Myoclonus associated with tranexamic acid administration in a patient on veno-arterial extracorporeal membrane oxygenation support: A case report

Abstract

BACKGROUND

Tranexamic acid (TXA) is widely used as an antifibrinolytic agent to reduce bleeding in cardiac and extracorporeal circulation settings. Neurological adverse effects, including seizures and myoclonus, are rare and not well documented in patients supported by extracorporeal membrane oxygenation (ECMO).

CASE SUMMARY

We report the case of a 52-year-old male with ST-elevation myocardial infarction and severe left ventricular dysfunction, who was transferred to our intensive care unit department under veno-arterial (VA)-ECMO support and continuous renal replacement therapy (CRRT). To maintain ECMO oxygenator function and due to decreasing fibrinogen levels, endovenous one gram TXA twice a day was administered and within hours after the second dose, the patient developed generalized myoclonic jerks. A non-contrast brain computed tomography revealed no acute or chronic abnormalities, and neurological evaluation attributed the findings to TXA as the most likely cause due to TXA overdose. Following discontinuation of TXA, the symptoms resolved within 48 hours.

CONCLUSION

This case highlights a rare neurological complication associated with TXA overdose, occurring in patient with VA-ECMO and CRRT. Clinicians should remain vigilant for such adverse effects in this context.

Key Words: Tranexamic acid; Extracorporeal membrane oxygenation; Myoclonic jerks; Continuous renal replacement therapy; Overdose; Case report

Core Tip: This article describes the first known case of tranexamic acid (TXA)-induced myoclonus in a patient receiving veno-arterial extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy. TXA accumulation due to impaired renal clearance led to neurotoxicity, which resolved after drug discontinuation. The case underscores the need for individualized TXA dosing and vigilant neurological monitoring in ECMO patients with renal dysfunction, given the absence of standardized dosing protocols and the delicate hemostatic balance in this setting.

INTRODUCTION

Tranexamic acid (TXA) is an antifibrinolytic agent frequently used to mitigate perioperative bleeding in cardiac surgery and during extracorporeal life support[1]. While generally well tolerated, TXA has been associated with central nervous system adverse events, including seizures and myoclonus. Its strong association with neurological adverse events, particularly seizures, has not received the proper attention in drug labelling[2]. The pathophysiology of TXA-induced neurotoxicity remains unclear but may involve gamma-aminobutyric acid type A (GABA-A) and glycine receptor antagonism[3]. Data from extensive retrospective cohorts have established a definitive dose-response correlation between the administration of TXA and the likelihood of postoperative seizures following cardiac surgery, especially with elevated dosing regimens (≥ 100 mg/kg). These findings highlight the imperative to reevaluate current dosing strategies and carefully consider the haemostatic benefits of TXA in relation to its potential neurological risks[4]. Ηowever, neurological side effects are rarely reported in patients supported with extracorporeal membrane oxygenation (ECMO), and to our knowledge, no previous cases of TXA-induced myoclonus in this population have been described so far.

CASE PRESENTATION

Chief complaints

A 52-year-old male was transferred to the intensive care unit (ICU) of our tertiary care hospital due to ST-elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS) and severe left ventricular (LV) systolic dysfunction. Three hours after symptom onset, he arrived at the first hospital and was promptly referred to the catheterisation laboratory for coronary angiography. Initial coronary angiography revealed complete occlusion (100%) of both the left anterior descending (LAD) and right coronary artery. He underwent primary percutaneous coronary intervention of the LAD artery. However, his clinical course was complicated by refractory CS. An intra-aortic balloon pump was subsequently inserted, but the patient showed no clinical improvement.

History of present illness

Following multidisciplinary consultation, he was transferred from the referring tertiary hospital to our centre for veno-arterial ECMO (VA-ECMO) implantation. At the time of admission, he was on inotropic and vasopressor support with continuous intravenous infusion of dobutamine (4 μg/kg/minute), norepinephrine (0.2 μg/kg/minute) and vasopressin (2 mL/hour). At that time, his blood pressure was 87/63 mmHg, urine output was approximately 70 mL/hour, and he was neurologically intact, alert, and fully oriented (Glasgow Coma Scale 15/15). Prior to admission to our department, and in line with our institutional protocol, the patient underwent a whole-body computed tomography (CT) scan, which did not reveal any significant abnormalities or evidence of systemic pathology. Transthoracic echocardiography depicted severely reduced LV ejection fraction (15%-20%) with spherical remodelling and apical aneurysm. The left ventricular outflow tract velocity-time integral measured 10 cm/second, while moderate mitral regurgitation was present. The right ventricle was not dilated and had preserved systolic function (s’ 13 cm/second). Additional findings included mild tricuspid regurgitation, a small pericardial effusion, an inferior vena cava diameter of 23 mm, and a small pleural effusion with atelectasis. Continuous intravenous infusion of unfractionated heparin (UFH) was initiated, and due to the gradual onset of oliguria, continuous renal replacement therapy (CRRT) was started. On the 7^th day post ECMO implantation, the patient was diagnosed with heparin-induced thrombocytopenia due to progressive thrombocytopenia (platelet count = 65 × 10⁹/L, more than a 50% drop of the baseline value). UFH was discontinued, and anticoagulation was switched to intravenous argatroban. During his clinical course, the patient had a progressive clinical improvement and remained awake and extubated without respiratory support under VA-ECMO and CRRT. However, a progressive decline of ECMO oxygenator function was observed after the 8^th day post-ECMO implantation, expressed by increased ECMO oxygenator transmembrane pressures. Thrombus accumulation was noted in the oxygenator, while antithrombin III (AT-III) levels were within normal limits. Laboratory evaluation also revealed markedly elevated d-dimers (> 35000 ng/mL), while fibrinogen levels showed a progressive decline to 174 mg/dL. The international normalised ratio was 1.12, the activated partial thromboplastin time was 38 seconds, and the platelet count measured 140 × 10⁹/L. To preserve and prolong ECMO oxygenator function intravenous TXA was administered at a dose of 1 g twice daily in an attempt to preserve ECMO oxygenator function.

History of past illness

The patient had a recent coronavirus disease 2019 infection, diagnosed 15 days before admission.

Personal and family history

The patient had a history of active smoking. His body weight was 70 kg, while his height was 175 cm. No allergies were reported.

Physical examination

Twenty-four hours later, the patient developed generalised myoclonic movements without losing consciousness. The patient was tachycardic (heart rate = 120 bpm), slightly confused, and mildly tachypneic (respiratory rate = 22/minute).

Laboratory examinations

Blood urea nitrogen and creatinine levels were within the target range, while no electrolyte disturbances were noted. The patient’s arterial blood gas profile was satisfactory, with adequate gas exchange.

Imaging examinations

A CT scan of the brain with endovenous contrast showed no acute pathology.

MULTIDISCIPLINARY EXPERT CONSULTATION

Neurological consultation confirmed the diagnosis of myoclonus, while diagnoses like cerebral ischaemia, metabolic and hypoxic encephalopathy, and serotonin syndrome were excluded.

FINAL DIAGNOSIS

In the context of impaired renal function and CRRT, TXA-induced neurotoxicity was considered the most likely aetiology, given the erroneous supratherapeutic dose administered[5]. A cumulative TXA dose of 3 g (three dosages of 1 g each) was administered to the patient.

TREATMENT

The discontinuation of TXA induced the complete resolution of the myoclonic activity, as observed within the next 48 hours.

OUTCOME AND FOLLOW-UP

The patient remained on VA-ECMO support for approximately 23 days, after which successful decannulation was achieved and he was subsequently taken to the operating room for implantation of a durable LV assist device (LVAD). He had thereafter a progressive clinical improvement and an uneventful ICU and hospital discharge. The patient undergoes regular assessments with close follow-up. The LVAD is functioning well, supporting satisfactory daily activity and quality of life. To date, no adverse events have been observed (Table 1).

Table 1 Clinical timeline and key events.

Time course	Clinical status/findings	Interventions
Day 0	STEMI complicated by cardiogenic shock; LVEF 15%-20%; LAD and RCA 100% occlusion	Primary PCI to LAD; inotropes and vasopressors; IABP insertion
Day 1	Hemodynamic instability despite maximal medical therapy	Transfer to tertiary center; VA-ECMO implantation; UFH anticoagulation
Day 7	Progressive thrombocytopenia (> 50% drop)	Diagnosis of HIT; UFH discontinued; switch to argatroban
Day 8	Rising ECMO oxygenator transmembrane pressures; thrombus formation; elevated D-dimers (> 35000 ng/mL); declining fibrinogen	Intravenous tranexamic acid 1 g twice daily
Day 9	Generalized myoclonic movements; mild confusion; normal brain CT and metabolic profile	Neurological consultation; exclusion of alternative causes/suspected TXA-induced neurotoxicity
Days 9-10	Cumulative TXA dose 3 g in setting of CRRT	Discontinuation of TXA- complete resolution of myoclonus within 48 h
Day 23	Time for VA-ECMO decannulation	Durable LVAD implantation
Follow-up	Stable clinical status; good LVAD function; good quality of life	Regular outpatient follow-up

STEMI: ST-elevation myocardial infarction; LAD: Left anterior descending; VA-ECMO: Veno-arterial extracorporeal membrane oxygenation; UFH: Unfractionated heparin; ECMO: Extracorporeal membrane oxygenation; CT: Computed tomography; TXA: Tranexamic acid; CRRT: Continuous renal replacement therapy; LVAD: Left ventricular assist device; LVEF: Left ventricular ejection fraction; RCA: Right coronary artery; PCI: Percutaneous coronary intervention; IABP: Intra-aortic balloon pump; HIT: Heparin-induced thrombocytopenia.

DISCUSSION

In this case report, we present a critically ill patient with extensive anterior STEMI complicated by refractory CS, requiring prolonged VA-ECMO support as a bridge to durable LVAD implantation that presented generalized myoclonic spasms after TXA administration overdose. This case illustrates the complex haemostatic disturbances observed in patients receiving ECMO support and underscores the clinical challenges in their management. During the course of ECMO therapy, the patient developed laboratory evidence of hiberfibrinolysis associated with thrombus formation within the oxygenator. Achieving an optimal haemostatic balance in patients supported with ECMO remains a major challenge, as little is known regarding the daily practice of correcting coagulopathy in this setting[6]. Most available data are derived either from paediatric populations or from bleeding adult ECMO patients, while evidence on the management of non-bleeding adults is scarce.

Fibrinolysis plays an essential role in maintaining vascular patency by regulating haemostasis to both limit clot formation and mediate clot resolution. Dysregulation of this system may lead to either bleeding or thrombosis. Thrombin generation and several other situations, such as hypoxia, trauma or sepsis, trigger the release of tissue-plasminogen activator (t-PA) which activates plasminogen to plasmin, leading to fibrin degradation. In ECMO patients, an initial decrease in t-PA and plasminogen activator inhibitors levels is observed, followed by a respective increase of both. Increased fibrinolytic activity has been correlated with haemorrhagic events, with plasma markers rising before the onset of severe bleeding[7]. Hyperfibrinolysis and hypofibrinogenaemia have been observed in patients on extracorporeal circulation, while the administration of antifibrinolytic agents might reduce the subsequent haemorrhagic complications[8]. Moreover, hypofibrinogenaemia and increased levels of fibrin degradation products in ECMO patients might be indicative of oxygenator-induced hyperfibrinolysis, requiring circuit exchange[7]. Thrombotic events-including circuit clotting, deep vein thrombosis, and ischaemic stroke-underscore the fragile equilibrium between haemorrhage and thrombosis, necessitating meticulous anticoagulation management[9].

The decision of administering antifibrinolytics remains complex, as diagnostic and therapeutic approaches for fibrinolytic dysfunction during ECMO are limited. Antifibrinolytic therapy, especially using lysine analogues like TXA, has been employed to mitigate hyperfibrinolysis and its related consequences, such as haemorrhage[7]. Nevertheless, its safety remains uncertain in this context. Retrospective studies have demonstrated that patients who experienced thrombotic complications on VA-ECMO were more likely to have received TXA than those without thrombosis, suggesting a potential association of concern. However, the available evidence is inconclusive, as a small study did not demonstrate an increased risk of intracardiac thrombus with TXA, in contrast to aprotinin[9]. Moreover, evidence from previous studies suggests that TXA can significantly decrease bleeding complications and transfusion requirements without a corresponding increase in thrombotic risk, while certain procoagulant agents have been associated with an increased risk of thrombosis and major adverse cardiovascular events[10].

Seizures are a somewhat common consequence of TXA, especially at elevated doses or in patients having heart surgery[10]. However, myoclonic movements are recorded less commonly. It is known that TXA crosses the blood-brain barrier and may exert proconvulsant effects by inhibiting GABA-A and glycine receptors[11]. In this case, we underscore a rare but clinically significant adverse effect of TXA-generalised myoclonus-in the context of ECMO support. The differential diagnosis included metabolic encephalopathy, cerebral ischaemia, and hypoxic brain injury. However, the normal CT scan, the temporal correlation with TXA administration, and the alleviation of symptoms after drug cessation corroborated the diagnosis. Furthermore, this adverse event was precipitated by excessive TXA dosing without adjustment for renal impairment and continuous venovenous haemodialysis (CVVHD). The dosing for CVVHD is based on an estimated glomerular filtration rate of 10-20 mL/minute, with an intravenous dose of 10 mg/kg every 24 hours. The recommended dose is 700 mg daily based on the patient’s weight. The dose administered to the patient was aligned with the conventional protocol typically employed for persons with haemorrhagic complications, but with normal renal function. A greater dose was unintentionally administered without consideration of the patient's impaired renal function[5]. Adjustment of the dose based on renal function may have averted the onset of myoclonus in this case. Clinicians must consistently adjust medicine dosages based on renal function, especially during urgent clinical scenarios, to prevent further difficulties and toxicities in critically ill patients[12].

One of the main predisposing factors for the induction of neurotoxicity following TXA administration is pre-existing structural brain injury or encephalopathy. In a recent case series with 47 ECMO-supported adult patients who received TXA via different routes (topical, nebulised, endobronchial or systemic), only 3 patients developed myoclonic jerks. However, 2 of them had significant pre-existing cerebral damage, such as intracranial bleeding and hypoxia-ischaemic injury. Importantly, none of them had received TXA intravenously, while mortality rates were very high. In addition, no protocols were described about the route, the rate, or the dosing of TXA administration in patients on CRRT[13].

Regarding the administration of TXA to patients undergoing CRRT or suffering from acute kidney injury, there is no established protocol. Even at cumulative doses exceeding 80-100 mg/kg, high-dose TXA regimens have shown acceptable safety profiles in cardiac surgery populations. In addition, a recent meta-analysis showed that TXA administered either as up to two doses of 30 mg/kg or as a single bolus of 30 mg/kg followed by an infusion not exceeding 16 mg/kg/hour effectively reduces postoperative bleeding and the need for reoperation, without increasing the risk of adverse events[14]. However, these results are not directly applicable to ECMO patients with impaired renal clearance. A recent systematic review and meta-analysis comparing high- vs low-dose TXA infusion in cardiac surgery patients confirmed the general safety of higher dosing regimens, yet the absence of renal impairment in the included population limits its applicability to ECMO patients under CRRT[15]. In our case, the appearance of neurological toxicity at a lower dose suggests that the accumulation of TXA due to impaired renal function may trigger neuroexcitation. This case highlights that when TXA is used in patients with ECMO treatments and renal dysfunction, specific dosing plans and careful neurological monitoring are required[16]. Given these findings, the use of antifibrinolytic therapy in ECMO patients remains complex. While bleeding and circuit-related coagulopathy are common challenges, the risk-benefit profile of agents like TXA must be considered carefully, especially in cases of predisposing neurological vulnerability. Additionally, sympathetic overactivity may result in tachycardia, hypertension, and life-threatening arrhythmias. General anaesthetics like propofol and inhaled agents may counteract TXA’s effects by enhancing glycine receptor activity[11]. To our knowledge, this is the first reported case of generalised myoclonic jerks associated with TXA in an ECMO-supported patient on CRRT. Clinicians should be aware of this potential complication, particularly when administering TXA to critically ill patients with concomitant renal dysfunction. Prompt identification and drug discontinuation may result in symptom resolution of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.

CONCLUSION

This case report highlights a rare adverse event of TXA neurotoxicity in an ECMO-supported patient undergoing CRRT, despite the absence of structural pathology in the central nervous system and the use of conventional doses. The case emphasises the importance of individualised strategies and close neurological monitoring, given the current lack of standardised protocols in this high-risk population.