Efficacy of Tranexamic Acid in Nasopharyngeal Hemorrhage; Single Center Prospective Study and Literature Review

Abstract

Nasopharyngeal hemorrhage is one of the most common ear, nose, and throat (ENT) emergencies that present in a hospital or primary care clinic. While many cases of hemorrhage are self-limiting, in more severe cases medical intervention is necessary, either to cauterize the bleeding vessel or to pack the nose with various materials (thus involving specialized medical care and time, which implicitly lead to additional costs). In the case of the packaging, the medical treatment can in some cases be extremely painful and unpleasant. Tranexamic acid is an affordable, inexpensive, easy-to-use antifibrinolytic agent and with no notable side effects, as demonstrated by numerous studies related to most surgical fields. The aim of this paper is to provide an evidence-based approach to the use of tranexamic acid (TXA) in nasopharyngeal hemorrhages in our research center, comparing with the available literature on the subject, but presented in an updated form. As a conclusion, the combined use (intravenous and topical) of TXA may be a reasonable, safe and non-invasive option for hemodynamic stabilization of rhino-pharyngeal bleeding.

Introduction

Epistaxis is a relatively common problem with a lifetime incidence of about 60% in the general population [1]. Causes of epistaxis include trauma, recent surgery of nose, tumors, hematological pathology, rapid temperature change, allergic rhinitis, specific medications, idiopathic sources, etc. [2].

Anterior epistaxis is accountable for most of the epistaxis cases that present in the emergency room, having usually a bleeding source at the anterior inferior septum in Kiesselbach’s plexus [3]. Management of active epistaxis in the ED generally begins with 10–15 min of direct local pressure, followed by an attempt to identify the source of bleeding by anterior rhinoscopy [4]. For better visualization at anterior rhinoscopy, it is necessary to remove any hematoma from applied pressure, which can be done by blowing the nose, suction, or direct removal [5,6].

Posterior epistaxis is less frequent (5–10% of cases), the source of hemorrhage being represented by the (sphenopalatine and posterior ethmoid) branches of the internal maxillary artery originating from the ophthalmic artery [7]. In such cases, the need for hospitalization and nasal packing is twice as likely [8]. Anterior rhinoscopy does not help to identify the source of bleeding and packing is necessary to first stop the bleeding, after which direct interventions are used. Endoscopy is often necessary to discover the source of bleeding, with a success rate of between 80 and 94% [9].

Nasal packing with nasal tampons or other commercial products is painful to insert and remove, the pain score of patients who were treated with this method was found to be higher than the average pain scores of acute myocardial infarctions [10,11]. This procedure also requires the patient to be hospitalized for at least 2 days, which adds to the unpleasant experience. Therefore, identifying an effective and inexpensive treatment would have an important medical, psychological and economic impact.

Tranexamic acid (TXA, first synthesized in 1962), is an anti-fibrinolytic agent which has been included into treatment algorithms of multiple surgical specialties where significant bleeding can occur.

This synthetic antifibrinolytic drug has a mechanism of action that interferes with the coagulation cascade by blocking the formation of plasmin and stabilizing the formed platelet plaques. This is the consequence of the fact that TXA is a synthetic analogue of the amino acid lysine, which binds and competitively blocks plasminogen molecules, and thus decreases the degradation of already formed plaques.

TXA can be administered orally or intravenously, having an oral bioavailability of 30–50% and a half-life of 2–3 h. It can also be applied locally, acting on the mucosa and blood supply where it is placed [12,13]. In the last decade, aerosol application of TXA in anatomically sequestered areas, such as the lungs and posterior nasal cavity, has been explored [14,15]. It has been hypothesized that TXA may be particularly effective for management of oropharyngeal bleeding because of the relatively high concentration of plasminogen and low concentration of intrinsic plasminogen inhibitors found in saliva [16,17,18,19].

There is a source of concern regarding prescription of TXA because of the theoretical possibility of an increased risk of thromboembolic event, but recent studies have suggested that such concerns may not necessarily be justified [20,21,22,23].

Materials and Methods

PubMed was systematically searched for relevant articles published up to November 2023 using the following keywords: tranexamic acid, rhino-pharyngeal, epistaxis. This search generated 18 articles with full text from the works published on this topic; studies which did not investigate the use of tranexamic acid as an antifibrinolytic agent were excluded. From this process, only 10 full text journals met the final inclusion criteria for the purpose of this review.

We included randomized controlled trials, clinical trial and randomized controlled trials investigating the efficacy of TXA in bleeding cessation in rhino-pharyngeal hemorrhage. These published works were thoroughly analyzed for the purpose of identifying the principal themes regarding the use of TXA for the management of hemorrhage in an attempt to understand and establish the evidence in support or against the use of the TXA for the management of Rhino- Pharyngeal hemorrhages.

We also present a small single center prospective study made on patients admitted to ENT Clinic of Emergency Hospital of Constanta referred by Emergency Room or by family doctor recommendation.

Results

We found ten studies that met our inclusion criteria, with a total of 1863 participants. One study used oral administration of tranexamic acid, two used I.V. form and the six studies used the topical application of the injectable form on sterile gauze and one by atomizer. One of ten studies were conducted over 30 years ago.

Three studies used it as a preoperative administration to demonstrate if it can improve the surgical field and reduce the bleeding. Tranexamic acid was generally well tolerated, with no reported side effects.

From the extensive review of the 10 published articles which investigated the use of the TXA in the hospital environment for the management of hemorrhage, the following main themes were identified: the route of administration, the dose, the clinical effectiveness and the safety profile.

In acute or chronic hemorrhage, the first aid is to apply pressure to the affected area. Thus, it is not surprising that, from the review of the studies which utilized TXA in hospital units, the most common route of administration was topical administration.

Reuben et al. in a controlled trial on 496 participants with spontaneous epistaxis after simple first aid and applications of topical vasoconstrictors, used tranexamic acid (injectable form) or placebo, on cotton wool dental roll applied to the bleeding nostril. The “rescue treatment” was anterior packing of the nose. The tranexamic group have had 43.7% (111 participants) and the placebo group had 41.3% success in the cessation of the hemorrhage. The difference was not statistically significant (odds ratio 1.107, 95% confidence interval 0.769 to 1.594; p = 0.59) [24].

In several studies, a cotton pledget in the injectable form of TXA (500 mg in 5 mL) was applied to the bleeding nostril. The study control group of all studies were treated with a cotton pledget soaked in lidocaine (2%) and epinephrine (1:100,000). The “rescue treatment” for both groups were nasal packing or cautery if needed. In the first study on 216 patients, within 10 min of treatment, hemorrhage was arrested in 71% of the patients in the tranexamic group, compared with 31.2% in the anterior nasal packing group [25]. In the second study, RCT had as inclusion criteria, patients treated with antiplatelet drugs (aspirin, clopidogrel or both). A total of 124 patients had participated in this study, and again, within 10 min of treatment hemorrhage were arrested in 73% of the patients in the TXA group and 29% in the anterior nasal packing group [26]. In both studies above mentioned, treatment with topical application of TXA resulted in faster bleeding cessation and higher patient satisfaction compared to classical nasal packing [25,26].

Hosseinialhashemi et al. published in 2022 a double-blind randomized trial with a total of 240 patients enrolled. Tranexamic acid was associated with a lower rate of need for anterior nasal packing (50% versus 64.2%) and a shortened stay in the ED (9.2% versus 20.8%) [27].

Ekmekyapar et al. had 108 patients included in a randomized double-blind study, who were evaluated in three treatment groups as topical lidocaine, epinephrine and tranexamic acid. The study found that for nasal packing procedures with lidocaine, epinephrine, and TXA, the recorded bleeding time was not statistically significantly different between groups [28].

Jahanshahi et al. used three pledgets soaked with TXA 5% versus phenylephrine 0.5% in a triple blind randomized clinical trial, conducted on 60 patients who underwent functional endoscopy sinus surgery. The first and second quarters showed significantly better surgical field quality in the intervention group than the control group (p = 0.002, versus p = 0.003), but not in the third quarter (p = 0.163). Additionally, bleeding was significantly reduced in the intervention group during all periods (p = 0.001). These results suggest that using topical TXA may be an effective method for improving the surgical field by lowering the bleeding in FESS in rhinosinusitis patients, particularly in the first 30 min of use [29].

Akkan et al. compared topical atomized tranexamic acid with simple nasal compression and Merocel packing in a randomized controlled trial including 135 patients. Applying external compression after administering TXA through the nostrils by atomize stops bleeding as effectively as anterior nasal packing using Merocel. The TXA group had 86.7% versus 74% no rebleeding within 24 h [30].

White et al. used tranexamic acid 1g, three times a day or placebo in double randomized study made on 89 patients with recurrent epistaxis. The difference between the two groups were not statistically significant [31].

Zaman et al. used tranexamic acid single dose i.v. 10mg/kg versus placebo in a 176 cohort. In a double blinded manner, the study group and the placebo one underwent septoplasty. Single dose tranexamic acid seems to be statistically more effective in preventing postoperative nasal bleeding (p = 0.018) [32].

In 2016, Kulkarni et al. conducted a double-blind, placebo-controlled study. The study’s findings revealed that the administration of preoperative intravenous TXA at a dosage of 10 mg/kg, repeated every 3 h after induction, did not result in a reduction in blood loss or the high necessity for blood transfusions in patients undergoing significant surgery for oral cancers, whether or not reconstruction was involved. Additionally, the administration of TXA was deemed safe, and there was no observed increase in the incidence of deep venous thrombosis [33].

In the above trials reviewed, the administration was topical on a pledget soaked in injectable form of TXA (500 mg in 5 mL) [24,25,26,27,28,29], one topical but distributed by an atomizer to the nostril [30], one by oral medication [31], one by intravenous single dose 10mg/kg [32] and one intravenous 10 mg/kg preoperative repeated every 3 h after induction [33]. Only 4 interventions had no statistically significance in cessation of hemorrhage after tranexamic acid administration [24,28,31,33].

The most common adverse effects are gastrointestinal (for example nausea, abdominal cramping), which are mild and uncommon manifestations. No any other major complications were described by the authors.

Single Center Small Series of Cases

This section introduces three distinct clinical categories of cases in terms of etiopathogenesis, clinical occurrence and response to treatment, from a broader cohort of 27 patients referred to our clinic for rhino-pharyngeal hemorrhage showcasing a diverse spectrum of patients in terms of ethnicity, residency, and clinical presentation. The groups were formed by the site of bleeding and elected type of surgical intervention. The initial category encompasses patients who underwent surgical intervention aimed at the complete excision of tumoral masses localized within the nasal fossa. The second category is formed of patients presenting with significant hemorrhagic events emanating from the tumoral mass. The final category comprises patients presenting with tumors localized in the rhino-pharynx who underwent diagnostic biopsy procedure.

These cases exemplify the varied applications of tranexamic acid (TXA), employing both intravenous and topical administration methods to effectively manage hemorrhages.

The initial patient cohort is comprised of five individuals, with a median age of 56 years. The predominant tumor type within this group is non-keratinizing carcinoma. In terms of ethnicity, two of the patients identify as Tatar and three as Romanian. A noteworthy observation is the predominance of rural residency among these patients, with four out of five hailing from rural areas, while only one patient resides in an urban setting. Additionally, it is important to note that the gender distribution within this group includes four males and one female. From this category of similar cases, we have chosen the case of a 49-year-old male residing in rural environment, Tatar ethnicity, patient presenting to the ENT clinic with a referral from the family doctor due to nasal obstruction, recurrent epistaxis, and predominantly oral breathing. Anterior rhinoscopy revealed a slightly bleeding formation occupying the entire right nasal fossa, a finding confirmed by CT examination. The decision was made to proceed with surgical intervention for the excision of the tumor with safe margins. After the induction of general anesthesia, intravenous TXA 10 mg/kg was administered. Under endoscopic control, excision was performed using electrocautery, concurrently achieving local hemostasis with the application of gauze soaked in injectable TXA solution (500 mg in 5 mL). Formation of clots and cessation of bleeding were observed in areas where the TXA-soaked gauze was applied. Nasal packing was performed and maintained for 96 h, with no hemorrhagic episodes after removal. Histopathological examination indicated a non-keratinizing nasopharyngeal carcinoma. In the entirety of this patient cohort, complete cessation of hemorrhage was not achieved; however, a noteworthy reduction in blood loss was consistently observed.

The secondary patient group is composed of two individuals, both males, with a median age of 61 years. Non-keratinizing carcinoma is the prevalent tumor type within this subset. Both patients identify as Romanian. The residential demographics are evenly distributed, with one patient from a rural area and the other from an urban place. In the second group of patients we chosen the case of a 58-year-old male patient, residing in urban environment, Romanian ethnicity known to have infiltrative, non- keratinizing squamous cell carcinoma (G3) of the buccal floor and left hemitongue, previously treated with radiotherapy, presenting to the Emergency Department with massive bleeding from the oro-rhino-pharinx. Intravenous administration of TXA at a dosage of 10 mg/kg is initiated, along with the application of compressive gauze soaked in TXA solution (500 mg in 5 mL) was done to achieve hemostasis. The patient was subsequently transferred to the operating room, where left external carotid artery ligation was performed and the evolution was favorable.

The third patient cohort comprises 20 individuals, with a median age of 55. The predominant tumor type in this group is non-keratinizing carcinoma. The ethnic distribution includes 4 Tatar, 2 Roma, 1 Turk and 13 Romanian individuals. In terms of residency, 12 individuals are from rural areas, while 8 are from urban zone. The gender distribution includes 14 males and 6 females. The third category of cases reveals a case of a 57-year-old male patient, residing in urban environment, Tatar ethnicity presenting to the Emergency Department with recurrent epistaxis and unilateral hearing loss. Upon nasopharyngolaryngoscopic examination, a tumoral formation was visualized in the nasopharyngeal cavity, further confirmed by CT examination. Nasal packing was performed using gauze soaked in TXA solution (500 mg in 5 mL), and intravenous TXA at a dosage of 10 mg/kg is administered before endoscopically guided biopsy sampling from the tumoral formation with minimal bleeding. Pathology examination indicated nasopharyngeal non-differentiated carcinoma and the efficacy of TXA was proved. In 6 patients the efficacy was not favorable and anterior packing was performed.

Discussions

If the efficacy of TXA in managing persistent hemorrhage is established in more exhausted cohorts, it could potentially eliminate the requirement for invasive procedures minimizing the hospital admission. Even if the literature data are controversial, the discovery of different constellation of patients who respond to TXA hemostasis would be of immense significance, benefiting both patients and healthcare systems.

While anterior nasal packing is a proven method for managing epistaxis, it can be an uncomfortable procedure that necessitates hospital admission. Topical TXA has been demonstrated to be a safe and effective treatment option in various scenarios, and there is some indication that it could be beneficial for specific patients with epistaxis, observations that may be validated by further research. The results of this study could lead to a decrease in the need for anterior nasal packing and subsequent hospitalization for patients with epistaxis, thereby reducing the use of an uncomfortable procedure that is associated with recognized complications.

Furthermore, El-Ozairy et al. performed a Randomized Controlled Trial (RCT) with the main aim of evaluating the effectiveness of local, intravenous and combined use of tranexamic acid (TA) in improving the surgical field quality during FESS. The combined use of topical and intravenous TXA provided the best surgical field assessment using a five-point Boezaart scale [34].

There is a hypothesis that TXA could be a particularly effective treatment for oropharyngeal bleeding due to the high concentration of plasminogen and low concentration of intrinsic plasminogen inhibitors that are present in saliva [16,17,18]. Extrapolating this route, the hypothesis is that combined topical and iv TXA treatment could be useful in rhino-pharyngeal hemorrhages.

The potential of TXA in reducing the need for invasive procedures and hospitalization in managing persistent hemorrhage, particularly in rhino-pharyngeal bleeding, is also evident from our case series. However, the efficacy of TXA can be influenced by several factors such as ethnicity, age, comorbidities, administration route, and concurrent medications [35,36,37].

Our case series did not demonstrate significant variation in TXA efficacy across different ethnic groups. However, it is important to consider that metabolic and genetic differences between ethnicities could potentially impact drug metabolism and response. Despite this, limited data directly links ethnicity to TXA’s effectiveness in hemorrhage control. Age is another crucial factor. Older patients, often with varying comorbidities and on multiple medications, might respond differently to TXA [38]. This is particularly relevant if they have a history of thromboembolic events or are on anticoagulant therapy [39]. Contrasting our findings, studies of Kulkarni et al. reported that preoperative intravenous TXA did not significantly reduce blood loss in major surgeries for oral cancers [33]. This discrepancy suggests that TXA’s efficacy may vary based on patient populations, types of hemorrhage, and study designs. This study stands alone in examining the effectiveness of TXA in patients with cancer in the rhino-pharyngeal area. Furthermore, it highlights the need for more targeted research, exploring the reasons behind these disparate findings.

Still, available evidence and our case series suggest that TXA is an effective and safe option for the treatment of hemorrhage of the rhino-pharyngeal region. A hemostatic benefit in rhino-pharyngeal hemorrhage following i.v. and topical TXA administration was observed in 78% of the patients with active hemorrhage in our small case series. However, its efficacy is influenced by various factors, including ethnicity, age, comorbidities, concurrent medications, and the administration route.

Conclusions

Given the therapeutic options for managing rhino-pharyngeal bleeding, the use of combined use of intravenous and topical TXA may be a reasonable, safe, non-invasive option for hemodynamic stabilization. Combined application of the drug offers the advantage of simple and fast delivery of the antifibrinolytic to the targeted tissue site while requiring minimal patient cooperation. Future randomized controlled trials would be valuable to better assess the effectiveness of TXA in patients with rhino-pharyngeal hemorrhage and provide insight into remaining questions, including optimal dosing and dilution method, optimal duration of administration, and the role of repeat or scheduled dosing, the constellation of patients who are best responsive to this treatment. Future studies should aim to dissect the factors contributing to the varying efficacy of TXA, potentially leading to more personalized approaches in managing perioperative bleeding in patients with rhino-pharyngeal cancer.