma centers have incorporated TXA as part of their massive transfusion protocols.
Tranexamic acid (and other antifibrinolytics) plays a pivotal role in cardiovascular surgery. Among patients undergoing coronary artery bypass surgery, the use of TXA after induction of anesthesia was associated with a significant reduction in postoperative bleeding as well as the need for reoperation and blood transfusions.3 The use of TXA in heart surgery has not been associated with increased thromboembolic complications. In one large clinical trial, TXA at doses of 50–100 mg/kg (significantly higher than usual prophylactic doses of 1 g) increased the risk of postoperative seizures (likely as a result of the γ-aminobutyric acid antagonist activity of TXA).3 The use of antifibrinolytic agents in cardiac surgery is currently standard of care. In orthopedic surgeries, perioperative use of TXA significantly decreases surgical bleeding and blood transfusion requirements.11 Similar findings have been reported in neurosurgery, otorhinolaryngology, and liver transplantation, among other surgical fields.12
EVIDENCE FOR THE USE OF TRANEXAMIC ACID IN OBSTETRICS
The increased fibrinolytic activity described in the immediate postpartum period has resulted in significant interest in the use of TXA for the prevention and treatment of obstetric hemorrhage. More than 30 studies evaluating the efficacy of TXA in preventing postpartum hemorrhage have been reported. Most of these studies have demonstrated the efficacy of TXA in reducing blood loss at the time of delivery (mostly after cesarean delivery) with no significant increase in thromboembolic complications.13–16
Two recent meta-analyses, including a total of 34 randomized trials, concluded that TXA administered at the time of delivery resulted in reduced blood loss and less need for blood transfusions.17,18 Again, no increased risk of thromboembolic complications was reported.
Unfortunately, many of the available studies on the role of TXA to prevent postpartum hemorrhage are of limited quality. The main limitations include small sample size, lack of proper randomization, lack of double masking, and the use of subjective endpoints (eg, estimated blood loss as opposed to transfusion of blood products). In addition, most were performed in low-resourced settings, limiting generalizability to practices in the United States. Ker et al19 recently performed a systematic review and concluded that a meta-analysis could not be performed as a result of “concerns about data quality and reliability.” The most recent Cochrane review on the topic concluded that TXA was associated with a reduction in both postpartum hemorrhage and the need for blood transfusion among women undergoing both vaginal and cesarean deliveries.20 The authors concluded that the latter is based on mixed quality studies. Furthermore, the effect of TXA on mortality and thromboembolic events requires further study.
In summary, the limited available evidence suggests that TXA may be beneficial for the prevention of postpartum bleeding; however, there is a clear need for a well-designed placebo-controlled randomized clinical trial with clinically meaningful outcomes.
Regarding the use of TXA for the treatment of established postpartum hemorrhage, a recent randomized placebo-controlled, international clinical trial included women with postpartum hemorrhage (diagnosed clinically) after a vaginal or cesarean delivery.6 In that trial, although TXA administration (maximum dose of 2 g within a 24-hour period) did not reduce the primary endpoint of death from all causes or hysterectomy within 42 days of delivery [5.3% in the TXA group compared with 5.5% in the placebo group; relative risk (RR) 0.97, 95% CI 0.87–1.09; P=.65], it did lower the risk of death resulting from bleeding (1.5% compared with 1.9%; RR 0.81, 95% CI 0.65–1.00; P=.045). When a subgroup analysis was performed according to timing of treatment, the benefit was particularly apparent when TXA was used within 3 hours of delivery (death resulting from bleeding 1.2% compared with 1.7%; RR 0.69, 95% CI 0.52–0.91; P=.008). Similar to trials in trauma, the difference between the groups was not significant when TXA was used late (more than 3 hours after delivery) (2.6% compared with 2.5%; RR 1.07, 95% CI 0.76–1.51). There was also a significant reduction in the need for laparotomy for bleeding with TXA (0.8% compared with 1.3%; RR 0.64, 95% CI 0.49–0.85; P=.02), particularly when TXA was given within 3 hours of birth. Again, no increased risk of thromboembolic complications was reported with the use of TXA in this study (any thromboembolic event 0.3% compared with 0.3%; RR 0.88, 95% CI 0.54–1.43; P=.603).
In a retrospective series of women with severe postpartum hemorrhage, Frimat et al21 reported an increased risk of bilateral renal cortical necrosis with the use of TXA. The mean cumulative TXA dose used in this case series was 5.3±2.8 g, significantly higher than the recommended dose of 1–2 g IV in a 24-hour period.
RECOMMENDATIONS FOR CURRENT USE OF TRANEXAMIC ACID DURING PREGNANCY
Tranexamic acid is currently recommended for the treatment of several inherited bleeding disorders during pregnancy and the postpartum period including hemophilia, von Willebrand disease, Bernard Soulier syndrome, and Glanzmann's thrombasthenia.22 In these conditions, TXA is usually started before delivery and continued orally for 1–2 weeks postpartum.
In terms of postpartum hemorrhage prevention, the dose used in most available studies is 1 g IV administered at the time of skin incision. Tranexamic acid does cross the placenta achieving cord blood concentrations that are similar to those in maternal plasma [Cyklokapron. New York (NY): Pfizer; 2016 (package insert)]. Even so, to our knowledge, there are no reports of neonatal adverse effects in the literature (based on a from-inception PubMed search with no language restrictions using the terms obstetric hemorrhage, tranexamic acid, and neonatal outcomes). Unfortunately, as discussed previously, the quality of the available evidence is very limited and at this moment we cannot recommend the use of TXA for the prevention of postpartum hemorrhage until a well-designed randomized clinical trial is performed.
In women with established postpartum hemorrhage, current evidence suggests that TXA should be used as early as possible, ideally within 3 hours of childbirth. The recommended dose in this setting is 1 g IV. The dose may be repeated if bleeding persists after 30 minutes or if bleeding abates but recurs within 24 hours.6 There is currently no data regarding the safety of higher doses in the immediate postpartum period.
Tranexamic acid is excreted into human milk; however, the concentrations achieved are fairly low (approximately 1% of the peak serum concentration).23 No adverse outcomes have been reported in children exposed to TXA through breastfeeding.24 If a patient requires TXA in the postpartum period, breastfeeding may continue with supervision and clinical follow-up of the infant.24 A summary of recommendations for the use of TXA during pregnancy is depicted in Box 1.
Summary of Recommendations for the Use of Tranexamic Acid During Pregnancy Cited Here...
- TXA crosses the placenta, achieving umbilical cord concentrations similar to maternal serum concentrations. The limited evidence does not suggest fetal or neonatal harm. The use of TXA before delivery may be recommend in specific cases such as in cases of hemophilia, von Willebrand disease, and platelet disorders. There is still insufficient evidence to use TXA for prevention of obstetric hemorrhage.
- TXA is cleared renally; as such, its use is contraindicated in patients with significant renal disease.
- In established postpartum hemorrhage, may administer 1 g intravenously within 3 hours of birth. If required, may administer a second dose within the next 24 hours. The half-life of TXA is 2 hours and its antifibrinolytic effect lasts for up to 7–8 hours in serum. A single dose should suffice in most cases.
- Avoid higher doses as may result in thrombotic complications and seizure activity.
- During postpartum, TXA is commonly used to prevent bleeding in women with congenital bleeding disorders such as von Willebrand disease and hemophilia. In these cases, oral administration is indicated (a common dose regimen is 1 g orally three times daily).
- In breastfeeding mothers, TXA achieves a concentration in milk close to one hundredth of the maternal serum concentration. Current evidence suggests TXA is safe during breastfeeding.
TXA, tranexamic acid.
Postpartum hemorrhage is the leading cause of maternal mortality worldwide. The increased prevalence of associated medical diseases in women of childbearing age will likely worsen the severity of postpartum hemorrhage. Tranexamic acid appears to be a safe, effective, and inexpensive option in the management of established obstetric hemorrhage. For prophylaxis, the limited available data suggest benefit; however, high-quality trials are needed before universal use can be recommended. For this, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network is starting a large double-blind placebo-controlled trial to determine whether TXA decreases the need for transfusion of blood products in women undergoing cesarean delivery (the first author, L.D.P., is the principal investigator for this trial). Until the results of this study are available, we do not recommend universal use of TXA for prophylaxis, but do suggest its use as early as possible for the treatment of established obstetric hemorrhage (especially if there is no initial response to uterotonics). A maximal dose of 2 g within a 24-hour period (starting dose of 1 g IV given as soon as possible and within 3 hours of delivery) is currently considered to be safe and effective in reducing risk of hemorrhage-related death. It remains to be determined whether the benefit of TXA in the treatment of obstetric hemorrhage reported in the WOMAN trial will be replicated in developed countries where availability of different treatment modalities (surgical and medical) is broader.
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4. Kruithof EK, Tran-Thang C, Gudinchet A, Hauert J, Nicoloso G, Genton C, et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood 1987;69:460–6.
5. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH 2): a randomized placebo-controlled trial. Lancet 2010;376:23–32.
6. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomized, double-blind, placebo-controlled trial. Lancet 2017;389:2105–16.
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10. Ducloy-Bouthors AS, Duhamel A, Kipnis E, Tournoys A, Prado-Dupont A, Elkalioubie A, et al. Postpartum haemorrhage related early increase in D-dimers is inhibited by tranexamic acid: haemostasis parameters of a randomized controlled open labelled trial. Br J Anaesth 2016;116:641–8.
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20. Novikova N, Hofmeyr G, Cluver C. Tranexamic acid for preventing postpartum hemorrhage. The Cochrane Database Systematic Review 2015, Issue 6. Art. No.: CD007872.
21. Frimat M, Decambron M, Lebas C, Moktefi A, Lemaitre L, Gnemmi V, et al. Renal cortical necrosis in postpartum hemorrhage: a case series. Am J Kidney Dis 2016;68:50–7.
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