Tranexamic acid
Tranexamic acid is a synthetic derivative of the amino acid lysine that functions as an antifibrinolytic agent by competitively inhibiting the activation of plasminogen to plasmin, thereby stabilizing fibrin clots and reducing excessive bleeding.[1] Mechanism of ActionIt works by binding to lysine receptor sites on plasminogen, preventing the enzyme from interacting with and degrading fibrin in blood clots, which helps control hemorrhage without promoting new clot formation.[1] This action also reduces fibrinolysis in various clinical scenarios, such as trauma or surgery, and has been utilized for decades as a hemostatic therapy.[2] Clinical Uses
Tranexamic acid is FDA-approved for treating heavy menstrual bleeding in women and for short-term prophylaxis in hemophilia patients undergoing dental procedures, where it significantly decreases blood loss.[3] Off-label applications are extensive, including reducing mortality from postpartum hemorrhage (as shown in the WOMAN trial, where a 1 g intravenous dose lowered death rates from bleeding), managing traumatic bleeding (per the CRASH-2 trial, which demonstrated improved survival when administered within three hours of injury), and minimizing blood loss in surgical settings like orthopedic and cardiothoracic procedures.[4][5][6] It is also employed for conditions such as epistaxis, hemoptysis, and gastrointestinal bleeding, supported by evidence from randomized controlled trials indicating reduced transfusion requirements.[4] Administration and Safety
Available in oral tablets (typically 650 mg, dosed at 1,300 mg three times daily for up to five days during menstruation), intravenous formulations (e.g., 1 g loading dose), and topical preparations, its use requires caution in patients with a history of thromboembolism, renal impairment, or color vision defects due to risks of seizures, visual disturbances, and thrombotic events.[1][3] Common side effects include nausea, headache, and joint pain, while serious reactions like allergic responses or chest pain necessitate immediate medical attention.[3] Guidelines from organizations like the American College of Obstetricians and Gynecologists endorse its role in obstetric hemorrhage management.[1]
Pharmacology
Mechanism of action
Tranexamic acid is a synthetic analog of the amino acid lysine that functions as an antifibrinolytic agent by competitively and reversibly inhibiting the activation of plasminogen to plasmin.[1][7] This inhibition occurs through its binding to specific lysine receptor sites on plasminogen molecules, typically four to five low-affinity sites and one high-affinity site, which prevents plasminogen from interacting with fibrin and undergoing conversion to the proteolytic enzyme plasmin.[7][4] By blocking this activation, tranexamic acid stabilizes the fibrin clot structure and reduces the breakdown of blood clots, thereby decreasing excessive bleeding without promoting new clot formation or affecting platelet aggregation.[1][8] At higher concentrations, it can also directly inhibit plasmin activity, further enhancing its antifibrinolytic effects.[7] Tranexamic acid is approximately 6 to 10 times more potent than ε-aminocaproic acid in binding to plasminogen and plasmin due to its stronger affinity for these sites.[4][8] This mechanism is particularly relevant in conditions involving hyperfibrinolysis, such as trauma or surgical bleeding, where it helps preserve clot integrity by limiting plasmin-mediated fibrinolysis.[1] In non-hemostatic contexts, such as hereditary angioedema, it indirectly reduces complement activation by decreasing the consumption of C1 esterase inhibitor through stabilized fibrin matrices.[1]Pharmacokinetics
Tranexamic acid is rapidly absorbed following oral administration, with peak plasma concentrations (Cmax) achieved approximately 3 hours after a 1300 mg dose.[9] The absolute oral bioavailability is approximately 45% in women of reproductive age, though earlier studies reported values around 34% based on urinary excretion comparisons between oral and intravenous routes.[9][10] Food intake modestly increases both Cmax and area under the curve (AUC) by about 7% and 16%, respectively, without significantly altering the time to peak concentration.[9] Steady-state plasma concentrations are reached after the fifth dose in multiple dosing regimens, such as 1300 mg three times daily.[1] The drug exhibits a volume of distribution of 9 to 12 L following intravenous administration, indicating moderate tissue penetration.[1] Tranexamic acid binds minimally to plasma proteins (about 3%), primarily to plasminogen, and shows no significant affinity for albumin.[9] It readily crosses the placenta, with cord blood concentrations around 30 mg/L after maternal intravenous dosing, and achieves concentrations in cerebrospinal fluid and aqueous humor that are approximately one-tenth of plasma levels.[9] Metabolism of tranexamic acid is limited, with only about 5% of the dose undergoing biotransformation.[1] Elimination occurs primarily through renal excretion via glomerular filtration, with over 95% of the administered dose recovered unchanged in the urine.[11] Approximately 90% is excreted within 24 hours after a 10 mg/kg intravenous dose.[9] The elimination half-life is approximately 2 hours following intravenous administration and around 11 hours for the terminal phase after oral dosing, reflecting its biphasic elimination profile.[1] Plasma clearance ranges from 110 to 116 mL/min, with urinary recovery exceeding 95% within 8 hours of intravenous administration.[10]Uses
Medical uses
Tranexamic acid (TXA) is an antifibrinolytic medication primarily employed to control or prevent excessive bleeding in conditions characterized by hyperfibrinolysis. It inhibits the activation of plasminogen to plasmin, thereby stabilizing blood clots and reducing hemorrhage.[1] The drug is available in oral, intravenous, and topical formulations, with dosing tailored to the indication and route of administration.[7] The U.S. Food and Drug Administration (FDA) has approved TXA for two specific indications. Orally, it is indicated for the treatment of cyclic heavy menstrual bleeding in women of reproductive potential, where it significantly reduces blood loss and improves quality of life compared to placebo, as demonstrated in randomized controlled trials.[12] Intravenously, it is approved for short-term use (2 to 8 days) in patients with hemophilia A or B to reduce or prevent hemorrhage during and following tooth extraction, often in combination with factor replacement therapy; evidence from Cochrane reviews supports its efficacy in minimizing bleeding in this setting.[13] Off-label uses of TXA are extensive and supported by high-quality evidence from large-scale trials. In trauma patients with significant bleeding, early intravenous administration (within 3 hours of injury) reduces all-cause mortality and deaths due to bleeding, as shown in the CRASH-2 trial involving over 20,000 participants (relative risk for death 0.91).[14] For postpartum hemorrhage, TXA decreases bleeding-related mortality when given promptly, with the WOMAN trial (over 20,000 women) reporting a relative risk of 0.81 for death due to bleeding.[15] In elective surgeries, including orthopedic procedures like total knee arthroplasty, cardiac operations, and gynecological interventions, TXA reduces perioperative blood loss and the need for transfusions; meta-analyses confirm these benefits across various surgical contexts.[16] It is also used in neurosurgery, spinal surgery, and prostatectomy to minimize intraoperative bleeding.[17] Additional off-label applications include traumatic brain injury, where the CRASH-3 trial (9,202 patients) demonstrated a modest reduction in head injury-related deaths in those with mild to moderate severity (relative risk 0.89), though overall mortality benefit was not significant.[18] TXA is recommended by the World Health Organization as an essential medicine for trauma, postpartum hemorrhage, and high-risk surgical bleeding, but it is not advised for gastrointestinal or spontaneous intracranial bleeding due to lack of benefit and potential risks in those scenarios.[19] Topical TXA has shown utility in managing traumatic hyphema and epistaxis, reducing rebleeding rates based on systematic reviews.[1]Cosmetic uses
Tranexamic acid (TXA) is widely employed in cosmetic dermatology for addressing hyperpigmentation disorders, particularly melasma, due to its anti-melanogenic and anti-inflammatory properties.[20] In topical formulations, TXA inhibits the plasminogen/plasmin pathway, which reduces the activation of melanocytes and suppresses vascular endothelial growth factor (VEGF), thereby diminishing melanin production and pigmentation intensity.[21] Common cosmetic products include serums, creams, and lotions with concentrations ranging from 2% to 5%, often applied once or twice daily to affected areas.[22] Clinical evidence supports the efficacy of topical TXA for cosmetic skin lightening. A randomized trial demonstrated that a 2% TXA lotion significantly reduced melasma area and severity index (MASI) scores after 12 weeks of use compared to placebo, with improvements maintained post-treatment.[23] Similarly, 5% TXA cream alone improved facial melasma in patients over 12 weeks, showing statistical significance in pigmentation reduction.[22] For post-inflammatory hyperpigmentation (PIH) associated with acne, a 10% TXA serum decreased inflammatory lesions and PIH after 8 weeks, outperforming vehicle controls.[24] Beyond melasma and PIH, topical TXA is used cosmetically for telangiectasias and rosacea-related redness, where it exhibits anti-angiogenic effects to fade visible blood vessels.[21] Combinations with procedures like microneedling enhance penetration and outcomes; for instance, 10% TXA applied via microneedling improved melasma scores more effectively than standalone topical application.[25] Overall, topical TXA is well-tolerated in cosmetic settings, with adverse effects limited to transient mild irritation in less than 5% of users across studies.[26]Contraindications and interactions
Contraindications
Tranexamic acid is contraindicated in patients with active thromboembolic disease, such as deep vein thrombosis or pulmonary embolism, due to its antifibrinolytic action that may exacerbate clotting risks.[12][1] It is also contraindicated in individuals with a history of arterial or venous thromboembolism, including retinal vein or artery occlusion, as this increases the potential for recurrent thrombotic events.[12][13] Hypersensitivity to tranexamic acid or its components represents an absolute contraindication, as it can lead to severe allergic reactions including anaphylaxis.[13][12] For the intravenous formulation, administration via neuraxial routes (intrathecal, epidural, intraventricular, or intracerebral) is strictly contraindicated due to risks of serious adverse reactions such as seizures or cerebral infarction; as of 2025, the FDA has issued alerts on medication errors leading to inadvertent intrathecal administration, resulting in life-threatening events like cardiac arrhythmias and paraplegia.[13][27][28] Additionally, use is prohibited in cases of subarachnoid hemorrhage, where it may cause cerebral edema and infarction.[13][1] In patients with hemophilia, particularly those with hemophilia B receiving prothrombin complex concentrates, tranexamic acid is contraindicated owing to heightened risk of thromboembolism.[1] For the oral formulation used in treating heavy menstrual bleeding, it is contraindicated in females of reproductive potential using combined hormonal contraceptives, those with intrinsic risks of thrombosis (e.g., thrombogenic valvular or cardiac rhythm diseases).[12] Active intravascular clotting conditions further prohibit its use to avoid promoting further thrombotic complications.[13]Drug interactions
Tranexamic acid, an antifibrinolytic agent, primarily interacts with medications that affect hemostasis, coagulation, or fibrinolysis, potentially increasing the risk of thrombotic events or altering therapeutic efficacy.[12] These interactions are particularly relevant in patients with underlying hypercoagulable states or those receiving therapies for bleeding disorders.[1] Concomitant use with prothrombotic agents is generally avoided to minimize the risk of thromboembolism, such as deep vein thrombosis or pulmonary embolism.[13] A major contraindication involves combined hormonal contraceptives, including those containing estrogen and progestin (e.g., ethinyl estradiol with levonorgestrel), which heighten the thrombotic risk when used with tranexamic acid due to its antifibrinolytic properties exacerbating estrogen-induced coagulability.[12] This combination is explicitly contraindicated, especially in women over 35, smokers, or those with obesity, as it may lead to serious cardiovascular events.[29] Tranexamic acid antagonizes the effects of fibrinolytic agents like tissue plasminogen activators (tPAs), such as alteplase, by inhibiting plasmin formation and clot breakdown, thereby reducing the efficacy of thrombolytic therapy in acute settings like stroke or myocardial infarction.[12] If tPA administration is urgently required, tranexamic acid should be discontinued immediately to restore fibrinolytic activity.[1] Co-administration with coagulation factor concentrates, including Factor IX complex concentrates or anti-inhibitor coagulant concentrates, is not recommended as it can potentiate thrombogenic effects, increasing the likelihood of disseminated intravascular coagulation or other clotting complications in hemophilia patients.[12] Similarly, use with other antifibrinolytics like aminocaproic acid may amplify hemostatic effects, though clinical data on this specific pairing is limited.[1] In patients with acute promyelocytic leukemia undergoing induction therapy, tranexamic acid should not be combined with all-trans retinoic acid (oral tretinoin), as this may worsen procoagulant states and differentiation syndrome, leading to heightened bleeding or thrombotic risks.[12] Monitoring for signs of thrombosis is essential with any concurrent hemostatic therapy, and dose adjustments may be needed in renal impairment due to prolonged drug exposure.[29]Adverse effects
Common adverse effects
The most frequently reported adverse effects of tranexamic acid are mild to moderate and often resolve with continued use or dose adjustment, primarily affecting the gastrointestinal and musculoskeletal systems.[12] In clinical trials for oral tranexamic acid (LYSTEDA) used in heavy menstrual bleeding, involving 232 patients at 3900 mg/day, headache occurred in 50.4% of treated subjects (versus 46.8% placebo), nasal and sinus symptoms in 25.4% (versus 17.3%), back pain in 20.7% (versus 15.1%), and abdominal pain in 19.8% (versus 18.0%).[12] Musculoskeletal complaints, including pain (11.2%), arthralgia (6.9%), and muscle cramps or spasms (6.5%), were also common, alongside fatigue (5.2%).[12] Gastrointestinal disturbances represent another prevalent category, with nausea, vomiting, and diarrhea noted across multiple formulations and indications. For intravenous tranexamic acid (CYKLOKAPRON), postmarketing reports highlight nausea, vomiting, and diarrhea as the most common effects, often manageable by slowing infusion rates.[13] Oral administration similarly associates these symptoms with use, though their incidence is not precisely quantified in some datasets; they may occur alongside abdominal discomfort or tenderness.[30] Additional common effects include giddiness or dizziness and allergic dermatitis, particularly with parenteral routes.[13] In broader clinical contexts, such as surgical or dermatologic applications, headache, fatigue, and upper respiratory symptoms like stuffy or runny nose are frequently observed, with muscle stiffness, joint pain, or chills also reported.[1] These effects are generally dose-dependent and self-limiting, but monitoring is advised, especially in outpatient settings.[30]| Adverse Effect | Formulation/Indication | Incidence (if reported) | Source |
|---|---|---|---|
| Headache | Oral (menstrual bleeding) | 50.4% | FDA LYSTEDA label[12] |
| Nausea/Vomiting/Diarrhea | IV (general) | Common (not quantified) | FDA CYKLOKAPRON label[13] |
| Back Pain | Oral (menstrual bleeding) | 20.7% | FDA LYSTEDA label[12] |
| Abdominal Pain | Oral (menstrual bleeding) | 19.8% | FDA LYSTEDA label[12] |
| Fatigue | General | Common (not quantified) | StatPearls NCBI[1] |