A 2004 case series reported on seven patients with chronic, non-histaminergic angioedema who were unresponsive to antihistamines and corticosteroids. All patients were treated with tranexamic acid at a dosage of 1 gram three times daily. This regimen led to complete remission of symptoms in three patients and a marked reduction in frequency and intensity of episodes in the remaining four. The diagnosis in these cases was idiopathic non-histaminergic (bradykinin-mediated) angioedema, supported by normal C1 inhibitor levels and function in six patients, with one showing transient dysfunction linked to estrogen use. For acute attacks, administration of 1 to 2 grams of tranexamic acid every four hours over 24 hours was associated with a reduction in edema duration and severity. No adverse effects were reported during an average follow-up of 20 months. Notably, these findings suggest that tranexamic acid may be both a diagnostic aid and a therapeutic option for non-histaminergic angioedema. [1]
A 2009 retrospective observational analysis evaluated the clinical characteristics, diagnostic timeline, and response to TA in 35 patients diagnosed with sporadic idiopathic bradykinin-mediated angioedema (BAO). This non-hereditary, non-drug-induced form of BAO was characterized by the absence of urticaria and resistance to conventional therapy with H1-antihistamines, corticosteroids, and epinephrine. Episodes varied in frequency from daily to less than once per year and lasted a mean of 36.3 hours, with presentations involving various anatomical sites; however, head and neck involvement was universal. Despite some hospitalizations, no invasive interventions were required. Out of the 35 patients, 25 received on-demand TA at a dosage of 1 gram during acute episodes. TA demonstrated clinical efficacy in 23 of these cases, evidenced by significant reductions in episode intensity and duration, which led to the initiation of daily maintenance therapy at 3 grams. Twelve patients achieved complete remission, with six eventually able to reduce the dose. Eleven patients experienced substantial decreases in episode frequency and severity. TA was generally well tolerated over a mean follow-up of 20 months, showing a more favorable safety profile compared to danazol, with only two patients discontinuing due to ineffectiveness or gastrointestinal intolerance. Ten individuals did not receive TA due to various reasons, including thromboembolic risk, alternative therapies, or infrequent symptomatology. Based on these findings, TA offers a viable diagnostic and therapeutic approach in cases of idiopathic, bradykinin-mediated angioedema unresponsive to standard treatment, supporting its use as a first-line option in the absence of contraindications. [2]
A 2024 retrospective study evaluated the use of tranexamic acid in patients with angiotensin-converting enzyme inhibitor-induced angioedema (ACE-IIA) across 17 emergency departments. The study included 262 adult patients, with 73 receiving tranexamic acid and 189 serving as controls. The primary outcome was emergency department (ED) length of stay (LOS), with secondary outcomes including ICU admissions, intubations, and safety events. Patients treated with tranexamic acid had a significantly longer median ED LOS (40.3 vs. 21.1 hours, p <0.0001), higher rates of ICU admission (45.2% vs. 15.9%, p <0.0001), and increased intubation rates (12.3% vs. 6.4%, p = 0.11). No differences were observed in 7-day return visits, thrombotic events, or mortality. The most common initial dose of tranexamic acid was 1000 mg IV, with a range of 1000–2000 mg; total doses ranged from 1000–3000 mg. Overall, the study concluded that while tranexamic acid appears safe, its administration was associated with more severe presentations and did not reduce LOS. Prospective randomized controlled trials are recommended to determine its efficacy in ACE-IIA. [3]
The international 2021 updated guidelines published by the World Allergy Organization (WAO) and European Academy of Allergy and Clinical Immunology (EAACI) recommend the use of icatibant or ecallantide for on-demand treatment of hereditary angioedema (HAE) attacks as early as possible. In contrast, fibrinolytic agents like tranexamic acid (TA) are not recommended for the acute management of angioedema due to reporting no or minimal benefit. While icatibant and ecallantide are not used for long-term prophylaxis, they may be retained for use during acute episodes. TA for long-term prophylaxis (LTP) is only recommended if first-line prophylactic agents are unavailable and androgens are contraindicated (e.g., pediatric patients). While data is lacking for TA prophylaxis, the safety profile is deemed acceptable for the agent's recommendation. For long-term prophylaxis, the doses of TA used range from 30 to 50 mg/kg body weight daily divided into two or three doses to a maximum of 6 g per day. [4]
Per the United States Hereditary Angioedema Association Medical Advisory Board (US HAEA MAB) 2020 Guidelines for the Management of Hereditary Angioedema, antifibrinolytic medications (e.g., TA or epsilon aminocaproic acid) have been successfully used for LTP in HAE-C1INH but are less effective than recommended first-line therapies (e.g., intravenous [IV] pdC1INH replacement, subcutaneous [SC] pdC1INH replacement, monoclonal inhibitor of plasma kallikrein), thus seldom used for LTP of HAE due to a deficiency of C1INH (HAE-C1INH) in the US. TA (Lysteda) is available with the usual dose starting at 650 mg PO BID, increasing to 1300 mg PO BID bid if required. Creatinine should be monitored for any impairment requiring dose adjustment. Potential related side effects include thrombosis, gastrointestinal upset, myalgia, and dysmenorrhea. [5]
A 2023 review article discusses the role of tranexamic acid for angiotensin-converting enzyme inhibitor-induced angioedema (ACE-IA). The mechanism of action for tranexamic acid in treating ACE-IA is not thoroughly understood. However, tranexamic acid’s inhibition of plasmin activation is integral to its antifibrinolytic effect, crucial in enhancing kallikrein (a precursor of bradykinin) activation. Tranexamic acid hinders the generation of inflammatory peptides induced by fibrin and reduces the transformation of kininogen into bradykinin. C1 esterase activates plasma kallikrein and factor XIIa, facilitating downstream bradykinin development. Further research is necessary to elucidate the precise mechanisms through which tranexamic acid exerts its therapeutic effects in this patient population. [6]
A 2018 systematic review evaluated the efficacy of icatibant, ecallantide, and TA for angiotensin-converting enzyme inhibitor (ACEi) induced and idiopathic AE (non-hereditary AE). This systematic review included 61 studies, with 38 describing treatment in the acute setting, although most of the evidence was from case reports. There were no direct comparisons between icatibant, ecallantide, or TA. For idiopathic AE, a single study on TA use observed a 54% response rate (13 to 24 patients). Data for icatibant and ecallantide are limited to response times. Icatibant reported an initial response time of 20 to 45 minutes. For complete response, icatibant reported a range between 45 minutes to 26.6 hours, while ecallantide complete response was <1 hour. However, only one case report was available for ecallantide, while icatibant presented various case reports and two cohorts. Prophylactic treatment of idiopathic AE using TA found improvement of symptoms in 73% of patients, based on six studies, and 16% achieved complete absence of symptoms. Prophylaxis with icatibant and ecallantide was unexplored. Based on these results, the authors prefer icatibant over ecallantide for ACEi-induced or idiopathic AE, while TA may have been used as a prophylaxis agent against idiopathic AE. However, with the lack of direct comparative data, the optimal agent of the three remains uncertain. [7]
Overall, data regarding the use of TA in managing ACEi-AE are severely limited. Aside from a non-comparative retrospective study (see Table 1), a case report, and an untranslated French study have described the successful use of TA in treating patients with ACEi-AE. The French study was unique in that TA was the sole therapeutic option for severe ACEi-AE. Twenty-seven of 33 patients observed significant improvement, while the other 6 patients were treated with icatibant or C1INH concentrates. The authors of the French study concluded that TA may serve as an effective treatment or help while awaiting more specific treatment such as icatibant. [8], [9]