Toxicity Following Tranexamic Acid Overdose

Introduction

Tranexamic acid (TXA) is a synthetic lysine derivative with anti-fibrinolytic activity. TXA exerts this activity via reversible binding to plasminogen resulting in decreased fibrin degradation [1, 2]. TXA is approved by the United States Food and Drug Administration (FDA) for reduction or prevention of hemorrhage in patients with hemophilia undergoing dental procedures in its intravenous form [1] and for decreasing bleeding in patients with menorrhagia in its oral form [2]. The anti-fibrinolytic effects have led to multiple off-label uses including intravenously for decreasing hemorrhage after trauma [3] and reducing blood loss during surgical procedures [4] and topically for refractory epistaxis [5].

Therapeutic use has been associated with gastrointestinal symptoms, vision changes, headaches, rare cases of allergic drug-skin reactions, seizures, and thromboembolic events [1, 2]. Overdose data is limited and consists primarily of case reports of severe toxicity associated with accidental intrathecal administration [6, 7]. In this study, we report the outcomes of patients with TXA exposures reported to a regional poison control center.

Methods

This is a retrospective observational study of TXA exposures reported to the California Poison Control System (CPCS) between January 1, 1997, and December 31, 2021. All cases were manually reviewed by one of the study authors (JC) who is a board-certified toxicologist with training in clinical research and proper chart abstraction methods. Demographic data, exposure data, symptoms, treatments, and medical outcomes were manually abstracted from the free-text case forms. Information and normal therapeutic use cases (i.e., use in the hospital for bleeding) were excluded. Wilcoxon rank-sum test was used to compare the amount ingested in patients that experienced adverse effects after oral exposures and those that did not. All statistical analysis was performed in Stata® (StataCorp, College Station, Texas). This study was reviewed by the local institutional review board and determined to be exempt.

Results

A total of 62 cases were reviewed for inclusion with 48 meeting inclusion criteria. Reasons for exclusion were cases where TXA was used appropriately in a healthcare setting (five cases), medication identification (five cases), interaction checks (three cases), and a case where no TXA exposure was documented. Forty-one cases involved oral exposures, but other routes identified included two cases of intravenous administration of a therapeutic dose of TXA intended for topical use, two cases of subcutaneous injection, and two cases in which the TXA was mistakenly given intrathecally in place of local anesthetic. Six of the cases involved intentional overdoses, while 29 were medication errors involving taking/giving the wrong medication, taking the wrong dose, or taking/giving the medication via the wrong route. Dose information was available in 31 cases with the median ingested dose being 1300 mg (25–75% interquartile range 650–1950 mg). Two patients with oral exposures required hospitalization, one for treatment of acetaminophen overdose with n-acetylcysteine and the other for a polysubstance overdose (amlodipine, clonazepam, and zolpidem). Of the remaining oral exposure cases, 28 were treated at home, six were treated in the emergency room (ER) and released, four were referred to the ER but lost to follow-up, and one was transferred to a psychiatric facility. There were a total of 11 accidental oral exposures in pediatric patients, only one of which developed symptoms (vomiting).

Cases with adverse effects following oral exposures are described in Table 1. The lowest oral dose with reported adverse effects was 500 mg. There was no statistical difference between the amounts ingested in the patients that experienced adverse effects and those that did not (p = 0.277). Serious adverse events occurred in two patients who were receiving spinal anesthesia for joint arthroplasty when TXA was inadvertently administered intrathecally. The first case involved a 50-year-old male who was inadvertently given 200 mg of intrathecal TXA instead of a local anesthetic intended for spinal anesthesia. After the inhalation anesthetic wore of, the patient was noted to be in status epilepticus which did not initially respond to midazolam, fosphenytoin, or propofol. A loading dose of pentobarbital was given in addition to a propofol infusion which terminated the seizure activity. The patient subsequently became hypotensive and was started on norepinephrine and vasopressin. Cerebrospinal fluid (CSF) exchange was recommended by the poison center but was not performed. On hospital day 2, propofol was weaned and patient did not suffer any further seizure activity. On the last poison center follow-up (hospital day 9), the patient was awake and reporting difficulties with memory and upper extremity weakness.

Table 1.

Description of cases with adverse effects after TXA exposure

Age and gender	Amount ingested (mg)	Circumstances of exposure	Reported adverse effects	Coingestions	Case outcome
43-year-old female	1950	Extra dose	Headache	None	Treated at home
12-year-old female	5850	Wrong medication	Vomiting	None	Treated in ER and released
36-year-old female	650	Extra dose	Chest pain	None	Referred to ER (lost to follow-up)
52-year-old female	500	Therapeutic dose	Facial and oral edema	None	Referred to ER (lost to follow-up)
Unknown age female	1300	Therapeutic dose	Headache	Ethanol, zolpidem, and Ibuprofen	Treated at home
17-year-old female	6500	Intentional overdose	Nausea and Vomiting	Acetaminophen, aspirin, and caffeine	Treated in ER and released
20-year-old male	1300	Intentional overdose	Somnolence	Diazepam and clorazepate	Treated in ER and released
15-year-old female	Not reported	Intentional overdose	Somnolence, hypotension	Amlodipine, clonazepam, zolpidem, and acetaminophen	Admitted to ICU

TXA tranexamic acid, ER emergency room, ICU intensive care unit

The second case was a 70-year-old male who inadvertently received 250 mg of intrathecal TXA instead of local anesthetic for spinal anesthesia. He was noted to rapidly develop generalized tonic–clonic seizure activity. Seizure activity improved with propofol and midazolam infusion. He subsequently developed labile blood pressures. CSF exchange was performed on hospital day 1. Following CSF exchange, the patient suffered no additional seizure activity. On the last poison center follow-up (hospital day 4) he was oriented × 4 with no reported neurologic abnormalities.

Discussion

TXA has seen increased off-label use for its ability to decrease hemorrhage after trauma and during operative procedures [4]. This increased use is mirrored by increases in adverse events reported to the FDA Adverse Event Reporting System [8]. Despite this increased use, very little data has been available regarding inadvertent or intentional overdose of TXA. We found very little toxicity associated with isolated oral overdose. Furthermore, none of the cases of isolated TXA ingestion required admission to the hospital.

In contrast to oral exposures, inadvertent intrathecal administration causes rapid onset of severe toxicity, the hallmark of which is status epilepticus. Seizures occur due to competitive binding at GABA_A receptors and are further exacerbated by glycine receptor antagonism and increased sympathetic tone [7]. Initial treatment in these cases includes aggressive seizure control with benzodiazepines and barbiturates. Treatment with magnesium, mannitol, dexamethasone, inhalational anesthetics, and propofol have also been suggested along with CSF exchange, which was performed in one of our patients [6, 7].

Our study only had two cases of intravenous exposure. The best available data on the toxicity of intravenous TXA comes from two case reports and observational data of cardiac surgery patients [9, 10]. Toxicity resulted in a seizure in one patient [9] and vision changes in the other [10]. For cardiac surgery patients, an increased incidence of post-operative seizures has been noted (4.6% vs 1.2%) in those that received TXA [11].

Our study has several limitations. First, data was abstracted by a single individual which could result in mischaracterization of cases and their outcomes. Given its retrospective nature, outcomes data was limited to what was reported in the poison control center case files which does not allow for an assessment of the risk of thromboembolic events after oral overdose. There are also the limitations inherent to poison center research as only cases that were reported to CPCS are included.

Conclusion

TXA exposures rarely result in serious adverse events via the oral route but can cause serious adverse events when mistakenly given intrathecally. Management of oral overdose is supportive and can usually be done outside of a healthcare facility if there are no concerning coingestions, while management of intrathecal administration should focus on aggressive seizure control and consideration of CSF exchange. Given the severe morbidity and possible mortality associated with intrathecal TXA, labeling prevention strategies along with pharmacy and operating room procedures should be developed to prevent intrathecal delivery.

Abbreviations

TXA

Tranexamic acid

CSF

Cerebrospinal fluid

CPCS

California Poison Control System

Funding

None.

Declarations

Conflict of Interest

None.

Prior Presentation

Data in this manuscript were previously presented at ACMT’s Virtual Annual Scientific Meeting, March 10–13, 2022.