What is the mechanism of action of tranexamic acid (TXA)?

Mechanism of Action of Tranexamic Acid (TXA)

Tranexamic acid is a synthetic lysine amino acid derivative that inhibits fibrinolysis by occupying the lysine receptor binding sites of plasmin for fibrin, preventing plasmin from binding to fibrin monomers, thus preserving and stabilizing the fibrin clot matrix structure. 1

Primary Mechanism

• TXA acts through reversible interactions at multiple binding sites within plasminogen 1
• Native human plasminogen contains 4-5 lysine binding sites with low affinity for TXA (Kd = 750 μmol/L) and 1 site with high affinity (Kd = 1.1 μmol/L) 1
• The high-affinity lysine site of plasminogen is involved in its binding to fibrin 1
• Saturation of this high-affinity binding site with TXA displaces plasminogen from the surface of fibrin 1
• Although plasmin may still form through conformational changes in plasminogen, the binding to and dissolution of the fibrin matrix is inhibited 1

Pharmacodynamic Effects

• TXA in concentrations of 1 mg/mL and 10 mg/mL prolongs the thrombin time 1
• An antifibrinolytic concentration of TXA remains in different tissues for about 17 hours, and in the serum for up to 7-8 hours 1
• In vitro studies have suggested that a concentration of 10 μg/mL is required to inhibit fibrinolysis 2
• TXA concentrations between 10-15 mg/L result in substantial inhibition of fibrinolysis, while concentrations between 5-10 mg/L are partially inhibitory 3
• TXA in concentrations up to 10 mg/mL has no influence on platelet count, coagulation time, or various coagulation factors in whole blood or citrated blood from healthy subjects 1

Clinical Applications Based on Mechanism

• TXA is effective in conditions with abnormal bleeding where local or systemic hyperfibrinolysis is involved 4
• The antifibrinolytic effect makes TXA useful in:
  • Trauma-related bleeding (prevents accelerated fibrinolysis) 2
  • Surgical procedures to reduce perioperative blood loss 4
  • Gynecological bleeding disorders including heavy menstrual bleeding 4
  • Upper gastrointestinal bleeding 5
  • Hereditary angioneurotic edema 4

Pharmacokinetic Considerations Affecting Mechanism

• TXA is distributed throughout all tissues with an initial volume of distribution of about 9-12 liters 1
• Plasma protein binding is minimal (about 3% at therapeutic levels) and is fully accounted for by binding to plasminogen 1
• TXA is primarily eliminated unchanged through renal excretion (>95% of the dose) 1
• The terminal elimination half-life is approximately 2 hours after intravenous administration 1
• Dose adjustment is necessary in patients with renal impairment as blood levels increase with declining renal function 1

Important Cautions Related to Mechanism

• TXA is contraindicated in disseminated intravascular coagulation (DIC) as it may worsen the condition by inhibiting the breakdown of widespread clots 6
• TXA should be used with caution in patients taking oral contraceptives due to increased thrombotic risk 6
• TXA is contraindicated in patients with active thromboembolic disease or history of thrombosis 6
• Caution is needed in patients with massive hematuria due to risk of ureteric obstruction from preserved clots 6