Tranexamic Acid, a Widely Used Antifibrinolytic Agent, Causes Convulsions by a γ-Aminobutyric Acid_A Receptor Antagonistic Effect

Abstract

Application of 4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid; TAMCA) to the central nervous system (CNS) has been shown to result in hyperexcitability and convulsions. However, the mechanisms underlying this action are unknown. In the present study, we demonstrate that TAMCA binds to the ␥-aminobutyric acid (GABA) binding site of GABA A receptors in membranes from rat cerebral cortex and does not interfere with N-methyl-D-aspartate receptors. Patch-clamp studies using human embryonic kidney cells transiently transfected with recombinant GABA A receptors composed of ␣1␤2␥2 subunits showed that TAMCA did not activate these receptors but dose dependently blocked GABA-induced chloride ion flux with an IC 50 of 7.1 Ϯ 3.1 mM. Application of TAMCA to the lumbar spinal cord of rats resulted in dose-dependent hyperexcitability, which was completely blocked by coapplication of the GABA A receptor agonist muscimol. These results indicate that TAMCA may induce hyperexcitability by blocking GABA-driven inhibition of the CNS.

Refractory status epilepticus after inadvertent intrathecal injection of tranexamic acid treated by magnesium sulfate

“…13 The proposed mechanisms for the cardiac and neurologic manifestations include central sympathetic discharge, GABA A inhibition, and direct cerebral ischemia. [6][7][8][9][10][11]14 In a report similar to ours, a patient was inadvertently given 500 mg intrathecal tranexamic acid and developed convulsions followed by a pulseless electrical activity arrest treated with diazepam, multiple defibrillation attempts, epinephrine, and amiodarone. 6 Her seizures were successfully terminated with diazepam; however, she developed refractory ventricular fibrillation, cardiac collapse and died.…”

“…This has been echoed by other authors. 8,14 A third hypothesis is that tranexamic acid causes seizures through direct cerebral hypoperfusion. Mahmoud and Ammar described tranexamic acid 300 mg given accidentally as a spinal dose for lower extremity skin grafting.…”

Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors

“…13 Tranexamic acid binds competitively, in a dose-dependent fashion, to c-aminobutyric acid (GABA) type A receptors, which results in reduced inhibitory activity and increased neuronal excitation. 14 There are reports of TA causing seizures when in direct contact with the central nervous system in animals 15,16 and humans. 17,18 It is therefore mechanistically plausible that TA is associated with seizures after cardiac surgery.…”

Postoperative seizure in a neurosurgical patient: Should tranexamic acid be on the differential?

“…1 Potential mechanisms include direct inhibition of glycine and gamma-aminobutyric acid A (GABAa) receptors as well as direct central nervous system toxicity. 2,3 A recent study showed that TXA inhibits glycine receptors to a greater extent than GABAa receptors and that this effect is attenuated by isoflurane and propofol in vitro. 2 Although these data suggest that propofol and isoflurane may prevent or treat TXA-associated seizures, the optimal management of antiepileptic drugs for TXAassociated seizures in the clinical setting is unclear.…”