The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients

Abstract

Clinically significant bleeding can occur as a consequence of surgery, trauma, obstetric complications, anticoagulation, and a wide variety of disorders of hemostasis. As the causes of bleeding are diverse and not always immediately apparent, the availability of a safe, effective, and non-specific hemostatic agent is vital in a wide range of clinical settings, with antifibrinolytic agents often utilized for this purpose. Tranexamic acid (TXA) is one of the most commonly used and widely researched antifibrinolytic agents; its role in postpartum hemorrhage, menorrhagia, trauma-associated hemorrhage, and surgical bleeding has been well defined. However, the utility of TXA goes beyond these common indications, with accumulating data suggesting its ability to reduce bleeding and improve clinical outcomes in the face of many different hemostatic challenges, without a clear increase in thrombotic risk. Herein, we review the literature and provide practical suggestions for clinical use of TXA across a broad spectrum of bleeding disorders.

1 |. INTRODUCTION

Antifibrinolytic agents including tranexamic acid (TXA) have been shown to be effective at preventing bleeding complications in a variety of hemostatic challenges and reduce mortality with minimal adverse effects in some settings.^1,2 The landmark WOMAN study showed a survival benefit to the use of TXA in patients with postpartum hemorrhage.³ In a systematic review and meta-analysis, TXA was shown to reduce blood loss in surgical patients by nearly one-third compared to placebo.⁴ The CRASH-2 trial confirmed the efficacy of TXA in acute traumatic hemorrhage, demonstrating a one-third reduction in mortality when given within three hours of the inciting event.⁵

In addition to these well-studied indications, there are numerous other uses of TXA for which evidence is less robust, but clinical benefit has been demonstrated. At the time of this review, there are 407 trials listed on clinicaltrials.gov related to TXA. Some of the novel areas that are being investigated include subdural and subarachnoid hemorrhage, gastrointestinal bleeding, chemotherapy-induced thrombocytopenia, spontaneous chronic urticaria, and ruptured abdominal aortic aneurysms.

A hemostatic agent with broad applicability and minimal adverse effects such as TXA is attractive as a component of supportive care for many forms of pathologic hemorrhage. We therefore sought to review the latest data on TXA, including efficacy, safety, and dosing, in a number of clinical situations including obstetric indications, acute trauma, orthopedic and cardiothoracic surgeries, dental procedures, hemoptysis, epistaxis, and disorders of primary and secondary hemostasis. Dosing and supporting evidence for each indication is expanded upon in each subsequent section and compiled in Table 1.

TABLE 1.

Summary of indications and Dosing of TXA

	Indications	Dose	Evidence
Heavy Menstrual Bleeding6,9–11,65	Cyclic heavy menstrual bleeding	1300 mg PO 3 times daily (3900 mg/day) for up to 5 days during monthly menstruation	Strong—FDA-approved regimen and indications
Postpartum Hemorrhage3,8	Clinical diagnosis of primary postpartum hemorrhage with estimated blood loss >500 mL after vaginal birth, 1000 mL after cesarean section, or any blood loss sufficient to compromise hemodynamic stability	1 g (100 mg/mL) of TXA IV at 1 mL/min. If bleeding continues after 30 min or stopped and restarted within 24 h of the first dose, a second dose of 1 g can be given	Strong—International, randomized, double-blind placebo-controlled trial
Trauma5,15–17	Trauma cases where patients are at risk of or are exsanguinating	1 g loading dose plus 1 g if deemed appropriate	Strong—Randomized controlled trial with placebo and high power
Cardiothoracic Surgery26	Patients scheduled for coronary artery surgery at risk of bleeding complications	100 mg/kg IV (later 50 mg/kg in Jan 2012) of body weight administered >30 min after the induction of anesthesia	Moderate—Largely double-blinded study with good outcomes with perioperative care
Orthopedic Surgeries27–30,66,67	Conservation of blood transfusion requirements perioperatively for hip fractures	10 mg/kg IV loading dose prior to skin incision followed by a maintenance infusion of 1 mg/kg/hr	Moderate—Double-blinded studies
	Total knee arthroplasty (unilateral and bilateral) with concern for blood loss
	Prophylaxis against blood loss in spine surgeries (discectomies, laminectomies, decompressive surgery, excision of tumor, spinal stenosis, elective posterior thoracic/lumbar instrumented spinal fusion surgery)
Dental31–33	Patients on warfarin undergoing dental extraction with clinically observable bleeding	Compression with gauze soaked in TXA (250 mg/5 mL). Starting dose 4–5 g, followed by 1 to 1.25 g/hour. Maximum dose 24 g per 24 h	Weak—Homogenous patient population with variable inclusion criteria
Hemoptysis34–37	Patients with or without underlying pulmonary disease and hemoptysis. Also, in patients with cystic fibrosis and a history of recurrent or severe hemoptysis	Loading dose of 1 g, followed by 1 g over 8 h IV infusion in patients with underlying pulmonary conditions 500 mg of TXA in 15 mL of saline endobronchially in patients with hemoptysis 500 mg TID nebulized In patients with CF: Scant or mild hemoptysis: TXA 650–1300 mg PO TID × 5 d or EACA 500–1000 mg PO QID × 5 d Moderate hemoptysis: TXA 1300 PO TID × 5 d or EACA 1.00 mg PO QID × 5 d Massive hemoptysis: EACA 4000–5000 mg IV q4–5 h until controlled. If uncontrolled, TXA 1300 mg PO TID × 5 d or EACA 1000 mg PO QID × 5 d	Moderate—Double-blind studies with statistically significant resolution of hemoptysis
Epistaxis38,40	To prevent blood loss and morbidity in patients with epistaxis who are taking and not taking antiplatelet medications	Cotton pledget soaked in injectable form of TXA (500 mg in 5 mL)—for patients on and not on antiplatelet therapy	Moderate—Statistically significant reduction in bleeding in randomized trial
Hematologic Disorders42–45	Clinical diagnosis of APL (AML-M3) Patients with amegakaryocytic thrombocytopenia with bleeding episodes Patients with AML undergoing induction or post remission consolidation chemotherapy	2000 mg Q8 × 6 days with daunorubicin 2 mg/kg × 6 days 20 mg/kg TID × 4 weeks, or until a platelet transfusion is required to control bleeding, followed by a 1-week rest period 1 g every 6 h	Weak—Trial consisted of 12 patients, but treatments arms were double-blinded Moderate—Double-blinded trial Moderate—Double-blinded trial
Hemophilia A/B47	For prophylactic treatment of patients with hemophilia A/B	10 mg/kg	Weak—Moderate—In vitro trial consisted of only 8 patients and used proxy measure
Von Willebrand Disease50,51	To control acute bleeds and to prevent bleeding in high-risk situations	20–25 mg/kg Q8–12 h in conjunction with DDAVP/VWF containing concentrates	Moderate—Literature review of smaller compiled studies
Hereditary Angioedema55,56	Long-term prophylaxis to reduce number and severity of attacks	1000 to 1500 mg PO 2 to 3 times daily; reduce to 500 mg/dose PO once or twice daily when frequency of attacks decrease	Weak—Case studies
Hereditary Hemorrhagic Telangiectasia57,59–61	HHT patients with severe recurrent epistaxis	1 g PO TID	Moderate—Compilation of multiple cohort studies
Melasma62–64	Clinically observable melasma	500–1500 mg/day PO for 2–6 months. 4 mg/ mL injected intradermal into the melasma lesion at 1 cm intervals. 250 mg PO twice daily	Weak—Poor intra-observer reliability and subjective clinical endpoints

2 |. TRANEXAMIC ACID: MECHANISM OF ACTION

Tranexamic acid is a synthetic derivative of lysine that exerts antifibrinolytic effects by blocking lysine binding sites on plasminogen molecules, inhibiting the interaction of plasminogen with formed plasmin and fibrin. As a result, inhibition of plasminogen activation results in stabilization of the preformed fibrin meshwork produced by secondary hemostasis.

Tranexamic acid is available in intravenous and oral formulations. Intravenous TXA has a reported half-life of two hours when studied in healthy volunteers. Food intake does not affect time to maximum concentration, as measured through AUC.⁶ Bioavailability of oral and intravenous TXA was reported to be 33%–34%. Elimination of the intravenous form of TXA is exponential with approximately 90% cumulative excretion of the drug in urine in a time span of 24 hours. Renal clearance is the major mechanism of excretion. This correlates to an increased incidence of complications of TXA with renal dysfunction.^7,8 A dose reduction in both oral and intravenous formulations should be made depending on serum creatinine measurements.

Tranexamic acid when compared to similar compounds, namely ε-aminocaproic acid, is six to ten times more potent in binding affinity to plasminogen and plasmin. TXA induces suppression of fibrinolysis, which manifests as reductions in serum D-dimer levels but does not affect results of serum markers of coagulopathy. Additionally, concurrent heparin administration does not affect the activity of TXA making it a useful adjunct in heparinized patients.⁹

3 |. OBSTETRIC INDICATIONS

3.1 |. Abnormal uterine bleeding

Abnormal uterine bleeding (AUB) is a common complaint accounting for one-third of all gynecologic evaluations. In addition to standard of care which involve treatment of the underling etiologies of the AUB, prospective trials have shown that TXA when used as a supplemental therapy reduces menstrual blood loss by 54% (mean blood loss 164 mL before treatment, 75 mL during treatment).³ Limited data suggest TXA may be as effective as oral contraceptives in the prevention of heavy menstrual bleeding (HMB) in adolescents.¹⁰ A dose of 1300 mg by mouth 3 times daily for up to 5 days during menses is approved for this indication by the US Food and Drug Administration (FDA).^6,9,11

3.2 |. Postpartum Hemorrhage

Postpartum hemorrhage (PPH) is an obstetric emergency and one of the top five causes of maternal mortality worldwide. Generally defined as 500–1000 mL of blood loss within the first 24 hours following delivery, PPH complicates approximately 6% of pregnancies.^7,12,13 Given the associated morbidity and mortality, adjunctive treatment for PPH with TXA has been well-studied.³ The landmark WOMAN trial randomized over 20 000 women with PPH to receive either TXA or placebo.³ Death due to hemorrhage was significantly decreased in the TXA arm (1.5% vs 1.9%, P = .045), while there was no appreciable difference in rates of thrombosis. Data are less robust evaluating the use of TXA for the prevention of postpartum hemorrhage. The TRAAP trial randomized over 4000 women to TXA or placebo for the prevention of PPH but did not find a significant difference in the rate of bleeding.⁸

In general, TXA is used when estimated blood loss exceeds 500 mL after vaginal birth or 1000 mL after cesarean section, or with any blood loss sufficient to compromise hemodynamic stability.³ A loading dose of 1 g (100 mg/mL) of TXA intravenously at a rate of 1 mL/min is the standard. If bleeding continues after 30 minutes, or recurs within 24 hours of the first dose, a second dose of 1 g of TXA can be given.³

4 |. ACUTE TRAUMA

Acute trauma is a common cause of mortality worldwide across all age groups. Among the many complications that accompany significant trauma, blood loss is the most common cause of life-threatening cardiovascular compromise, and thus prevention of active hemorrhage remains a major aim in trauma management. Emergent or urgent surgery in the setting of acute trauma is associated with a high risk of mortality due to hemorrhage. TXA used in this setting can reduce perioperative bleeding and reduces the need for blood transfusions.¹⁴ The landmark CRASH-2 trial randomized over 20 000 trauma patients to TXA or placebo, with TXA associated with significantly improved mortality (4.9% vs 5.7%, P = .0077).⁵ The standard dose used in trauma is 1 g intravenously as a loading dose, with administration of an additional 1 g for continued bleeding.^5,15–17 Newer data on empiric TXA used in the pre-hospital setting for traumatic brain injury found fewer deaths in patients given a 2 g TXA bolus compared to placebo (unpublished data, NCT 01990768).

Though the utility of TXA in acute trauma is well established, knowledge gaps and limitations still exist. The CRASH-2 trial helped establish that TXA is most effective when given within three hours of trauma.¹⁸ However, this effect may be limited to the three-hour window as when TXA was given beyond that time-frame, there was no mortality benefit. Some hypothesize that there may even be an increased risk of bleeding with TXA use after three hours of injury.¹⁸ As in other clinical settings, there is a concern for venous thromboembolism (VTE) with TXA use in acute trauma. This end point requires further research, as there is no current consensus if TXA administration causes a statistically significant increased risk of VTE. One retrospective study indicated a threefold increased risk of VTE in a patient cohort treated with TXA compared to the untreated cohort—15.3% vs 7.4%.¹⁹ A separate review concluded that the frequency of thrombotic events among trauma patients who receive antifibrinolytic agents is not fully known at the time of publication.²⁰ A recent editorial reiterates the limitations of the CRASH-2 study; though rates of both pulmonary embolism (PE) and deep venous thrombosis (DVT) were low, they might not have been actively evaluated for in many of the participating hospitals. It also brings up the contested point that the MATTERs study showed—rates of DVT and PE among patients who received TXA were 9 and 12 times the rates of those untreated.²¹ In a systematic review and meta-analysis by Benipal et al, the concern for thromboembolic events was further investigated and elucidated a possible limitation of the CRASH-2 trial. In the review, it was found that compared to the CRASH-2 trial, adult trauma patients receiving TXA had a lower incidence of mortality, but a higher incidence of in-hospital events. This suggests that the patient population from the CRASH-2 trial may different that settings outside of the trial and requires further investigation.²²

Some authors have addressed concerns regarding the CRASH-2 trial, mostly revolving around the trials data collection and methodology.²³ In a review article by Binz et al, the authors highlight how the CRASH-2 trial was spearheaded in England, but conducted in low-to-moderate income countries without mature trauma systems, likely dissimilar to hospitals in higher income settings.²³ While some articles highlight these points, large meta-analysis support the overall safety and effective of TXA in acute trauma.²⁴

The recently published CRASH-3 trial investigates the use of TXA in acute trauma patients with traumatic brain injuries (TBI). The trial concluded that TXA is safe in patients with TBI and that treatment within 3 hours of injury reduces head injury-related death compared to placebo.²⁵ The dosing used in the study was 1 g loading dose over 10 minutes, then infusion of 1 g over 8 hours. The trial found no increase in disability among survivors who received TXA, and the risk of vascular occlusive events was similar in the TXA and placebo groups.²⁵

5 |. SURGICAL INDICATIONS

5.1 |. Cardiothoracic surgery

Bleeding in cardiothoracic surgery is a major complication that pro-longs hospital stays, increases the need for blood transfusions, and contributes to overall mortality, including from complications such as thrombotic events and stroke. In a randomized controlled trial (RCT) of patients at risk for bleeding undergoing coronary artery bypass grafting, preoperative TXA was associated with a lower risk of bleeding without a detectable increase in thrombotic complications within 30 days after surgery compared with placebo.²⁶ The composite end point of death and thrombotic events (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) during the initial 30 postoperative day course was significantly decreased in the cohort assigned to TXA, as were transfusion needs and re-operation due to major hemorrhage or cardiac tamponade. Postoperative seizure was more common in those who received TXA (0.7% vs 0.1%), and after enrollment of approximately 1300 patients, the initial trial dose of 100 mg/kg IV was reduced to 50 mg/kg. In prior reviews of cardiothoracic surgery, initial trials of TXA were limited by seizures during the postoperative period. As such the initial trial dose of 100 mg/kg IV was reduced to 50 mg/kg.¹¹ Similarly based upon prior studies, a prior prospective cohort study completed in 8929 patients noted that a high dose of TXA at greater than 100 mg/kg was independently associated with increased risk of seizure.¹² In a retrospective cohort analysis of 11 529 patients conducted who have had a history of cardiopulmonary bypass surgery seizure was a notable consequence especially in patients with predisposing risk factors including age, preoperative neurological disease and prior pre-existing cardiovascular disease.¹³ Given these results, few centers utilize medium- or high-dose TXA secondary to seizure activity. The incidences of such complications correlate with renal dysfunction; TXA is renally excreted with case reports supporting the observation that patient treated with TXA reported increased myoclonic movements with increased episodes of generalized seizure.^7,8 In a retrospective analysis of 12 000 patients who underwent cardiopulmonary bypass surgery, low-dose TXA was associated with a lower incidence of seizures (46 of 7452 cases [0.70%] v 34 of 2190 cases [1.55%], respectively; P < .0001).¹⁴ Further confirmation of the decreased seizure incidences in low-dose TXA are demonstrated by a large July 2019 meta-analysis with additional systemic reviews and protocols actively being investigated.^15,16 Dose reduction of TXA is the standard for reduction of post cardiopulmonary bypass surgery seizures.

5.2 |. Orthopedic Surgeries

Blood loss in orthopedic procedures is a common indication for TXA, which has been shown to be effective for both the prevention and treatment of adverse perioperative complications. Several studies have attempted to assess the efficacy and safety of TXA in patients who required orthopedic surgeries. An RCT of 57 patients undergoing total hip arthroplasty found that perioperative TXA resulted in a 30% reduction in transfusion requirement compared to placebo.²⁷ Notably, this trial was an outlier in showing an increased rate of vascular events in the group that received TXA. The results from Zufferey et al showed a threefold increased risk of vascular events with the use of TXA, which was not statistically significant. However, this contradicted previous findings that showed no increased risk of VTE and TXA remains safe for usage.²⁷ Kim et al published a similar RCT evaluating the efficacy of TXA in both unilateral and bilateral total knee replacements. In patients undergoing unilateral total knee replacement, there was decreased total blood loss in the TXA group compared to the control group (905 mL vs 1018 mL, P = .018).²⁸ There was no difference in the rate of transfusion. In patients undergoing bilateral total knee replacement, TXA did not result in a significant difference in absolute blood loss (1282 vs 1379 mL) but was associated with a significant reduction in need for transfusion (7% vs 27%, P = .002).²⁸ No symptomatic deep venous thrombosis or pulmonary embolism was found in any tested group.

Blood loss during spinal surgeries is also a significant cause of morbidity. Data support the use of TXA in reducing bleeding and perioperative complications in this setting. An RCT conducted in patients who underwent spinal operations found a 49% reduction in blood loss (P < .007) with TXA and an 80% reduction in need for blood transfusion (P < .008) compared to placebo.²⁹ Similarly, a 151-patient trial evaluating efficacy of TXA in elective posterior thoracic/lumbar instrumented spinal fusion found that perioperative blood loss in the TXA group was reduced by 25%−30% compared with the placebo arm (P < .05).³⁰ In all of these orthopedic surgery studies, the standard dose of TXA was 10 mg/kg IV loading dose prior to skin incision, followed by a maintenance infusion of 1 mg/kg/h.

5.3 |. Dental procedures

Excessive bleeding associated with dental extraction is common in patients with bleeding disorders and those on anticoagulation and may also occur in patients without a known bleeding diathesis. Antifibrinolytic agents are frequently prescribed in patients with excessive bleeding following dental extraction. A number of small studies have demonstrated the effectiveness of TXA to reduce oral bleeding. For example, in patients anticoagulated with warfarin, topical application of TXA-soaked gauze, followed by an oral TXA regimen, resulted in a reduction in the time to hemostasis compared with placebo-treated patients.^31,32 In a double-blind trial of patients with hemophilia A or B, TXA (1 g by mouth three times a day for five days) was shown to significantly reduce blood loss and transfusion requirements after dental extraction.³³

6 |. HEMOPTYSIS

Hemoptysis is a common complication of primary pulmonary diseases including malignancies, cystic fibrosis (CF), and bronchiectasis. Complications include increased requirements for hospitalization along with requirements for blood transfusion which ultimately prolong and complicate hospital stays. In addition to standard of care, in the event for continued bleeding, TXA has been shown to reduce such aforementioned complications. In an RCT of 66 adults with hemoptysis related to a variety of underlying pulmonary diseases, an 8-hour IV TXA infusion resulted in reduced bleeding, transfusion requirements, and length of hospital stay.³⁴ Endobronchial, topical administration of TXA in patients with ongoing hemoptysis has been shown to be effective.³⁵ In an RCT of 47 adults with non-massive hemoptysis, patients randomized to nebulized TXA had less expectorated blood volume, shorter hemoptysis duration, required fewer procedures to control bleeding, and had shorter hospital length of stay.³⁶ TXA may also be useful as on-demand, outpatient treatment in patients with hemoptysis, as demonstrated by a retrospective cohort study of 21 adults with CF and a history of recurrent or severe hemoptysis who were enrolled on a clinical pathway utilizing on-demand outpatient TXA or epsilon-aminocaproic acid (EACA) initiated at the first sign of bleeding.³⁷ This study found that use of antifibrinolytics was safe and associated with a 50% reduction in hospitalizations for hemoptysis.

7 |. EPISTAXIS

Epistaxis is a common complaint in the outpatient setting; 60% of healthy adults report having experienced at least one episode of epistaxis during their lifetime, with 6% requiring medical attention.^38,39 In an RCT of anterior nasal packing with topical TXA in patients taking antiplatelet medications, 73% of the patients in the treatment arm had cessation of bleeding in less than 10 minutes, compared to 29% of the patients in the placebo group.³⁸ Discharge times, rebleeding rates, and complications in the emergency department favored TXA, though results were not statistically significant. Similarly, in an RCT of 216 patients with anterior epistaxis, 71% of the patients in the treatment arm had bleeding that resolved in the first 10 minutes after receiving topical TXA, compared with 31.2% of patients in the anterior nasal packing group (P < .001).⁴⁰ Rebleeding was reported in 4.7% and 11% of patients during the first 24 hours in the TXA and anterior nasal packing groups, respectively (P = .128).⁴⁰

8 |. DISORDERS OF PRIMARY AND SECONDARY HEMOSTASIS

8.1 |. Coagulopathy and Thrombocytopenia Secondary to Hematologic Malignancy

In disorders of coagulopathy and thrombocytopenia secondary to hematologic malignancy, complications of bleeding can arise.⁴¹ Blood product transfusions and treatment of the primary disease are mainstays of treatment however in cases of continued bleeding, TXA has been evaluated as a prophylactic intervention in multiple scenarios where hematologic disorders, or their treatment, lead to thrombocytopenia. Studies are limited in number, with variable inclusion criteria and evaluative assessments. TXA 2000 mg every 8 hours for 6 days, combined with induction chemotherapy, has been evaluated for prophylaxis of bleeding in acute promyelocytic leukemia.⁴² While the trial included only 12 patients, it suggested that TXA during the first week of antileukemic therapy significantly reduces hemorrhage and transfusion requirements.⁴²

For treatment of patients with amegakaryocytic thrombocytopenia with bleeding episodes, a TXA regimen of 20 mg/kg TID for 4 weeks, or until a platelet transfusion was required to control bleeding, showed no efficacy in reducing bleeding.⁴³

TXA 1 g every 6 hours has been evaluated for the prevention of bleeding in a single arm trial of patients with AML undergoing induction chemotherapy and appeared to be beneficial.⁴⁴ In contrast to the induction period, there was significantly less severe bleeding and a lower platelet transfusion requirement in the group that received TXA.⁴⁵

A more in-depth evaluation of use of TXA in thrombocytopenic patients, including in the perioperative setting, can be found in a review article by Nagrebetsky et al.⁴⁶

8.2 |. Hemophilia

Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are X-linked, inherited coagulation factor deficiencies that result in multiple complications as a result of a lifelong bleeding diathesis. The treatment of hemophilia has largely involved the administration of factor replacement to correct the coagulopathy. However, in vitro studies suggest that TXA may also provide some benefit in conjunction with standard of care. Hvas et al sought to evaluate whether simultaneous treatment with TXA and recombinant factor VIII (rFVIII) significantly improved clot stability in patients with hemophilia A. TXA and rFVIII both improved clot stability parameters based on thromboelastography in patients with hemophilia A.⁴⁷ While evidence is limited, major guidelines suggest TXA or EACA may be used after dental procedures in patients with hemophilia to reduce the need for factor replacement therapy.^48,49

8.3 |. Von Willebrand disease

Von Willebrand disease (vWD), the most common hereditary bleeding disorder, results from either a quantitative or qualitative defect in functioning von Willebrand factor, resulting in impaired primary hemostasis. Additionally, acquired vWD can arise as a result of hematologic, immunologic, drug-induced, and cardiovascular causes. Patients frequently present with mucocutaneous bleeding. Treatment is tailored to the subtype of vWD, and typically includes vWF concentrates with or without FVIII, or desmopressin, either prophylactically or on-demand.⁵⁰ In cases of persistent bleeding, antifibrinolytics, such as TXA, have been used as an adjunct at a dose of 1 g by mouth three to four times daily for all subtypes of vWD.⁵¹

TXA administered at a dose of 20–25 mg/kg every 8–12 hours in management of heavy gastrointestinal or genitourinary bleeding, in conjunction with desmopressin or vWF containing concentrates, has shown efficacy.⁵⁰ In minor bleeds, use of TXA alone has been shown to improve outcomes. TXA, in conjunction with hormonal contraceptives, have also shown efficacy in reducing menstrual blood loss in women with vWD, once additional causes of menorrhagia have been ruled out.⁵¹

In the perioperative setting, studies report a reduction in bleeding in children with vWD undergoing otolaryngologic surgery receiving desmopressin acetate and tranexamic acid, compared to receiving FVIII.⁵² In a prospective, controlled study of 41 children with vWD who underwent surgical procedures, the incidence of immediate postoperative bleeding and delayed bleeding was low, at 5% and 0%, respectively.^52,53

The efficacy of TXA for the reduction of bleeding in vWD patients was further demonstrated by Eghbali et al In their double-blind, controlled trial, 17 patients with vWD were treated with TXA and experienced a significant reduction in bleeding episodes. Additionally, TXA therapy was associated with a significant decrease in the use of factor concentrates.⁵⁴

9 |. OTHER DISORDERS

9.1 |. Hereditary Angioedema

Hereditary angioedema (HAE) is an inherited condition that presents with swelling of the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts and may result in airway compromise. TXA has been proposed as a means of long-term reduction in the frequency and severity of HAE flares. Based upon a series of case reports, the optimal dosing of TXA has been suggested to be 1000 to 1500 mg by mouth 2 to 3 times daily. This dose is reduced to 500 mg once or twice daily when frequency of attacks decreases.^55,56

9.2 |. Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT, or Osler-Weber-Rendu disease) is a multisystem vascular disorder of abnormal angiogenesis. With a prevalence of 1 in 5000 people, it is the second most common hereditary bleeding disorder worldwide.⁵⁷ HHT results in bleeding secondary to disruption of abnormal, friable vascular malformations along the mucocutaneous surfaces of the upper aerodigestive and gastrointestinal tracts. Additionally, hyperfibrinolysis clearly contributes to the bleeding phenotype in HHT, which may be reversed by the action of antifibrinolytics on the wall of anomalous vessels.⁵⁸ Nearly all patients with HHT develop recurrent epistaxis and many develop chronic gastrointestinal hemorrhage. Chronic bleeding may lead to severe iron deficiency anemia and red cell transfusion dependence in these patients. While anti-angiogenics are now being used to reverse the underlying vascular defects to prevent HHT-associated bleeding, antifibrinolytic agents may be utilized to correct the component of the hemostatic defect caused by hyperfibrinolysis.⁵⁹ A randomized, double-blind, placebo-controlled, crossover study of 22 HHT patients with severe recurrent epistaxis, who were treated with TXA or placebo, demonstrated a 54% reduction in epistaxis in patients receiving TXA.⁶⁰ Similar findings have been seen in larger retrospective cohort studies.⁶¹

9.3 |. Melasma

Melasma is an acquired condition of the skin where hyperpigmentation is driven by sun exposure, usually occurring in women with exposure to high amounts of ultraviolet radiation.^62–64 Though not a commonly employed technique, TXA, both in oral and parenteral formulations, has been used in treatment of melasma. Dosing varies, but regimens include 500–1500 mg/day by mouth for 2–6 months, 250 mg by mouth twice daily, or 4 mg/mL injected intradermally into the melasma lesion at 1 cm intervals.^62–64 Results were notable for a reduction in melasma severity score along with a noted improvement in cosmesis with use of both oral and injected formulations of TXA.^62–64 Of note, these results were from a small population of test subjects, and thus may not be generalizable to the broader population.

10 |. DISCUSSION

TXA has been shown to prevent bleeding in multiple clinical scenarios without increasing the risk of thrombosis and has a wide range of clinical indications. While data are limited in some settings, major conclusions can be drawn about indications, treatment dosing, and outcomes in many others, as seen in Table 1.

TXA is clearly efficacious in the management of PPH.³ Similarly, TXA has demonstrated efficacy for heavy menstrual bleeding, which remains the only FDA-approved indication for the drug.^6,9,11

Use of TXA is also well established in acute blood loss in the setting of trauma.^5,15–17 Dosing regimens and protocol occasionally differ owing to variability in practitioner assessment of whether re-dosing is required, but outcomes support its use in prevention of life-threatening hemorrhage with minimal side effects.

It is difficult to draw firm conclusions regarding the clinical utility of TXA in conditions that are not as well studied. This holds especially true for conditions with limited morbidity, including dermatologic and dental conditions. The theoretical risk of thrombosis is the primary concern limiting use of TXA, though a recent meta-analysis concluded that thrombosis was not significantly increased by TXA.² Other potential adverse effects are rare, but relevant, most prominently including seizure. An example is the use of TXA in coronary artery bypass graft surgery, in which the high seizure incidence mandated a TXA dose reduction. However, at doses used in most other clinical scenarios, seizures have been uncommon.²⁶

In conclusion, TXA is a non-specific hemostatic agent with numerous clinical uses. For many indications, data are limited and use remains off-label. Additional prospective studies are needed to confirm the findings of many of these small and/or retrospective studies demonstrating safety and effectiveness of TXA. Future investigation will also aim to better characterize outcomes of TXA use in novel clinical contexts.

NOVELTY STATEMENT.

1. This review article provides practical suggestions for clinical use of tranexamic acid across a broad spectrum of disorders.

2. Tranexamic acid is safe and effective in both medical and surgical patients.

3. This work provides guidance for clinicians on how to best treat patients with tranexamic acid.