How Tranexamic Acid (TXA) Works
Mechanism of Action
Tranexamic acid is a synthetic lysine derivative that prevents the breakdown of blood clots by blocking plasmin's ability to bind to and dissolve fibrin. 1
Molecular Mechanism
TXA competitively occupies the lysine receptor binding sites on plasminogen and plasmin, preventing these enzymes from attaching to fibrin monomers 1
Native plasminogen contains 4-5 low-affinity lysine binding sites (Kd = 750 μmol/L) and one high-affinity binding site (Kd = 1.1 μmol/L) that TXA targets 1
The high-affinity lysine site is critical for plasminogen's binding to fibrin—when TXA saturates this site, it physically displaces plasminogen from the fibrin surface 1
Although plasmin may still form through conformational changes in plasminogen, TXA prevents it from binding to and dissolving the fibrin matrix, thereby preserving clot stability 1
Clinical Pharmacology
Antifibrinolytic concentrations of TXA remain in tissues for approximately 17 hours and in serum for 7-8 hours 1
TXA at therapeutic concentrations (up to 10 mg/mL) does not affect platelet count, coagulation time, or coagulation factors in whole blood 1
TXA prolongs thrombin time at concentrations of 1-10 mg/mL 1
Plasma protein binding is minimal (approximately 3%) and is fully accounted for by binding to plasminogen, with no albumin binding 1
Critical Considerations for Patients with Thromboembolic History or Renal Impairment
Thromboembolic Risk Profile
Despite theoretical concerns, large-scale evidence demonstrates that TXA does not increase thromboembolic risk in most clinical settings, though specific high-risk populations require caution. 2, 3
The CRASH-2 trial (>20,000 trauma patients) showed lower rates of thrombosis and myocardial infarction with TXA compared to placebo 2
A 2021 meta-analysis of 216 trials including 125,550 patients found no association between intravenous TXA and total thromboembolic events (risk difference = 0.001; 95% CI, -0.001 to 0.002; P = 0.49) 3
Importantly, no increased risk for venous thrombosis, pulmonary embolism, myocardial infarction, or cerebral infarction was found even in patients with a history of thromboembolism 3
However, a 2025 trauma registry study showed dose-dependent risk: single TXA administration had OR 1.56 for thromboembolic events, two administrations OR 1.79, and three administrations OR 1.50 4
Absolute Contraindications
Active thromboembolic disease or disseminated intravascular coagulation (DIC) are absolute contraindications per FDA labeling 5, 1
History of thrombosis or thromboembolism is an FDA contraindication 5
Spontaneous coronary artery dissection (SCAD) is a specific contraindication due to association with myocardial infarction 5
Renal Impairment: Critical Dosing Adjustments Required
TXA is 90-95% renally excreted unchanged, making dose reduction mandatory in renal impairment to avoid neurotoxicity and ocular toxicity. 1
Pharmacokinetics in Renal Dysfunction
Renal clearance equals plasma clearance (110-116 mL/min) in normal kidney function 1
Following 10 mg/kg IV dose, 24-hour urinary excretion decreases with worsening renal function: 51% with serum creatinine 1.4-2.8 mg/dL, 39% with creatinine 2.8-5.7 mg/dL, and only 19% with creatinine >5.7 mg/dL 1
Plasma concentrations show direct relationship to degree of renal impairment, with sustained elevations above therapeutic threshold for approximately 12 hours in stages 3-5 chronic kidney disease 6
Specific Dosing Recommendations for Renal Impairment
For cardiac surgery patients with chronic kidney disease, a pharmacokinetic study recommends reduced maintenance infusions: 7.5 mg/kg/h for good renal function (eGFR ≥60) versus 5 mg/kg/h for poor renal function (eGFR <60) 6
For major joint arthroplasty in chronic kidney disease, use 15 mg/kg bolus over 15 minutes followed by 5 mg/kg/h maintenance infusion for 2 hours in patients with eGFR <60 mL/min/1.73 m² 7
Even for topical use, dose adjustment may be necessary if significant systemic absorption occurs in renal insufficiency 8
Toxicity Risks in Renal Impairment
Neurotoxicity manifesting as seizures, convulsions, mental status changes, and myoclonus is the primary concern with TXA accumulation 9, 5, 1
High-dose TXA in cardiac surgery has been associated with increased postoperative seizures 2, 6
Risk of ureteric obstruction from clots exists in patients with massive hematuria, though TXA has been used successfully in polycystic kidney disease with severe hematuria when carefully monitored 10
Common Pitfalls to Avoid
Do not administer TXA more than 3 hours after trauma injury—late administration (>3 hours) increases risk of death due to bleeding (RR 1.44,1.12-1.84; P = 0.004) 2
Do not use standard dosing in renal impairment—failure to adjust doses leads to drug accumulation and neurotoxicity 1, 6, 7
Do not give repeated doses without reassessing indication—each consecutive TXA administration independently increases thromboembolic risk 4
Do not extrapolate trauma/surgical bleeding data to gastrointestinal bleeding—GI bleeding involves different mechanisms (vascular injury, portal pressure) rather than pure fibrinolysis, and evidence shows no mortality benefit with increased VTE risk in this population 9
Do not ignore the timing window in trauma—early treatment (≤1 hour) significantly reduces bleeding death (RR 0.68,0.57-0.82), while treatment between 1-3 hours shows modest benefit (RR 0.79,0.64-0.97) 2