Continuing Education Activity

Tranexamic acid (TXA) is approved by the FDA for managing heavy menstrual bleeding and for short-term use in patients with hemophilia, including the prevention of bleeding during dental procedures and the treatment of menorrhagia. Off-label use extends to trauma settings, including massive transfusion protocols and combat injuries requiring blood transfusion within 24 hours, as well as surgical procedures to reduce intraoperative blood loss. TXA may be administered orally, topically, or intravenously, with the route of administration depending on the clinical context and severity of bleeding.

This activity provides healthcare professionals with evidence-based guidance on the appropriate use of tranexamic acid in various clinical scenarios. Topics include indications, mechanism of action, pharmacologic properties, adverse effects, contraindications, and toxicological considerations. Instruction also addresses monitoring parameters to ensure safety and efficacy in both approved and off-label settings. Emphasis is placed on optimizing therapeutic outcomes while minimizing the risk of adverse events. The content supports informed, individualized decision-making and reinforces the role of interprofessional collaboration in guiding the use of TXA.

Objectives:

• Evaluate the mechanism of action of tranexamic acid as a treatment for bleeding disorders.
• Identify the FDA-approved indications and off-label uses for tranexamic acid.
• Assess the adverse reactions associated with tranexamic acid administration.
• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from tranexamic acid therapy.

Indications

Tranexamic acid is a synthetic lysine analog that competitively inhibits plasminogen activation, stabilizing fibrin clots and reducing bleeding.

FDA-Approved Indications

The only FDA-approved indications for tranexamic acid (TXA) are heavy menstrual bleeding and short-term prevention in patients with hemophilia.

• Tooth extractions in patients with hemophilia: Two Cochrane reviews have shown limited data on patients with hemophilia undergoing tooth extractions. However, intravenous tranexamic acid (TXA) may reduce blood loss, postoperative bleeding, and the need for additional clotting factor replacement when administered in conjunction with clotting factor replacement for the specific type of known hemophilia.[1][2]
• Menorrhagia: An open, non-comparative study revealed that oral TXA reduced idiopathic menorrhagia and improved the quality of life in these patients.[3]

Off-Label Uses

Intravenous TXA is commonly administered to patients with severe bleeding who require massive transfusion protocols (MTP) or when hyper-fibrinolysis is suspected. TXA is most frequently administered to trauma patients, but may be given to any patient at significant risk of hemorrhage. The 2010 CRASH-2 trial was a multicenter, randomized, double-blinded, controlled trial in which patients received either TXA or a placebo. This trial involved adult trauma patients with significant hemorrhage with hypotension (systolic blood pressure <90 mmHg) and tachycardia (heart rate >110 bpm) within 8 hours of injury. The study data suggest that TXA improves survival when administered within 3 hours of the injury in patients with significant hemorrhage.[4][5] The 2011 MATTERs trial was a retrospective observational study aimed at validating CRASH-2. Combat trauma patients require at least one unit of blood within 24 hours of presentation. The MATTERs trial revealed that TXA decreased overall mortality, particularly in patients requiring MTP. This is the only trial that has demonstrated increased rates of thrombosis.[6] However, it should be noted that TXA is an antifibrinolytic and not a procoagulant.

Intravenous

• Elective cesarean sections: A randomized, double-blind, placebo-controlled study of 660 women who underwent elective cesarean showed the TXA group had less blood loss compared to the placebo group, with no increase in thromboembolic events.[7]
• Total knee arthroplasty: In a double-masked, prospective trial, patients were administered either TXA or normal saline to investigate whether TXA decreased the need for blood transfusions. The TXA group reduced both bleeding and the need for blood transfusion. They also noted no significant thromboembolic events.[8] The American Association of Hip and Knee Surgeons, the American Society of Regional Anesthesia and Pain Medicine, and the American Academy of Orthopaedic Surgeons advocate for TXA in total joint arthroplasty.[9]
• Orthognathic surgery: A double-blind, randomized, controlled trial of elective bi-maxillary osteotomy, where participants received either TXA or normal saline. Their results revealed statistically significant blood loss in the TXA group; however, there was no difference in the number of blood transfusions.[10]
• Cardiac surgery: A trial with a 2-by-2 factorial design was conducted, assigning patients undergoing coronary artery surgery to either an aspirin or placebo group, or a TXA or placebo group. Their results revealed that tranexamic acid was associated with a lower risk of bleeding than the placebo, without a higher risk of death or thrombotic complications within 30 days after surgery.[11]
• Spinal surgeries: One hundred thirty-two consecutive patients undergoing a multi-level posterior spinal segmental instrumented fusion (=5 levels) were analyzed retrospectively. The number of patients was 89 in the TXA group and 43 in the non-TXA group. The data revealed a significant reduction in blood loss in the TXA group, along with a decrease in blood transfusions, compared to the non-TXA group.[12]
• Transurethral retrograde prostatectomy (TURP): Patients undergoing a TURP were assigned to a TXA group versus a control group. Their data revealed that the TXA group had less hemoglobin loss per gram of resected prostate tissue compared to the control group.[13]
• Non-traumatic subarachnoid hemorrhage: A randomized, prospective, multicenter study was conducted to examine the administration of TXA and reduction of rebleeding rates. The data revealed reduced rebleeding and mortality compared to the group not treated with TXA.[14]
• Postpartum hemorrhage: The WOMAN Trial Collaborators in 2017 was a large multicenter, randomized, controlled, double-blinded study that showed that TXA reduces death in women with postpartum hemorrhage if given as soon as possible after bleeding onset. Meta-analysis further shows that TXA decreases the risk of life-threatening bleeding.[15][16]
• Gastrointestinal bleeding: Past trials have shown a trend toward reduced mortality and decreased blood product use; however, these findings were based on older therapies. Newer trials are underway to better understand the role of TXA in patients with gastrointestinal bleeding.[17][18][19]
• Intracranial hemorrhage: The Neurocritical Care Society and the Society of Critical Care Medicine recommend that, if cryoprecipitate is contraindicated or unavailable, IV TXA can be used for thrombolytic reversal in intracranial hemorrhage.[20]
• Total unilateral hip replacement surgery: A double-blind, randomized, controlled trial of 161 patients undergoing unilateral primary total hip replacement investigated the effect of topical intra-articular application of TXA on blood loss, showing that intra-articular TXA reduced the need for blood transfusion versus patients not receiving TXA.[21] Another study compared intra-articular with intravenous TXA, finding that the intra-articular form was non-inferior to the intravenous form. The authors recommended the continued use of intra-articular administration.[22]

Oral

• Post-procedural after cervical conization: A double-blind, randomized, controlled trial revealed that oral TXA regimen reduced post-procedural blood loss. TXA was also provided prophylactically, likewise reducing blood loss compared to the placebo group.[23]
• Hereditary angioedema (HAE): A systematic review was conducted involving 4 medications given prophylactically to reduce HAE attacks. All 4 drugs (including TXA) reduced the frequency of HAE attacks compared to a placebo.[24]
• Transurethral retrograde prostatectomy (TURP): One prospective and randomized trial was conducted involving TXA given to the treatment group, 2 g TXA 3 times daily, and on the first day after the operation. Their data revealed that short-term oral TXA reduced intraoperative blood loss during a TURP.[25]
• Tooth extractions in patients on oral anticoagulants: A prospective randomized, controlled trial examined a 2-day versus 5-day oral solution of TXA to prevent postoperative bleeding in patients on warfarin. The data suggested that a 2-day regimen was equally effective as the 5-day course in preventing blood loss.[26]
• Hemoptysis: The Infectious Diseases Society of America recommends considering oral TXA in cases of aspergillosis with hemoptysis.

Topical

• Traumatic hyphema: A multi-database review revealed that TXA reduces secondary hemorrhage in traumatic hyphema. TXA also reduced fibrinolysis of the clot and showed increased corneal staining.[27]
• Epistaxis: Patients receiving antiplatelet agents and unmedicated patients with nosebleeds treated with packing dipped in tranexamic acid (TXA) showed decreased bleeding, decreased rebleeding, shorter emergency department times, and improved patient satisfaction.[28] International guidelines on hereditary hemorrhagic telangiectasia endorse TXA for epistaxis in topical therapy failure.[29]
• Hemoptysis: Nebulized TXA has been shown in case series to reduce hemoptysis.[30][31][32]

Mechanism of Action

The antifibrinolytic effects of TXA are due to reversible interactions at multiple binding sites within plasminogen. TXA is a synthetic, reversible, competitive inhibitor of the lysine receptor found on plasminogen. The binding of this receptor prevents plasmin (the activated form of plasminogen) from binding to and ultimately stabilizing the fibrin matrix.[33] TXA used for hereditary angioedema works by its indirect effect of reducing complement activation. Reducing plasmin activity minimizes the consumption of C1 esterase inhibitors.[34]

Pharmacokinetics

Absorption: After oral administration, the peak plasma concentration is 3 hours. The absolute bioavailability of tranexamic acid tablets is approximately 45%. The steady-state plasma concentrations are achieved with the fifth dose of tranexamic acid.

Distribution: The volume of distribution (Vd) achieved by administering IV TXA is 9 to 12 L. The protein binding to plasminogen is about 3%. TXA is known to cross the placenta.[35] TXA is also present in cerebrospinal fluid (CSF) and the aqueous humor of the eye.[36]

Metabolism: Approximately 5% of TXA is metabolized.

Elimination: Tranexamic acid is eliminated by glomerular filtration, and 95% of the dose is excreted unchanged.[37] The elimination half-lives for oral TXA and IV TXA are approximately 11 hours and 2 hours, respectively.

Administration

Available Dosage Forms and Strengths

Intravenous TXA is available as 1000 mg in 10 mL. Oral TXA formulation is available as 650 mg tablets.

IV Uses

• Hemorrhagic shock: intravenous TXA, including for postpartum hemorrhage and trauma patients.
• Adult dose: 1 g bolus in 100 mL of normal saline over 10 minutes (slow intravenous push). Rapid infusion may cause hypotension. May repeat a 1 g dose over the next 8 hours, but do not exceed 2 grams.
• Pediatric dose: Weight-based, an initial dose of 20 mg/kg intravenous bolus over 10 minutes. May repeat 10 mL/kg/hr over the next 8 hours.
• Elective cesarean section: Intravenous (IV) TXA 1 g over 5 minutes at least 10 minutes before skin incision
• Hip fracture surgery: 15 mg/kg IV TXA at the time of skin incision, followed by a similar second dose 3 hours later
• Non-traumatic SAH: 1 g IV TXA at diagnosis of SAH, then 1 g every 6 hours until the aneurysm is occluded
• Unilateral and bilateral knee arthroplasty: 10 to 15 mg/kg IV TXA over 10 minutes before deflating the first tourniquet, 3 hours after the first dose
• Bleeding associated with cervical conization: 1 g IV during the procedure, followed by 1 g oral 3 times a day for 14 days, or 1.5 g every 8 hours the evening after the procedure for 12 days
• Cardiac surgery: 50 mg/kg IV administered at least 30 min after anesthesia
• Spinal surgery: 2 g IV over 20 minutes before incision, followed by 100 mg/hr during surgery and continued 5 hours postoperatively
• Dental extraction in patients with hemophilia (with factor replacement therapy): 10 mg/kg IV immediately before surgery, then 10 mg/kg oral 3 to 4 times daily

Oral Uses

• Cyclic heavy menstrual bleeding: 1300 mg TID for up to 5 days during menstruation
• HAE for long-term prophylaxis: 1 to 1.5 g, 2 to 3 times daily. The dose may be reduced to 500 mg once or twice daily when attacks occur less frequently.
• Oral TXA rinse: For dental procedures involving patients on oral anticoagulants, oral rinse may be administered with a 4.8% solution. Rinse 10 mL of the solution in the mouth for 2 minutes, then spit it out. May repeat 4 times. Avoid eating or drinking for 1 hour after administration.

Other Uses

• Epistaxis: Nasal packing dipped in TXA applied into the nares for epistaxis once
• Nebulized TXA for massive hemoptysis: 1000 mg in 20 mL of normal saline nebulized.[38]

Specific Patient Populations

Hepatic impairment: No adjustments are required for patients with hepatic impairment.

Renal impairment: TXA has not been well-studied in patients with renal impairment. Ninety-five percent of TXA is excreted unmetabolized in the urine, so renal dosing is recommended, and judicious administration is recommended for patients with severe renal impairment.

Pregnancy considerations: TXA crosses the placenta and is classified as a pregnancy category B (formerly assigned by the FDA) medication. No harm or small risk has been noted in animal studies; however, no adverse effects have been observed in human studies. TXA significantly reduces perioperative blood loss in high-risk women undergoing cesarean delivery.[39] According to the American College of Gynecology and Obstetrics, TXA can be considered in obstetric hemorrhage when initial medical therapy fails.[40] Thromboembolic events do not differ significantly between the TXA and the placebo.[41] If there is a congenital hemostatic disorder or a known history of thromboembolic events, TXA should be prescribed only after a risk-benefit evaluation.

Breastfeeding considerations: A prospective, controlled observational study showed that while the infant is likely exposed to some TXA via the mother's breast milk, it is in such low concentrations that it recommends continued use of TXA in a lactating mother.[42] TXA appears in breastmilk in minimal amounts, with studies showing no adverse effects in infants at maternal doses up to 4 g daily. Despite earlier caution from international panels, clinical use in breastfeeding women, such as 3 g daily for bleeding disorders, has been well tolerated. TXA remains a second-line option for hereditary angioedema when C1-INH is unavailable. Breastfeeding may continue during treatment, but infant monitoring is recommended until more safety data are available.[43]

Pediatric patients: The safety and effectiveness of TXA tablets have been established in women of reproductive potential. Intravenous TXA is recommended for dental procedures involving patients with hemophilia by the World Federation of Hemophilia guidelines.[44]

Older patients: TXA reduces perioperative blood loss with a hemoglobin-sparing effect in older adults undergoing primary total hip arthroplasty, similar to that seen in younger patients. Hence, there is no need to adjust the TXA dosage in older patients. TXA administration is a crucial component of blood management programs for patients undergoing hip replacement surgery in older age groups.[45]

Adverse Effects

Adverse effects include seizures, headaches, backache, abdominal pain, nausea, vomiting, diarrhea, fatigue, pulmonary embolism, deep vein thrombosis, anaphylaxis, impaired color vision, and other visual disturbances. Seizures can occur due to accidental intrathecal administration.[36]

Drug-Drug Interactions

• Hormonal contraceptives: Because TXA is antifibrinolytic, concomitant use of combined hormonal contraception and TXA may increase the thrombotic risk associated with oral contraceptives. Concomitant use of TXA with combined hormonal contraceptives is avoided.
• Tissue plasminogen activators: Tissue plasminogen activators can decrease the efficacy of TXA. Discontinue treatment if a patient urgently needs tissue plasminogen activators.
• Anti-inhibitor coagulant concentrates or Factor IX complex concentrates: TXA is not recommended with anti-inhibitor coagulant concentrates or Factor IX complex concentrates because of the risk of thrombosis.
• All-trans retinoic acid: TXA is not recommended in patients with acute promyelocytic leukemia who are taking all-trans retinoic acid for remission induction because it may exacerbate the procoagulant effect of all-trans retinoic acid.

Contraindications

Contraindications

Contraindications for TXA administration include known allergy, intracranial bleeding, known defective color vision, subarachnoid hemorrhage, history of venous or arterial thromboembolism, or active thromboembolic disease. TXA is also contraindicated if more than 3 hours have passed since the traumatic injury. Tranexamic acid is avoided in patients with hemophilia B receiving prothrombin complex concentrates, as it increases the risk of thromboembolism.[44]

Warning and Precautions

• Seizures: Inadvertent neuraxial injection of TXA or high doses, particularly during cardiac surgery, may cause focal or generalized seizures. Reduce the dose in renal dysfunction and during surgery. Monitor closely and consider EEG for seizure history or signs (eg, twitching, myoclonus). Discontinue if seizures occur.
• Hypersensitivity Reactions: Severe reactions, including anaphylaxis, have been reported. Discontinue immediately and manage appropriately. Reinitiation is contraindicated in patients with prior hypersensitivity to TXA.
• Visual Disturbances: Though not seen in humans at standard doses, high-dose animal studies showed focal retinal degeneration. For treatment lasting longer than 3 months, consider baseline and follow-up ophthalmic exams. Discontinue if ocular changes occur.
• Dizziness: TXA causes dizziness, especially with rapid IV administration or when used with other CNS depressants. Advise patients to avoid driving or operating machinery until they know their response. Infuse slowly to prevent dizziness and hypotension.

Monitoring

Clinicians must monitor hemodynamics and watch for thromboembolic events.[46] Monitor EEG in patients with a known history of epilepsy. An ocular exam, including visual acuity and optical coherence tomography, is required in prolonged treatment.[47] Recent research has highlighted the importance of optical coherence tomography in the management of melasma.[48][49]

Toxicity

Signs and Symptoms of Overdose

Oral overdose of TXA typically causes minimal toxicity and rarely requires hospital admission. In contrast, intrathecal administration results in rapid and severe symptoms, especially status epilepticus, due to antagonism at GABA-A and glycine receptors. Seizures are the most prominent feature. Intravenous exposure has also been linked to seizures and visual changes. Observational studies in cardiac surgery patients have shown a higher rate of postoperative seizures in those given TXA.

Management of Overdose

Oral overdose is usually managed with supportive care and does not require hospitalization in the absence of co-ingestants or symptoms. Intrathecal exposure requires urgent seizure control with benzodiazepines and barbiturates. Additional treatments may include magnesium, mannitol, dexamethasone, propofol, or inhaled anesthetics. CSF exchange has been reported to be helpful in some cases. Clear labeling, adherence to proper pharmacy practices, and implementation of operating room safety protocols are strongly recommended to prevent such events.[49]

Enhancing Healthcare Team Outcomes

Even though TXA only has a few approved usages, it is a well-researched drug and has many uses to help reduce blood loss. Tranexamic acid has a low adverse effect profile and is generally considered safe for administration in most instances. TXA is often a clinician-driven decision in the acute setting with hemorrhagic shock or expected MTP activation. Studies have shown that administering it within an hour of injury decreases the relative risk of death from bleeding by 32%, and if given within 1 to 3 hours after injury, by 21%. If clinical indications for administering TXA are present, it is vital to communicate with all interprofessional team members. Ensure the medical professional administering the drug knows to give it via a slow intravenous push over 10 minutes. Clinicians should consider TXA for patients with religious concerns about blood transfusions.

Thromboelastography enables the real-time assessment of fibrinolysis during surgery, facilitating the selective use of TXA. Avoiding TXA in patients with fibrinolysis shutdown helps lower the risk of thromboembolic complications. This tailored approach strikes a balance between bleeding control and patient safety.[50] Hematologists provide specialized expertise on blood clotting issues and help determine when TXA is appropriate in various medical situations. Physicians and advanced practice providers prescribe and monitor for adverse effects. Pharmacists ensure proper dosing and check for drug interactions. Nurses administer tranexamic acid, monitor patients for reactions, and promptly report any concerns. An interprofessional team approach and communication among physicians, advanced practice providers, hematologists, pharmacists, and nurses are essential for minimizing adverse effects and optimizing patient outcomes related to tranexamic acid therapy.

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Disclosure: John Chauncey declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.