Update on Applications and Limitations of Perioperative Tranexamic Acid : Anesthesia & Analgesia

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Update on Applications and Limitations of Perioperative Tranexamic Acid

Patel, Prakash A. MD, FASE*; Wyrobek, Julie A. MD; Butwick, Alexander J. MBBS, FRCA, MS; Pivalizza, Evan G. MD§; Hare, Gregory M. T. MD, PhD, FRCPC; Mazer, C. David MD; Goobie, Susan M. MD, FRCPC

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doi: 10.1213/ANE.0000000000006039
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Abstract

Tranexamic acid (TXA), or trans 4 aminomethylcyclohexane-1-carboxylic acid, is a synthetic lysine analog that inhibits the activation of plasminogen to plasmin.1 It was first developed in the 1960s with clinical applications for menstrual bleeding and hereditary bleeding disorders.2,3 While approved by the US Food and Drug Administration (FDA) for use in hemophilia patients, intravenous (IV) off-label TXA has been studied with varying dosing regimens in acute trauma, postpartum hemorrhage (PPH), gastrointestinal bleeding, and intraoperative scenarios (Table 1).4–9 TXA is currently on the World Health Organization’s (WHO) List of Essential Medicines.19 Despite clinical use for >50 years, investigations into TXA continue to provide updates on applications, efficacy, and risks. In some settings, prior well-established use has come into question with the availability of recent findings. The goal of this review is to provide an update on the current use of TXA in cardiac surgery, obstetrics, acute trauma, orthopedics, neurosurgery, and pediatric surgery.

MECHANISM OF ACTION AND RISK PROFILE

As an antifibrinolytic, TXA stabilizes existing clot by preventing the breakdown of fibrin in a clot matrix and inhibiting the process of fibrinolysis (Figure).20–22 Hyperfibrinolysis has been shown to be a contributing factor in excessive bleeding during acute trauma and surgical procedures.3,23 TXA may also have anti-inflammatory effects by reducing vasoactive peptide release.24 It is excreted in the urine largely unchanged, with filtration inversely proportional to plasma creatinine.25–27 TXA is not dialyzable, and dose adjustments are recommended in renally impaired patients.4,27 Terminal half-life is approximately 2 hours.28 TXA permeates all tissues, crossing the blood-brain barrier, synovial membranes, and placenta.29

Table 1. - Typical Dosing Regimens for Perioperative TXA Administration
Setting Typical TXA dosing regimen a Notes
Adult cardiac surgery 10,11 10–30 mg/kg IV loading dose; then 2–16 mg/kg/h infusion; ±1–2 mg/kg for pump prime Target plasma concentrations 20–100 µg/mL (depending on desired degree of fibrinolysis inhibition) b
Obstetrics 8 1 g IV over 10 min; can repeat 1-g IV if bleeding persists after 30 min Recommended to give within first 3 h of birth
Acute trauma 6,12 1 g IV over 10 min; then 1 g infused over 4–8 h Recommended to give within first 3 h of injury (ideally within first hour)
Orthopedic surgery 13,14 10–20 mg/kg IV in single or divided doses (or 1–3 g topical dose) Target plasma concentration ≥10 µg/mL
Neurosurgery 15 10 mg/kg IV loading dose; then 0.5–2 mg/kg/h infusion
Pediatric surgery 16 10–30 mg/kg IV loading dose; then 5–10 mg/kg/h infusion Maximum loading dose 2 g; target plasma concentrations between 20 and 70 µg/mL b
Pediatric cardiac surgery 16–18 30 mg/kg (age <12 mo) or 10 mg/kg (age ≥12 mo) IV loading dose; then 10 mg/kg/h infusion; ±addition to pump prime for concentration of 60 µg/mL Maximum loading dose 2 g; intermediate target plasma concentration 60 µg/mL (lower target concentration of 20 µg/mL or higher target concentration of 150 µg/mL requires dosage scheme adjustment) b
Abbreviations: IV, intravenous; RCT, randomized controlled trial; TXA, tranexamic acid.
aWhile these values represent commonly used regimens, there exists significant variability in TXA dosing strategies. Furthermore, more RCTs are needed to confirm safety and efficacy of these recommended doses in various clinical situations and in high-risk populations.
bTXA dosing regimens extrapolated from pharmacokinetic studies.

F1
Figure.:
TXA mechanism of action. Fibrinolysis is primarily controlled by the proteolytic enzyme plasmin. Plasmin’s precursor, plasminogen, adheres to fibrin via a lysine-binding site in the presence of plasminogen activators such as tPA or urokinase. This binding activates plasminogen to plasmin, which subsequently degrades the fibrin within a fibrous clot into FDPs. In the presence of an antifibrinolytic such as TXA, there exists competitive and reversible binding at the lysine-binding sites on plasminogen, which prevent its activation to plasmin. FDP indicates fibrin degradation product; tPA, tissue plasminogen activator; TXA, tranexamic acid.
Table 2. - Tranexamic Acid in Cardiac Surgery: Key Take-Home Points
Routine antifibrinolytic use with TXA is well-established and strongly recommended in guidelines in cardiac surgery for reducing blood loss and allogeneic transfusion.
Recent investigations have demonstrated TXA’s safety in patients with coronary artery disease with no increase in thrombotic complications or differences in coronary graft patency compared to placebo.
Observational studies have reported that lower dose TXA regimens are associated with a lower incidence of seizures.
Ongoing TXA investigation in cardiac surgery is warranted to determine optimal dosing strategies that account for patient factors, surgical factors, and pharmacokinetic models.
Abbreviation: TXA, tranexamic acid.

While TXA is efficacious in several settings without an increased risk of thrombotic events, it may be contraindicated in patients with active intravascular clotting, active thromboembolic disease, or with unbalanced hemostatic systems favoring thrombosis.3,6,8,30,31 Other contraindications include a history of TXA hypersensitivity and subarachnoid hemorrhage due to the risk of cerebral edema and infarction; however, TXA in the latter population is currently being studied.4,32 TXA has been associated with dose-dependent seizures, anaphylaxis, dizziness, gastrointestinal disturbances, and visual disturbances.1,21 Several case reports have described seizures and death after accidental intrathecal injection of TXA, presumably due to look-a-like vials.33–42 This is especially a concern in obstetrics where spinal anesthesia is a commonly performed procedure, as well as in spine surgery where topical TXA may be mistaken for bupivacaine.

TXA IN CARDIAC SURGERY

Routine use of TXA in cardiac surgery is well established (Table 2). TXA administration reduces blood loss and the need for allogeneic red blood cell (RBC) transfusion in cardiac surgical patients.43 As a blood conservation strategy, guidelines have consistently given Class IA recommendations to antifibrinolytic use with lysine analogs, with the latest 2021 patient blood management (PBM) guidelines providing the same strong recommendation.43–45 Efficacy has been demonstrated in patients undergoing closed- and open-chamber procedures.5,46 Similarly, aortic procedures involving deep hypothermic circulatory arrest (DHCA), where the effects of hypothermia can further promote fibrinolysis, benefit from TXA.47,48 However, several questions and concerns remain despite antifibrinolytics becoming a standard of care in this setting. These questions have resulted in a lack of universal adoption into clinical practice.49 Ongoing concern for the safety and efficacy of TXA has warranted further investigation into prothrombotic complications, as well as optimal dosing to prevent hyperfibrinolysis without increasing adverse events.

TXA Safety Profile and Optimal Dosing

With aims to clarify the safety profile of TXA in cardiac surgery, specifically in coronary artery bypass graft (CABG) surgery, Myles et al5 report a prospective, randomized trial of TXA versus placebo (Aspirin and Tranexamic Acid for Coronary Artery Surgery [ATACAS] trial). Compared to placebo, TXA use in CABG surgery reduces the need for transfusion (P < .001) and reexploration (P = .001). By studying the impact of TXA’s potency on potential prothrombotic complications, the ATACAS trial aimed to provide new information on TXA’s safety. When compared to placebo, TXA administration did not lead to a difference in a composite of death and thrombotic complications (myocardial infarction, stroke, pulmonary embolism, renal failure, and bowel infarction) within 30 days (P = .22). One-year follow-up analysis also confirms no difference in graft patency between both groups.5

Determining the optimal dose of TXA administration during cardiac surgery remains a challenge. The ATACAS trial found that patients receiving a TXA dose of 50 or 100 mg/kg had a significantly higher rate of seizures (0.7%) when compared to placebo (0.1%) (P = .002).5 In a post hoc analysis, the investigators noted an increased incidence of stroke in those patients who had one or more postoperative seizures, which led them to suggest a potential thromboembolic cause for the seizure. The impact of TXA on postoperative seizures in patients undergoing surgery requiring DHCA remains a concern as DHCA has been identified as an independent predictor of postoperative seizures.50 More recent data also suggest an increased burden of neurologic complications after valve surgery in patients who receive TXA.51 This leads to further investigation regarding ideal TXA dosing in cardiac surgery. A 2019 meta-analysis (49 studies; 10,591 patients) found that lower dose TXA (<50 mg/kg bolus only or ≤10 mg/kg bolus + infusion) equally decreased transfusion requirements compared to higher dose TXA (≥50 mg/kg bolus only or >10 mg/kg bolus + infusion).10 However, the higher dose group had a 4.83 times higher risk of seizures than the lower dose group. To further explore TXA dosing, a multicenter, randomized, double-blind trial is currently underway (ClinicalTrials.gov: NCT03782350) comparing 2 dosing regimens with primary outcomes looking at efficacy and safety.52

Pharmacokinetic Studies

Pharmacokinetic models offer a valuable tool when deciding on the safest and most efficacious therapeutic TXA dosing regimen in cardiac surgery. The limiting factor is that the optimal plasma concentration to inhibit fibrinolysis has not been determined with precision. An analysis comparing TXA at varying doses (high and low dose) found that a plasma concentration of 20 mcg/mL is sufficient for 80% fibrinolysis inhibition, while 100 mcg/mL offers 100% inhibition of fibrinolysis.11 The clinical difference may not be significant, but given that cardiac surgery with cardiopulmonary bypass creates a hyperfibrinolytic state, a higher plasma concentration may indeed offer improved efficacy. The balance is maximizing efficacy while not compromising safety. Practitioners should, therefore, account for bleeding risk (eg, first-time sternotomy versus redo; expected bypass duration and degree of hypothermia) when determining dosing and desired degree of fibrinolysis inhibition.

Table 3. - Tranexamic Acid in Obstetrics: Key Take-Home Points
TXA prophylaxis does not reduce the risk of PPH among women undergoing vaginal delivery.
TXA prophylaxis may not have a clinically meaningful effect on reducing the risk of PPH after cesarean delivery.
In an international RCT in patients who delivered predominantly in low- and middle-income countries, PPH treatment with TXA was associated with a 37% reduction in the risk of death from hemorrhage (if given within 3 h).
As a therapeutic adjunct, it is unclear whether TXA reduces the risk of hemorrhage-related morbidity.
Catastrophic neurological injury can occur after accidental intrathecal injection of TXA. TXA vials should not be stored in the same location as similar-looking anesthesia drug vials.
Abbreviations: PPH, postpartum hemorrhage; RCT, randomized controlled trial; TXA, tranexamic acid.

Incorporating patient factors in pharmacokinetic models is also important. A recent study examining TXA dosing in cardiac surgical patients with chronic kidney disease (CKD) reported prolonged elevation in therapeutic concentrations of TXA in CKD stages 3, 4, or 5 when compared to stages 1 or 2.53 To account for these elevated concentrations, which could be associated with a higher risk of adverse events, the authors created an optimized dosing regimen based on CKD stage and glomerular filtration rate (lower doses with worsening renal function). These recommendations suggest that TXA may not be contraindicated in CKD when appropriate dosing is utilized. Further investigations that include patient factors and comorbidities will be needed to determine a dose that balances risk versus benefit.54 Future incorporation of viscoelastic testing, fibrinolytic patterns, and assessment for therapeutic concentrations may better guide an individualized perioperative antifibrinolytic therapy approach in cardiac surgery.55–57

TXA IN OBSTETRICS

PPH is a leading cause of maternal death and morbidity.58 Less clear is the extent to which hyperfibrinolysis contributes toward the magnitude of blood loss in women with severe PPH.59 Studies have reported increased postpartum D-dimer levels among women with PPH compared to women without hemorrhage.60,61 However, the validity of D-dimers as accurate markers of hyperfibrinolysis is debatable.62 Furthermore, data suggest that there is a low incidence of hyperfibrinolysis detected using viscoelastic testing in PPH. In a small observational study of 188 women with PPH, only 15 (13%) women had an LY30 value (% lysis at 30 minutes after maximum amplitude) ≥3% using kaolin-activated thromboelastography.63 Elevated LY30 values may also be associated with platelet-mediated clot retraction as opposed to hyperfibrinolysis alone. Despite this limited evidence of efficacy, large-scale studies have examined TXA as a prophylactic adjunct for preventing PPH and as a therapeutic adjunct for reducing the risk of severe bleeding and major morbidity after PPH onset (Table 3).

Can TXA Prevent PPH?

Recent meta-analyses indicate that prophylactic TXA is associated with less blood loss and a reduced likelihood of blood transfusion compared with placebo, with no concomitant increased risk of venous or arterial thrombosis.64–70 However, the robustness of pooled data from randomized studies in these meta-analyses has been questioned because of inadequate reporting of prespecified outcomes and potential bias from inadequate blinding and randomization, data inconsistencies, and potential plagiarism.71 In addition, these meta-analyses report relatively modest mean reductions in blood loss with TXA versus placebo ranging from 65 to 160 mL, which may be of limited clinical significance.

Emerging data from pharmacokinetic and pharmacodynamic studies indicate that prophylactic doses between 600 and 650 mg may be sufficient to suppress clot lysis for up to 1 hour after delivery.72,73 However, determining whether TXA prophylaxis has a meaningful effect on reducing the risk of PPH is of clinical importance.

Two multicenter randomized placebo-controlled trials provide high-quality data to inform discussion about TXA efficacy for PPH prevention. In the Tranexamic Acid for Preventing Postpartum Hemorrhage Following a Vaginal Delivery (TRAAP1) study, 4079 women who underwent vaginal delivery were randomized to receive 1-gram TXA versus placebo.74 In this trial, PPH was defined as blood loss ≥500 mL in a collector bag. The PPH rate was not significantly different in the TXA and placebo groups (8.1% vs 9.8%; relative risk [RR], 0.83; 95% confidence interval [CI], 0.68–1.01; P = .07). In a separate study, the Tranexamic Acid for Preventing Postpartum Hemorrhage Following a Cesarean Delivery (TRAAP2) study, 4551 women who underwent cesarean delivery were recruited.75 In TRAAP2, PPH was classified differently: a “calculated” (not measured) blood loss >1000 mL or an allogeneic RBC transfusion within 2 days of delivery. Using this definition, women who received 1-gram TXA had a lower likelihood of PPH compared to placebo (26.7% vs 31.6%; adjusted RR, 0.84; 95% CI, 0.75–0.94; P = .003). However, using clinical and laboratory measurements of blood loss, the PPH rate was not significantly different between groups. The average between-group blood loss difference was also small (approximately 100 mL). In both studies, the risk of thromboembolic events did not differ between groups. Given the null finding of the TRAAP1 study, the mixed findings of the TRAAP2 study, and the low quality of prior studies examining TXA for PPH prevention, current data are, at best, equivocal for justifying routine TXA administration for PPH prophylaxis before vaginal or cesarean delivery.

Should TXA Be a Therapeutic Adjunct for PPH?

The largest study to date examining therapeutic efficacy of TXA was the pragmatic, randomized placebo-controlled multicenter the World Maternal ANtifibrinolytic trial (WOMAN trial).8 In this trial, 20,060 women with PPH from 21 low- and middle-income countries received TXA (1–2 grams) or placebo. The main finding was a 19% decrease in the RR of death from exsanguination in women given TXA versus placebo (mortality rate, 1.9% vs 1.5%; RR, 0.81; 95% CI, 0.65–1.0; P = .045). Furthermore, the treatment benefit appeared strongest if TXA was administered within 3 hours of birth. Following publication, experts have debated whether the findings are statistically significant and generalizable to women who deliver in well-resourced hospitals in high-income countries.76,77 Nonetheless, the WHO endorsed TXA use for all women with PPH regardless of the type and level of health care center and delivery mode.78 This will likely put pressure on national obstetric societies to modify future guidelines for PPH management.

The efficacy of TXA on reducing maternal morbidity is less clear. Data from the WOMAN trial and a subsequent Cochrane systematic review indicate that TXA is not associated with a reduced risk of transfusion or hysterectomy to control bleeding compared with placebo.79 These findings are supported by data from an observational study of 1260 patients with persistent PPH.80 In this study, women with severe PPH who received early TXA did not have a lower incidence of severe maternal morbidity compared with women receiving late TXA or no TXA (odds ratio, 0.92; 95% CI, 0.66–1.27). Experts recommend that providers consider TXA as a therapeutic adjunct for treating PPH after vaginal or cesarean delivery and that future studies examine goal-directed treatment protocols using functional coagulation assays.24,81,82 Clinicians based in developing countries or hospitals with limited access to blood products and other resources may have a lower threshold for using TXA than those based in well-resourced and well-staffed hospitals.

TXA IN TRAUMA

Increased understanding of the dynamic process of fibrinolysis and the multidimensional pathophysiology of trauma-induced coagulopathy (TIC) continues to influence the TXA narrative in severely injured trauma patients (Table 4). TIC is clinically significant, has multiple causes in addition to fibrinolysis, and is challenging to diagnose and treat.83 Current use of viscoelastic coagulation assays is more useful than discrete laboratory analyses in early detection and treatment of TIC, although they may be less able to detect smaller fibrinolysis signals.84 Three possible trauma fibrinolytic phenotypes may be present, with both hyperfibrinolysis and hypofibrinolysis portending higher mortality.85 Changes in fibrinolytic signal in acute trauma victims are dynamic, likely associated with resuscitation and develop over time.86 Teleologically, abrupt elevation in tissue plasminogen activator after massive injury is followed by a rise in plasminogen-activator inhibitor and potential hypofibrinolysis, which may manifest over the course of resuscitation.87

Table 4. - Tranexamic Acid in Acute Trauma: Key Take-Home Points
Fibrinolysis after acute trauma is a dynamic process with temporal changes after injury that may result in hyperfibrinolysis or hypofibrinolysis.
If used, TXA should be administered within 3 h of injury, preferably within the first hour, to maximize clinical benefit including reduced mortality.
Monitors of subtle changes in fibrinolysis remain elusive; however, VET can detect gross aberrations to guide initial TXA therapy.
Current TXA dosing regimens in trauma suggest no significantly increased thromboembolic risk.
Abbreviations: TXA, tranexamic acid; VET, viscoelastic testing.

The current dilemma of TXA use in acute trauma is the necessity to intervene early (<3 hours) to maximize possible benefit in the highest risk period for hemorrhagic death, balanced with unknown fibrinolytic status until data from viscoelastic or other assays become available. This has crystallized in a discussion of prehospital TXA use and appreciation that TXA alone is unlikely to arrest acute traumatic hemorrhage and TIC.

Prior TXA Data

Over the last decade, military and civilian evidence of variable strength suggested a positive survival benefit of early TXA use. In the large, prospective Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) study, 28-day mortality and death from bleeding were reduced with TXA.6 Retrospective military data demonstrated an absolute reduction in mortality in those receiving TXA as well as those receiving TXA with cryoprecipitate.12,88 Early administration was recognized as a key factor with best results within 3 hours and adverse effects thereafter. These robust outcome data supported the uniform use of TXA early in the treatment of severely injured, bleeding patients, affirmed in both Europe and the United States. Experts acknowledged the austere conditions in these 3 studies and awaited investigation in mature, urban trauma centers where time to admission would likely be faster.

Current TXA Data and Recommendations

Simultaneous with improved understanding of fibrinolysis in trauma patients, subsequent data found a less frequent benefit of TXA use. One study found increased transfusion and mortality in the TXA group, although this was likely influenced by timing of administration.89 Subanalysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) study reported a 13.6% incidence of hyperfibrinolysis according to LY30 > 3% on thromboelastography, where TXA use was only associated with a 6-hour survival benefit and no longer term survival or transfusion outcomes.90 These findings, along with description of the fibrinolytic pattern, led to calls for more nuanced TXA use and identification of patients with fibrinolysis/hyperfibrinolysis, who would be the most appropriate candidates to receive TXA.91 Until more sensitive markers of fibrinolysis are immediately available to guide clinical intervention, TXA should ideally be used in severely injured bleeding patients, within 1 hour after injury and with viscoelastic testing as soon as possible to detect gross changes in fibrinolysis.

The recent CRASH-3 study investigated TXA use in patients with isolated traumatic brain injury (TBI). TXA only reduced death in those with mild to moderate TBI, with no improved long-term functional recovery.7 Similarly, prehospital TXA use in a TBI cohort showed no reduction in 28-day mortality or functional recovery.92

Given the potential benefit of early TXA use, prehospital administration in bleeding trauma victims was a natural clinical extension. A recent systematic review found only 3 observational cohorts and 1 randomized trial with meta-analysis showing reduction in 24-hour mortality but with no benefit at 28 or 30 days.93 Post hoc subgroup analyses in the prospective study did find survival benefit in those where TXA was administered within 1 hour of injury and those with severe shock (systolic blood pressure ≤70 mm Hg).94

Regarding safety of TXA in trauma, development of posttraumatic venous thromboembolism after TXA administration has been reported from a single-center analysis.95 However, systematic review and meta-analyses found no increased thromboembolic risk with TXA, although reports are dominated by nontrauma studies.96 In the trauma-specific studies to date, no adverse thrombotic signal has been detected, although there was an increase in seizures in the higher dose (2 grams) TXA group in a TBI study.7

TXA is one strategy that may improve short-term survival when used in acutely injured, bleeding trauma patients as early as possible (within 1 hour and not >3 hours of injury). However, given the dynamic fibrinolytic process, empiric administration in these clinical conditions should transition to guided-use by viscoelastic testing (unless laboratory markers of fibrinolysis such as D-dimers or fibrin degradation products are promptly available) on hospital arrival. Testing should be repeated to follow the developing fibrinolytic patterns.86 In the absence of pharmacokinetic data in the trauma population, a loading dose of 1 gram is recommended, and an infusion of the second gram over 4 to 8 hours should be supported by viscoelastic evidence and stopped if/when there is evidence of hypofibrinolysis. Proactive chemical thromboprophylaxis should be initiated as soon as clinically feasible after the initial control of hemorrhage given the likelihood of developing postresuscitation hypercoagulability.

TXA IN ORTHOPEDIC SURGERY

Elective, urgent, and emergent orthopedic surgery is associated with significant blood loss, and RBC transfusion, providing the rationale for broad utilization of PBM measures including perioperative TXA use.13 The results of small randomized-controlled trials, as well as subsequent systematic reviews and meta-analyses, demonstrate that perioperative TXA is effective at reducing surgical blood loss and allogeneic transfusion in orthopedic surgery.97–100 A recent retrospective analysis assessed prophylactic TXA use in noncardiac surgeries at high risk for blood transfusion in 14,300 patients between 2014 and 2016.98 The results demonstrated that TXA was most frequently used in patients undergoing orthopedic surgery (~41%) with a higher utilization for pelvic surgery (~68%) and hip arthroplasty (~67%). This degree of TXA utilization was much higher than was observed for other types of noncardiac surgery.

TXA for Joint Arthroplasty and Bone Fractures

TXA utilization in patients undergoing primary and revision total hip or knee arthroplasty has been endorsed by clinical practice guidelines.14,101 The guidelines for major joint arthroplasty recommend that: (1) all routes of TXA administration (IV, oral, and topical) are effective at reducing blood loss and transfusion, relative to placebo; (2) the dose of TXA did not impact outcomes with 1-gram IV being the median dose; (3) no added benefit of multiple TXA doses has been observed; (4) TXA administration before skin incision may provide the largest benefit in terms of preventing blood loss; and (5) no increased risk of venous or arterial thromboembolic events was observed with TXA utilization.14 TXA efficacy has been demonstrated in terms of reduced intraoperative blood loss, increased postoperative hemoglobin, and reduced RBC transfusion.97,102 The use of TXA, as a component of PBM, has been strongly advocated for, and compliance with TXA administration has reached as high as 95% of elective patients in some centers.13

TXA use for elective long bone procedures and repair of bone fractures has undergone several investigations.99,103,104 Patients with acute fractures differ from elective patients in that they usually face urgent/emergent surgery and may have increased risks associated with thrombosis. An analysis of the use of TXA for surgical repair of hip fractures demonstrated efficacy in terms of reduced total blood loss (mean difference, –273 mL; 95% CI, –353 to –193 mL; P <.0001) and blood transfusion rates (risk ratio, 0.66; 95% CI, 0.56–0.78; P < .003) without evidence of thromboembolic events (risk ratio, 1.38; 95% CI, 0.74–2.55; P = .31).99

Safety of TXA

TXA’s efficacy at reducing blood loss in a variety of orthopedic procedures, as demonstrated in several small trials, may have contributed to the absence of an appropriately large, randomized trial to fully assess safety. As the incidence of adverse events (eg, thrombosis, myocardial infarction, stroke, and seizures) is very low, only a larger randomized study can provide prospective nonbiased assessment of actual risk. A surrogate approach has been to compare the incidence of adverse events in large systematic reviews.105,106 The outcomes of these trials have not demonstrated evidence of adverse events associated with TXA for orthopedic surgery. A recent large retrospective analysis assessed 26,808 patients at risk with a history of coronary artery disease or coronary stents having total joint arthroplasty >8 years. No increased risk of venous thrombosis or myocardial infarction was observed in those patients who received TXA.106 However, in the absence of a large prospective randomized-controlled trial, the potential risk of thrombosis must be weighed against the benefit of minimizing blood loss in each patient at high thrombosis risk (eg, patients with recent coronary artery stents, recent stroke, or hypercoagulability). With respect to seizure risk, TXA doses utilized in orthopedic surgery (10–20 mg/kg) do not appear to be associated with an increased risk of seizure.107

TXA Method of Administration and Drug Dose

Pharmacokinetic studies have established that the optimal serum TXA concentration in orthopedic surgery is >10 µg/mL.98,108,109 Therapeutic levels can be achieved via oral, topical, or IV administration by different pharmacokinetic profiles.108,110,111 Current evidence demonstrates that there is no difference in the effect of TXA on reduced blood loss, transfusion, or incidence of thrombotic complications when assessing studies that utilized different routes of TXA administration for major joint arthroplasty.102,105,112–115 Use of 10 to 20 mg/kg of TXA intravenously, in single or divided doses, remains one of the most common doses and methods of drug administration.13,14 One analysis suggested that combining IV and intraarticular use was superior to IV TXA alone at reducing blood loss and transfusion.100

Table 5. - Tranexamic Acid in Orthopedic Surgery: Key Take-Home Points
TXA has demonstrated efficacy in hip and knee arthroplasty with a reduction in bleeding and allogeneic transfusion.
Despite theoretical concerns for thrombosis, TXA appears safe in bone fracture surgery without an increased thromboembolic risk.
TXA does not appear to increase the risk of adverse events in orthopedic surgery patients with a history of coronary artery disease or prior coronary stents.
Effective concentrations of TXA for orthopedic surgery can be achieved with oral, topical, or intravenous routes of TXA administration.
Abbreviation: TXA, tranexamic acid.

Table 6. - Tranexamic Acid in Neurosurgery: Key Take-Home Points
TXA in cases of subarachnoid hemorrhage has been limited due to previous concerns for cerebral ischemia and infarction; however, investigations of efficacy and safety continue in this setting.
TXA may reduce blood loss, without an increase in thrombotic complications, in tumor resection surgery.
While TXA may reduce bleeding in intracranial aneurysm and intracerebral hemorrhage, TXA use has raised concerns for harm (ischemia) or no net clinical benefit.
TXA use in spine surgery results in reduced bleeding and transfusion without an increase in adverse thrombotic complications.
Caution should be maintained when using topical TXA to avoid inadvertent CSF administration due to proximity of surgical site or similar-looking anesthesia drug vials.
Abbreviations: CSF, cerebrospinal fluid; TXA, tranexamic acid.

The routine use of TXA for a variety of orthopedic procedures is effective at reducing blood loss and transfusion (Table 5). Safety has been assessed for patients undergoing major joint arthroplasty, and no clear signal for increased adverse events has been identified. Consideration for the risk of thrombosis in high-risk patients is important.

TXA IN NEUROSURGERY

TXA use in neurosurgical procedures has demonstrated reduced acute blood loss and RBC transfusion (Table 6).116 A recent retrospective review indicated that TXA was utilized in 18% of spine cases and only 0.7% of neurosurgical cases.98 The low incidence of TXA use may be due to the fact that subarachnoid hemorrhage is listed in the Canadian (2018) and US (2020) product monograph as a contraindication for TXA, due to possible concerns of cerebral ischemia and infarction.117 Although little evidence exists to support this concern, the recommendation emphasizes the perception of potential harm of a “prothrombotic” drug on cerebral perfusion, and it must be weighed against the evidence for efficacy and safety.118

TXA for Brain Surgery and Intracranial Hemorrhage

Two small randomized-controlled trials (n < 50 patients) have assessed the impact of TXA on acute blood loss following craniotomy for brain tumor resection.119,120 Both studies demonstrated small, but significant, reductions in blood loss, without any increase in adverse outcomes. A larger retrospective cohort study suggested that TXA reduced the degree of surgical blood loss and RBC transfusion (7% vs 13%; P = .04) for complex skull-based surgery, without evidence of increased thrombotic complications.121

Assessment of TXA efficacy in the context of a ruptured cerebral aneurysm was assessed in 9 studies, including 7 small randomized-controlled trials.116 The majority of these trials demonstrated a positive impact on reduced bleeding without evidence of increased thrombotic complications. Two of the largest studies (n = 462 and 505 patients) demonstrated reduced occurrence of rebleeding (RR, 0.58 [95% CI, 0.42–0.80]) and a reduction in rebleeding rate from 10.8% to 2.4%, respectively.122,123 However, 2 systematic reviews demonstrated that while the risk of bleeding was reduced with TXA therapy (RR, 0.65 [95% CI, 0.44–0.97] and RR, 0.65 [95% CI, 0.44–0.97]), the risk of cerebral ischemia was increased (RR, 1.4 [95% CI, 1.04–1.91] and RR, 1.41 [95% CI, 1.04–1.91]), dampening enthusiasm for use of TXA in this scenario.124,125 As many cerebral aneurysms are currently treated by endovascular coiling, this therapeutic application may have further limitations.

Results from the Tranexamic acid for hyperacute primary IntraCerebral Hemorrhage (TICH-2) study did not show significant benefit with TXA treatment in patients with intracerebral hemorrhage due to stroke. In this randomized, placebo-controlled, phase 3 superiority trial, TXA did result in fewer deaths by day 7 compared to placebo, but functional status and mortality at 90 days were not different between the groups.126

TXA for Spine Surgery

The use of TXA in spine surgery has shown a larger benefit.127–130 A recent summary of outcomes found that TXA reduced intraoperative, postoperative, and total blood loss, with variable reduction in RBC transfusion and no clear signal for prothrombotic complications.15 Another meta-analysis of topical TXA in spine surgery also found reduced blood loss with favorable effects on postoperative hemoglobin and no increase in deep vein thrombosis and pulmonary embolism.131 However, care is advised in using topical TXA for spine surgery since its packaging may resemble that of bupivacaine, and inadvertent intrathecal administration of TXA can produce myoclonus, seizure, paraplegia, arrhythmias, and death.41,132

Table 7. - Tranexamic Acid in Pediatric Surgery: Key Take-Home Points
TXA for prophylaxis or treatment in pediatric surgery with high/moderate risk of bleeding is recommended to reduce blood loss and transfusion.
Dosing regimens for pediatric surgery have been suggested based on pharmacokinetic modeling and simulation, which also account for bleeding risk.
TXA use in pediatric cardiac surgery should also account for additional bleeding risk, as well as the patient’s age and cardiopulmonary bypass circuit prime.
Seizures are not a contraindication to use of TXA in pediatric surgery.
Given that pediatric trials are often small or single center, thrombotic risk in the pediatric population is often extrapolated from larger multicenter adult trials, which is low.
Abbreviation: TXA, tranexamic acid.

Accumulating evidence suggests that TXA can reduce bleeding and transfusion in a variety of neurosurgery settings. Older low-level evidence suggesting a risk of cerebral ischemia/edema/infarction with TXA has not been substantiated in recent studies from the modern era. More evidence is needed to establish optimal dosing, safety, and efficacy of TXA for managing patients with neurologic injury or having neurosurgical procedures.

TXA IN PEDIATRIC SURGERY

TXA should be considered as an important modality for the prevention and treatment of bleeding in children and an essential component of an effective perioperative PBM strategy (Table 7). Expert consensus guidelines recommend TXA for pediatric patients undergoing high blood loss surgery.16,133–136 Bleeding and transfusion are associated with significant morbidity and mortality in neonates, infants, children, and adolescents.137–139 Utilizing optimal blood conservation strategies, which include TXA, and the prevention of unnecessary transfusion may decrease risk, improve outcomes, and lower costs; however, evidence to support this claim in pediatrics is still progressing.

TXA Efficacy and Indications

TXA is indicated in the pediatric patient for the reduction of blood loss and the subsequent need for blood transfusion due to major/moderate bleeding expected or occurring in the presence of trauma or in the context of cardiac and noncardiac surgeries.16,133–136 Prospective randomized-controlled trials have demonstrated that TXA use in children undergoing cardiac, craniosynostosis, and spinal fusion surgery is effective in reducing blood loss and transfusion.17,140,141 A blood loss reduction of 25% to 50% has been reported with TXA with a corresponding reduction in transfusion requirements.141,142 In adolescent idiopathic scoliosis (AIS) surgery, TXA when utilized with other blood conservation strategies was effective compared to placebo at reducing blood loss by half. Treating 4 AIS patients prevented 1 from blood loss of >20 mL/kg, and treating 9 AIS patients prevented 1 from receiving an allogeneic transfusion.141

While evidence is evolving, TXA also has a beneficial role in other pediatric high/moderate blood loss scenarios such as neurosurgery, plastic and maxillary surgeries, organ transplantation, head and neck surgeries, major abdominal surgeries, and in those children with higher risk such as in the trauma setting.16,143–145 An ongoing prospective trial (ClinicalTrials.gov NCT02840097) is evaluating the benefits and harm of TXA in severely injured children.

TXA Safety and Contraindications

Regarding TXA-associated reduction in morbidity and mortality, there have been no large prospective multicenter trials to date in the pediatric population. However, a multicenter observational study reports that TXA administration in pediatric craniofacial surgery is independently associated with a 37% reduction in the odds of a major perioperative adverse event.142

Absolute contraindications for the pediatric patient include hypersensitivity, active thromboembolic disease, and fibrinolytic conditions with consumption coagulopathy.16 Relative contraindications should take into consideration the risk-to-benefit ratio. TXA trials in pediatrics are small and/or single center, and they are not powered to report on thrombosis risk. However, given that TXA is a clot stabilizer and not a clot promoter, risk can be considered similar to that reported in large multicenter adult trials, which is low.5,6,8 TXA is not contraindicated in children with a seizure disorder given the growing evidence supporting the safety profile of therapeutic dosing regimens. TXA-associated seizures have been reported in high-risk pediatric cardiac surgery patients with high doses (eg, 100 mg/kg) in small retrospective studies (incidence 3.5%).146 In pediatric craniofacial surgery, the seizure incidence with antifibrinolytics is comparable to the incidence in children not exposed to TXA (incidence 0.6%).147 While more evidence supports the safety of TXA, larger prospective multicenter and adequately powered trials designed to study the efficacy and safety in various pediatric settings are urgently needed.

The pharmacokinetic profile of TXA in pediatrics has been reported. Taking into consideration uncertainties regarding ideal therapeutic plasma concentrations, an evidence-based dosing regimen using pharmacokinetic simulation and computer modeling has been published to guide TXA dosing for pediatric patients who are bleeding or at risk for blood loss.16

Using pharmacokinetic modeling and simulation, a dosing regimen of 10- to 30-mg/kg loading dose (maximum 2 grams) and 5- to 10-mg/kg/h maintenance infusion rate to maintain TXA plasma concentrations in the 20- to 70-mcg/mL range may be considered as a target for pediatric trauma and cardiac and noncardiac surgeries.16 TXA dosing in cardiac surgery has unique concerns taking into consideration the targeted plasma concentration, the patient’s age (with higher doses for neonates and infants), and TXA added to the cardiopulmonary bypass circuit prime.17,18 Obtaining maximal efficacy and minimal side effects with these dosage regimens (as well as determining the ideal target plasma concentration) remains an area of ongoing investigation that will require larger prospective trials. However, based on the current published evidence, prophylactic or therapeutic TXA is a safe and effective strategy to reduce bleeding, decrease transfusion need, and improve patient outcomes. TXA is now recommended in all recent expert consensus guidelines and remains an important part of pediatric PBM protocols.

CONCLUSIONS

TXA is a potent antifibrinolytic with recognized efficacy in several clinical settings. In the perioperative arena, TXA continues to be used as one component of routine blood conservation strategies in cardiac surgery. In obstetrics, TXA is associated with a reduced risk of mortality from PPH in predominantly under-resourced countries, but it is unclear whether it may reduce the risk of morbidity from PPH in well-resourced countries. Current evidence for using TXA as PPH prophylaxis before vaginal or cesarean delivery is, at best, equivocal. In the trauma population, selective use may be warranted as we learn more about fibrinolytic phenotypes. Orthopedic surgery has demonstrated benefit in several scenarios with no significant thrombotic events. Current practice has incorporated TXA use into spine surgery, but adoption into other neurosurgical cases is limited. Finally, TXA use in pediatrics includes a variety of surgical settings with confirmed value. Expansion of TXA to other perioperative settings as a PBM strategy is already occurring. Given the ongoing questions for safety and dosing, continued investigation into this well-established and essential drug is warranted and welcome. E

DISCLOSURES

Name: Prakash A. Patel, MD, FASE.

Contribution: This author helped conceive, write, edit, and submit the manuscript.

Name: Julie A. Wyrobek, MD.

Contribution: This author helped conceive, write, edit, and submit the manuscript.

Name: Alexander J. Butwick, MBBS, FRCA, MS.

Contribution: This author helped conceive, write, edit, and submit the manuscript.

Name: Evan G. Pivalizza, MD.

Contribution: This author helped conceive, write, edit, and submit the manuscript.

Name: Gregory M. T. Hare, MD, PhD, FRCPC.

Contribution: This author helped conceive, write, edit, and submit the manuscript.

Name: C. David Mazer, MD.

Contribution: This author helped conceive, write, edit, and submit the manuscript.

Name: Susan M. Goobie, MD, FRCPC.

Contribution: This author helped conceive, write, edit, and submit the manuscript.

This manuscript was handled by: Roman M. Sniecinski, MD.

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