Tranexamic Acid Impairs γ-Aminobutyric Acid Receptor Type A–mediated Synaptic Transmission in the Murine Amygdala

Kratzer, Stephan; Irl, H.; Mattusch, Corinna; Bürge, Martina; Kurz, Jörg; Kochs, Eberhard; Eder, Matthias; Rammes, Gerhard; Haseneder, Rainer

doi:10.1097/aln.0000000000000103

Cited by 57 publications

(43 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TXA also increased the frequency of spontaneous epileptiform field potentials or “seizurelike events” (see Fig 1B) 47. Another study showed that application of TXA (1mM) to mouse amygdala slices caused widespread neuronal depolarization 49. Collectively, these studies show that TXA directly increases the excitability of neuronal networks.…”

Section: Molecular Mechanism Of Txa‐associated Seizuresmentioning

confidence: 77%

“…Synaptic and tonic currents are mediated by different receptor subtypes that often exhibit different pharmacological properties 60. Surprisingly, the potency of TXA for synaptic currents (IC 50 = 0.8mM) and tonic inhibitory currents (IC 50 = 1mM) was similar 47, 49. Thus, although inhibition of GABA A receptors may contribute to TXA‐associated seizures, higher affinity target receptors are likely to exist in the CNS.…”

Section: Molecular Mechanism Of Txa‐associated Seizuresmentioning

confidence: 99%

See 1 more Smart Citation

Tranexamic acid–associated seizures: Causes and treatment

Lecker

Wang

Whissell

et al. 2015

Annals of Neurology

208

158

View full text Add to dashboard Cite

Antifibrinolytic drugs are routinely used worldwide to reduce the bleeding that results from a wide range of hemorrhagic conditions. The most commonly used antifibrinolytic drug, tranexamic acid, is associated with an increased incidence of postoperative seizures. The reported increase in the frequency of seizures is alarming, as these events are associated with adverse neurological outcomes, longer hospital stays, and increased in‐hospital mortality. However, many clinicians are unaware that tranexamic acid causes seizures. The goal of this review is to summarize the incidence, risk factors, and clinical features of these seizures. This review also highlights several clinical and preclinical studies that offer mechanistic insights into the potential causes of and treatments for tranexamic acid–associated seizures. This review will aid the medical community by increasing awareness about tranexamic acid–associated seizures and by translating scientific findings into therapeutic interventions for patients. ANN NEUROL 2016;79:18–26

show abstract

Section: Molecular Mechanism Of Txa‐associated Seizuresmentioning

confidence: 77%

Section: Molecular Mechanism Of Txa‐associated Seizuresmentioning

confidence: 99%

Tranexamic acid–associated seizures: Causes and treatment

Lecker

Wang

Whissell

et al. 2015

Annals of Neurology

208

158

View full text Add to dashboard Cite

show abstract

“…TXA is perceived to be an antifibrinolytic agent, but is known to interact with multiple receptors [17]. TXA has recently been suggested to improve platelet function in patients on dual antiplatelet therapy [18], but the mechanism remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Shock releases bile acidinducing platelet inhibition and fibrinolysis

Wiener

Moore

et al. 2015

Journal of Surgical Research

View full text Add to dashboard Cite

Introduction Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis. Methods TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM to 750 μM was utilized due to biologic relevance. Whole blood mixtures were assayed using thrombelastography (TEG) for clot strength (MA) and fibrinolysis (LY30) quantification. Tranexamic acid (TXA) was used to block plasmin mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model. Results Fibrinolysis increased, when 750 μM TUCA was added to whole blood (median LY30 0.08 to 5.7, p=0.010), and clot strength decreased (median MA of 53.3 to 43.8, p=0.010). The addition of TXA, to a 750 μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 vs. with 2.7) and the decrease in clot strength (MA: without 48.2 vs. with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100 μM TUCA. Rats had a median 52-fold increase in TUCA, following a shock state that stayed elevated following resuscitation. Conclusion TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding.

show abstract

“…Although the underlying mechanisms are not fully elucidated, two studies have suggested possible mechanisms. Kratzer et al suggested that TXA enhances neuronal excitation by antagonizing inhibitory γ‐aminobutyric acid (GABA) neurotransmission. Lecker et al showed that TXA inhibits neural glycine receptors, whereas inhibition of the inhibiting neurotransmitter glycine is an established cause of seizures.…”

Section: Main Articlementioning

confidence: 99%

Use of antifibrinolytics in pediatric cardiac surgery: Where are we now?

Faraoni

Rahe

CyBulski

2018

Pediatric Anesthesia

View full text Add to dashboard Cite

Summary Fibrinolytic activation is a major and preventable source of bleeding in neonates and children undergoing cardiac surgery with cardiopulmonary bypass. Based on the existing literature (adult and pediatric; cardiac and noncardiac), prophylactic administration of antifibrinolytic agents can help reduce fibrinolytic activation, and consequently reduces perioperative bleeding and the requirement for blood product transfusion. Due to the increased risk of renal failure and mortality reported in adults undergoing cardiac surgery, aprotinin should not be considered as a safe option in neonates and children. Further well‐designed studies would be required before the prophylactic administration of aprotinin could be considered in pediatric cardiac surgery. The lysine analogs, tranexamic acid and ϵ‐aminocaproic acid,, should be considered as safe and effective antifibrinolytic agents. Although no major side effects have been reported following the administration of lysine analogs in children undergoing cardiac surgery, high‐dose tranexamic acid should not be recommended in order to avoid the increased risk of clinical seizures. Despite the recent advances made in our understanding of the pharmacokinetics of tranexamic acid and ϵ‐aminocaproic acid,, the optimal plasmatic concentration to be targeted remains unknown. Further studies are therefore urgently needed to better define the optimal dose regimen to be used in neonates and children. In the meantime, the dose regimen published in the most recent pharmacokinetic studies can be used. Although no studies have assessed the effect of massive bleeding and transfusion on the plasmatic concentrations of the lysine analogs, additional boluses might be considered in the presence of bleeding and/or when signs of fibrinolytic activations are observed on viscoelastic hemostatic assays.

show abstract

Tranexamic Acid Impairs γ-Aminobutyric Acid Receptor Type A–mediated Synaptic Transmission in the Murine Amygdala

Cited by 57 publications

References 37 publications

Tranexamic acid–associated seizures: Causes and treatment

Tranexamic acid–associated seizures: Causes and treatment

Shock releases bile acidinducing platelet inhibition and fibrinolysis

Use of antifibrinolytics in pediatric cardiac surgery: Where are we now?

Contact Info

Product

Resources

About