Abstract
Tranexamic acid (TA) is a well-established antifibrinolytic agent utilized across various medical scenarios to manage bleeding, including surgical, traumatic, postpartum, and upper gastrointestinal bleeding. Despite its widespread application, the systematic evaluation of TA’s efficacy in achieving hemostasis during interventional pulmonary procedures remains limited. This review aims to address this gap by examining the utility and effectiveness of TA in promoting hemostasis during pulmonary interventions, encompassing procedures such as bronchial artery embolization, percutaneous lung biopsy, bronchoscopy, and pleural procedures. By synthesizing existing evidence, this review seeks to provide valuable insights into the potential role of TA in mitigating hemorrhage following interventional pulmonary procedures, thereby informing clinical practice and guiding future research endeavors.
Introduction
Tranexamic acid (TA) serves as a potent antifibrinolytic agent, effectively impeding the breakdown of blood clots. Demonstrating efficacy across diverse medical domains, including trauma surgery, obstetrics, major orthopedic (joint replacement and spine) surgery, and upper gastrointestinal bleeding, TA stands out for its ability to staunch bleeding and enhance patient outcomes.1–6 Beyond its antifibrinolytic properties, TA also exhibits multifaceted roles encompassing anti-inflammatory effects and wound healing promotion.7,8 Consequently, TA has garnered attention within interventional pulmonology as a prospective intervention for mitigating bleeding during various procedures.
Interventional pulmonology encompasses minimally invasive techniques aimed at diagnosing and treating lung diseases. Many of these procedures, such as bronchial artery embolization (BAE), percutaneous lung biopsy (PLB), bronchoscopy, and pleural interventions, entail inherent bleeding risks.9,10 While bronchial infusion of iced (4°C) saline and diluted (1:10,000) adrenaline have been recommended approaches for managing hemoptysis, the cardiovascular ramifications of adrenaline, including potentially fatal cardiac sequelae, pose notable concerns.11–13 Similarly, pituitrin, despite its efficacy in treating hemoptysis, is marred by adverse effects such as neurological symptoms, myocardial ischemia, and arrhythmias, limiting its applicability in patients with cardiovascular comorbidities. 14 Previous investigations have indicated TA’s association with reduced hemoptysis and intervention necessity, particularly in submassive hemoptysis cohorts, with fewer accompanying side effects.15,16 Nonetheless, the discourse surrounding TA’s implications for interventional pulmonology remains scarce.
Hence, this review endeavors to furnish a comprehensive elucidation of TA’s utility in interventional pulmonology, delineating its mechanism of action, applications across diverse procedures, and optimal dosage considerations. By shedding light on TA’s potential as a bleeding mitigation strategy during interventional pulmonology procedures, this review underscores its significance as a viable therapeutic avenue warranting further exploration.
What are the current hemostatic agents for interventional pulmonary procedures?
Table 1 illustrates commonly employed hemostatic agents in clinical settings, with 4°C iced saline and diluted adrenaline representing predominant modalities for achieving hemostasis during interventional pulmonary procedures. The mechanism of action underlying iced saline involves cold-induced vasoconstriction, facilitating cessation of bleeding and restoration of visual clarity via local irrigation. Studies have explored varying volumes of iced saline, typically ranging from 5–10 mL to 500 mL, primarily for managing minimal hemorrhage.17–19 Adrenaline, typically prepared as a 1:10,000 saline solution (2 mg adrenaline in 20 mL saline) for local intraluminal injection, induces hemostasis primarily through vasoconstriction. 20 However, caution is warranted in elderly patients and those with cardiac conditions, carcinoid tumors, or a history of cardiac arrhythmias due to its arrhythmogenic potential. 21 Smaller concentrations (1:100,000–1:20,000) are also utilized for hemostasis, emphasizing the need for judicious use based on patient-specific factors and underlying comorbidities. 21
Common hemostatic agents for bleeding during pulmonary procedures.
In addition to adrenaline, alternative vasoconstrictors are available, including norepinephrine and pituitrin. Norepinephrine elicits a robust peripheral vasoconstrictive response surpassing that of adrenaline, typically administered intraluminally in a 1:10,000 saline formulation. Pituitrin, recognized as a potent vasoconstrictor, demonstrates superior hemostatic efficacy compared to iced saline. However, its utility is tempered by notable cardiovascular side effects such as tachycardia and decreased mean arterial pressure. 22 Endoscopic application of thrombin or snake venom hemocoagulase has been documented in cases of severe hemoptysis, exhibiting hemostatic profiles akin to adrenaline but with reduced adverse effects.23,24 Moreover, recombinant activated factor VII has emerged as a therapeutic option for diffuse alveolar hemorrhage-induced hemoptysis. 25 Previous investigations have underscored the hemostatic prowess of TA in tracheal bleeding, amenable to local administration via drops or intralesional injections during bronchoscopy.15,26 Notably, topical hemostatic tamponade therapy utilizing oxidized regenerated cellulose has shown efficacy in locally controlling hemoptysis, albeit with a potential risk of obstructive pneumonia. 27
What are the mechanisms of action of TA?
TA operates by impeding the degradation of blood clots via its binding affinity to plasminogen, thereby inhibiting its conversion to plasmin.28,29 Plasmin, an enzyme pivotal in fibrinolysis, catalyzes the breakdown of fibrin, leading to clot dissolution. By antagonizing this process, TA, approved for intravenous, oral, and topical administration, exerts a stabilizing effect on blood clots, consequently mitigating bleeding.30,31
The pharmacokinetics of TA entail prompt and complete absorption post oral or intravenous dosing, with a half-life of approximately 2 h and predominant renal elimination. 32 Meta-regression analyses have not revealed an elevated risk of thrombotic events, seizures, venous thromboembolism, acute coronary syndrome, or stroke associated with TA administration, although seizure occurrence has shown a dose-dependent increase. 33 Common adverse effects, primarily observed with oral administration, encompass gastrointestinal disturbances (nausea, dyspepsia, diarrhea, and headache), albeit less frequently reported by anesthetists. 34 A study conducted by Ausen K indicates a notable absence of significant side effects with topical TA application, contrasting with the limitations encountered with systemic TA use.35,36 Consequently, topical TA emerges as the preferred primary intervention, notwithstanding the challenge of determining the optimal local drug concentration.
How is TA used in pulmonary interventions?
TA has several advantages in interventional pulmonology. It is inexpensive, readily available, and has a well-established safety profile. Its use has been associated with a reduced need for blood transfusions and shorter hospital stays. 37 Particularly beneficial for interventions carrying a potential for nonfatal bleeding, TA demonstrates efficacy without concomitant escalation of adverse event risks. Comprehensive insights into the pertinent applications of TA in interventional pulmonology are delineated in Table 2.
Main results of trials assessing the use of TA in interventional pulmonology.
IV, intravenous; TA, tranexamic acid; TBLB, transbronchial lung biopsies; VAS, visual analog scale.
TA in bronchial artery embolization
BAE represents a minimally invasive intervention employed in addressing massive and recurrent hemoptysis stemming from bronchiectasis and pulmonary arteriovenous malformation. 38 Nonetheless, studies have highlighted a substantial recurrence rate of bleeding post-BAE, ranging from 10% to 57%.39,40 Antifibrinolytic agents hold promise as interim therapeutic modalities for patients undergoing preparation for embolization or surgery due to massive hemoptysis, serving until these procedures can pinpoint and address the bleeding source. A recent randomized controlled trial conducted by Bellam BL et al. revealed that among patients receiving TA, 7 (16.27%) necessitated intervention for BAE, compared to 8 (38.1%) in the placebo control cohort, indicating a notably reduced requirement for intervention among those administered TA. 15 TA employment not only mitigated hemoptysis severity but also functioned as a bridge therapy to BAE. Select cases have additionally documented TA utilization as a safe interim measure for symptom management preceding a more definitive approach through BAE.41–45 In a study by B. Gopinath et al., comparison of nebulized TA (500 mg tid) versus intravenous (IV) TA (500 mg tid) demonstrated potential superiority of nebulized TA in attenuating hemoptysis volume and diminishing the necessity for BAE. 46 Future larger-scale investigations are warranted to comprehensively elucidate the comparative efficacy of nebulized TA vis-à-vis IV TA in patients necessitating BAE.
A study conducted by H. N. Lee et al. demonstrated that the combined therapy of BAE and TA offered notable advantages in short-term hemoptysis control rate (87.5%), technical success rate (96.9%), and immediate clinical success rate (96.8%). 47 These findings suggested that the amalgamation of TA and BAE may mitigate the risk of recurrent hemoptysis. TA’s role in reducing bleeding during BAE primarily stems from its ability to stabilize blood clots within the bronchial artery, thereby potentially augmenting the efficacy of embolotherapy. Collectively, consistent evidence from various studies underscores TA’s investigational utility as a potential adjunct to BAE, aimed at reducing bleeding and optimizing patient outcomes.
TA in percutaneous lung biopsy
PLB stands as a routine diagnostic modality for assessing lung nodules or suspicious pulmonary lesions. However, PLB carries inherent risks, notably pneumothorax and hemorrhage. Pulmonary hemorrhage ranks as the second most prevalent complication of PLB, with reported incidences ranging from 4% to 43%.48,49 A case series examining nebulized TA for recurrent hemoptysis in critically ill patients concluded that TA might hold promise for hemoptysis management across diverse etiologies. 44 A systematic review and meta-analysis of randomized trials assessing TA’s efficacy in reducing bleeding volume revealed a significant mean difference (MD) of −56.21 mL (95% CI −94.70 to −17.72 mL). 50 A Cochrane review in 2016 corroborated TA’s efficacy in decreasing bleeding time, reporting a weighted mean difference of −19.47 (95% CI −26.90 to −12.03 h); 51 however, due to limited randomized controlled trials, further investigations were advocated to establish both efficacy and safety. Subsequently, Ori Wand et al. conducted a double-blind, randomized controlled trial comparing nebulized TA (500 mg tid) to placebo (normal saline). 16 TA-treated patients exhibited significantly lower incidences of hemoptysis within 5 days post-admission compared to the placebo group (96% vs 50%; p < .0005), alongside a shorter mean hospital length of stay in the TA cohort (5.7 ± 2.5 days vs 7.8 ± 4.6 days; p = 0.046). Additionally, fewer TA-treated patients necessitated invasive interventions such as interventional bronchoscopy or angiographic embolization to manage bleeding (0% vs 18.2%; p = 0.041). 16
Mehra Haghi et al. innovatively devised an inhalable dry powder formulation of TA targeting hemoptysis management. 52 Meanwhile, Gopinath et al. conducted a comparative study evaluating nebulized TA (500 mg tid) vis-à-vis IV TA (500 mg tid), demonstrating a significant reduction in hemoptysis volume in the nebulization cohort across all observation periods (P values at 30 min = 0.011, at 6 h = 0.002, at 12 h = 0.0008, and at 24 h = 0.005). 46 This pragmatic, open-label, randomized, parallel, single-center, pilot trial underscores the efficacy of nebulized TA administration in curtailing post-procedural bleeding following lung puncture. Nevertheless, further robust investigations are warranted to comprehensively evaluate TA’s impact on post-pulmonary puncture hemorrhage. Of interest, a retrospective analysis suggested that hemocoagulase injection into the biopsy tract might mitigate the incidence of pulmonary hemorrhage subsequent to PLB. 53 However, scant literature exists regarding TA injection into the biopsy tract, necessitating additional research to ascertain whether intrachannel TA administration during lung puncture effectively mitigates pulmonary hemorrhage.
TA in bronchoscopy
Bronchoscopy stands as a cornerstone in the armamentarium for diagnosing and managing tracheobronchial disorders, offering a minimally invasive approach. Techniques such as endobronchial biopsy (EBB), transbronchial lung biopsy (TBLB), transbronchial cryobiopsy, and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA) are pivotal for procuring lung tissue samples to elucidate focal and diffuse pulmonary conditions.54-56 Despite its diagnostic utility, bronchoscopy carries inherent risks, including bleeding, pneumothorax, and acute exacerbation. 54 Procedures predisposed to bleeding encompass EBB, TBLB, transbronchial cryobiopsy, EBUS-TBNA, and airway tumor resection. Although mortality is exceedingly rare, post-bronchoscopy hemorrhage may prolong the procedure or necessitate its termination, resulting in inadequate biopsy material.
TA emerges as a pivotal agent in mitigating bleeding complications during bronchoscopy procedures. Kronborg-White et al. conducted a study where TA, administered intravenously at a dose of 0.5–1 g of body weight-adjusted prior to transbronchial cryobiopsies, effectively reduced the risk of bleeding, affirming its efficacy in bleeding management. 57 Although severe bleeding following TBLB is uncommon, even minor bleeding events can prolong the procedure and compromise sampling adequacy. Kuint et al. conducted a randomized, double-blind, placebo-controlled trial involving 50 patients undergoing TBLB, administering TA (500 mg in 10 mL of saline) vis-à-vis placebo (10 mL of 0.9% NaCl). The TA group exhibited significantly lower bleeding incidence (p = 0.0037) and yielded a greater number of biopsy samples (placebo 7 vs TA 9, p = 0.023). 58 Similarly, Zamani et al. investigated the efficacy of bronchoscopic intratumoral TA injection in 20 patients undergoing forceps biopsy, demonstrating its potential in mitigating significant bleeding during the procedure. 26 This approach could be considered as a pre-biopsy intervention for lesions at high risk of bleeding. Additionally, TA holds promise in reducing bleeding during bronchoscopic operations, with intratracheal topical administration serving as a viable strategy for managing iatrogenic bleeding. In addressing iatrogenic bleeding during bronchoscopy, Márquez-Martín et al. successfully treated all cases through endobronchial administration of TA. 59 This finding was corroborated by a study in 2009, which reached the same conclusion. 60 Subsequently, Badovinac et al. conducted a randomized, double-blind, single-center study comparing TA (100 mg, 2 mL) to adrenaline (0.2 mg, 2 mL, 1:10,000) in 130 patients who continued to experience iatrogenic bleeding despite three applications of cold saline during flexible bronchoscopy. 61 Their investigation revealed no significant difference between adrenaline and TA in controlling endobronchial bleeding. Moreover, another study affirmed the comparable hemostatic efficacy of endobronchial instillation of TA and adrenaline in managing pulmonary hemorrhage. 62 These collective findings underscore the safety and efficacy of TA utilization during bronchoscopy. Nonetheless, further research is warranted to explore the potential applications of TA in reducing bleeding during airway tumor resection and EBUS-TBNA.
TA in pleural procedure
Pleural procedures, such as medical thoracoscopy and indwelling pleural catheter insertion, 9 can inadvertently expose the plasma membranes (pleura, pericardium, and peritoneum) to surgical trauma, triggering a release of significant amounts of fibrinogen activator. This, in turn, intensifies local fibrinolytic activity, thereby exacerbating bleeding. TA has demonstrated efficacy both systemically and locally by competitively binding to the lysine binding sites of fibrinolytic enzymes and fibrinogen. By occupying these sites, TA impedes the interaction between fibrinogen and fibrin, consequently inhibiting fibrinolysis. 32 Dell’Amore et al. conducted a prospective randomized, double-blind, placebo-controlled trial investigating the topical application of TA within the pleural space. Their findings revealed a noteworthy reduction in blood loss within the first 12 h among the TA-treated group compared to the control (298.2 ± 73 vs 458.1 ± 89, p < 0.02). 20 Similarly, Sabry et al. demonstrated the efficacy of local intrapleural TA application in mitigating blood loss, with no significant adverse effects reported. 63 Additionally, case reports by De Boer et al. showcased the effectiveness of both oral and intrapleural TA in managing hemothorax secondary to malignant mesothelioma. 64 Given these findings, TA emerges as a promising therapeutic option for attenuating bleeding following intrathoracic interventions or surgeries. However, further research is warranted to delineate the optimal dosage and efficacy of intrathoracic TA administration in mitigating bleeding during pleural procedures, including thoracoscopy and chest tube placement.
Administration method and dosage of TA
The optimal dosage and route of TA administration lack a universal standard. Table 2 summarizes the primary outcomes of TA utilization. Systemic TA administration encompasses intravenous and oral routes. In certain investigations, intravenous TA was administered at a dosage of 500 mg thrice daily until hemorrhage cessation was achieved. 46 In cases of submassive hemoptysis, an initial intravenous TA loading dose of 1 g over 10 min was followed by a 1 g TA infusion over 8 h to manage bleeding. 19 Conversely, for prophylaxis against pulmonary hemorrhage during bronchoscopic biopsy, intravenous TA doses ranged from 0.5 to 1 g, adjusted based on body weight. 57 Oral TA administration typically involved a regimen of 250 mg thrice daily. 42
Topical TA application during bronchoscopy primarily involves nebulized TA and endobronchial instillation. In bronchoscopic procedures, TA doses ranged from 300 mg to 500 mg, administered through the working channel of the bronchoscopy into the target lobar bronchus.58-61 To mitigate bleeding, TA was injected into tumors at nominal doses of 250–500 mg. 26 Nebulized TA was typically administered at a dosage of 500 mg/5 mL, administered 3–4 times daily.16,46,60 For pleural cavity hemorrhage management, TA doses of 3 g or 5 g dissolved in 100 mL of saline solution were instilled throughout the pleural cavity.20,63 Overall, according to the findings of existing studies, the aforementioned methods of administration and dosages have demonstrated promising hemostatic effectiveness and favorable safety profiles in clinical practice.
Potential adverse effects of TA in application
The U.S. Food and Drug Administration database reported a total of 1,574 cases of adverse events related to TA. In addition to common thrombosis-related vascular disorders and cardiac issues, adverse reactions in the nervous system disorders category, including myoclonus, status epilepticus, and myoclonic epilepsy, were observed. 65 A meta-analysis assessing TA’s impact on hemoptysis suggested a potential increase in adverse events (peto odds ratio 3.15; 95% CI 0.85–11.63). 50 The TA group reported mild headache, slight chest discomfort, and nausea. 66 Nebulized TA administration was also associated with asymptomatic bronchoconstriction. 46 Fortunately, many trials demonstrated no significant or negligible side effects compared to clinical outcomes.1,3,4
Conclusion
The use of TA in interventional pulmonology has been relatively underexplored, with limited research available on its application. This review represents the first comprehensive examination of TA’s role in interventional pulmonology. Existing studies have consistently highlighted TA’s efficacy in reducing bleeding complications and enhancing patient outcomes across various interventional pulmonology procedures, including bronchoscopy, BAE, PLB, and pleural operations. Mechanistically, TA functions by stabilizing blood clots and inhibiting their breakdown, thereby mitigating the risk of bleeding during these procedures and improving overall patient prognosis. Consequently, TA stands poised to emerge as a standard adjunctive therapy for minimizing bleeding complications in interventional pulmonology.
However, the integration of TA in interventional pulmonology presents challenges and limitations. Variability in TA dosage and administration is a significant hurdle that can affect therapeutic efficacy. Therefore, additional studies are needed to clarify systemic absorption and conduct dose-response analyses for various TA concentrations. Furthermore, determining the optimal timing and route of administration is crucial. Comparative studies are necessary to evaluate the effectiveness of topical versus systemic TA and to provide comprehensive safety data on TA use. Moreover, TA administration may potentially predispose patients to thrombotic events, necessitating careful consideration during patient selection.
In summary, TA demonstrates considerable promise as an effective therapeutic strategy for managing hemorrhagic complications during interventional pulmonology procedures, serving as a bridge to more definitive treatments. Future investigations should prioritize elucidating optimal dosage regimens and administration protocols for TA, as well as exploring its applicability in innovative pulmonary interventions.
