Clinical Applications of Tranexamic Acid (TXA): Focus on Cardiovascular Patients Receiving Antithrombotic Agents

Kim, Jin-Young; Seo, Ki-Hyun; Jin-Young Kim; Ki-Hyun Seo

doi:10.14345/ceth.25003

Abstract

Tranexamic acid (TXA) is a synthetic antifibrinolytic agent that prevents fibrin clot degradation by inhibiting plasminogen activation. Widely used to reduce bleeding in trauma, surgery, and critical care, TXA has gained interest in cardiovascular patients receiving antithrombotic therapy due to their heightened bleeding risk. This review evaluates the mechanisms, safety, and clinical utility of TXA in this population. Evidence from randomized trials and systematic reviews supports TXA’s effectiveness in reducing blood loss and transfusion needs in trauma, cardiac surgery, orthopedic procedures, and intracranial hemorrhage. Early administration—particularly within 3 hours in trauma, and within 6 hours in Novel oral anticoagulant (NOAC)-associated intracranial bleeding—yields the most benefit. TXA generally does not increase thromboembolic complications, though high-dose use in cardiac surgery has been linked to seizures. Appropriately administered, TXA is a safe and cost-effective adjunct for bleeding control in cardiovascular patients on antithrombotic agents. While current data support its efficacy, further research is warranted to refine dosing strategies and to identify patient subgroups that may benefit most from its use.

Keywords: Tranexamic acid, Antifibrinolytic agents, Hemostasis, Cardiovascular diseases, Antithrombotic therapy

Introduction

Tranexamic acid (TXA), a synthetic lysine analog, was developed in 1962 by Drs. Shosuke and Utako Okamoto in Japan. Initially intended for treating excessive postpartum hemorrhage, TXA has since been widely used for various bleeding conditions, including menorrhagia, trauma, surgery, and hemophilia [1].

TXA was included in the WHO Model List of Essential Medicines in 2011 and is recommended by various international guidelines for trauma, obstetrics, and surgical use [2,3]. Due to its high costeffectiveness and broad clinical applicability, its global use has significantly expanded.

Cardiovascular disease (CVD) is a leading cause of death worldwide. Antithrombotic therapy—including antiplatelet and anticoagulant agents—is essential for CVD management but increases the risk of bleeding, particularly in invasive procedures or traumatic events.

TXA inhibits fibrinolysis by stabilizing blood clots without directly affecting platelet function or coagulation factors (Fig. 1). This pharmacological profile makes it a potentially safe adjunctive therapy for patients receiving antithrombotic agents. This review explores the pharmacologic mechanisms and clinical applications of TXA in CVD patients on antithrombotic therapy, supported by recent literature and evidence.

Hemostasis and mechanisms of antithrombotic agents

Hemostasis consists of three phases:

• Primary hemostasis: Platelet adhesion, activation, and aggregation, leading to the formation of a platelet plug.

• Secondary hemostasis: Activation of the coagulation cascade, resulting in the formation of a fibrin mesh.

• Tertiary hemostasis: Stabilization of the clot and regulation of fibrinolysis.

TXA acts during the tertiary hemostasis phase by competitively inhibiting the binding of plasminogen to fibrin, thereby preventing plasmin formation and subsequent fibrin degradation [1].

Antiplatelet agents primarily target primary hemostasis by inhibiting Adenosine diphosphate (ADP) receptors (e.g., P2Y12) or thromboxane A2 synthesis. Anticoagulants inhibit secondary hemostasis by blocking coagulation factors (e.g., Xa, IIa). Since TXA does not interfere with these mechanisms, it can be safely co-administered with these agents.

Clinical applications of TXA in patients on antithrombotic therapy

Patients on antiplatelet therapy

In cardiac surgery, continued use of aspirin or clopidogrel is associated with increased bleeding risk. A meta-analysis by Tian et al. [4] showed that TXA reduced intraoperative bleeding by approximately 370 mL and significantly decreased reoperation rates.

A randomized controlled trial by Shi et al. demonstrated that TXA significantly reduced blood loss, transfusion requirements, and reoperation rates in patients undergoing coronary artery bypass graft (CABG) while on clopidogrel [5]. In vitro findings by Weber et al. [6] indicated that TXA partially restored platelet aggregation induced by ADP and arachidonic acid, suggesting a potential benefit in patients with platelet dysfunction due to antiplatelet therapy.

Patients on anticoagulant therapy

The TICH-2 trial showed that TXA reduced hematoma expansion in patients with spontaneous intracerebral hemorrhage, although it did not significantly improve 90-day functional outcomes [7]. The TICH-NOAC study suggested a potential benefit when TXA was administered within 6 hours of symptom onset in NOAC users, with no significant increase in adverse events [8].

In emergency situations where specific reversal agents are unavailable, TXA may serve as an effective supportive therapy. This approach is endorsed by several practical guidelines, including those from Switzerland [9]. Additionally, TXA has been suggested as a supportive option for antiplatelet-associated bleeding, as summarized by Fischer et al. [10], who reviewed its potential role in mitigating bleeding related to antiplatelet agents.

Patients on dual therapy (antiplatelet+anticoagulant)

Patients receiving both antiplatelet and anticoagulant agents are at particularly high risk of bleeding. TXA may be beneficial in perioperative or acute bleeding scenarios in such patients.

In orthopedic surgery, Zak et al. confirmed the safety of TXA even in patients with a history of coronary artery disease, with both intravenous and topical administration proving effective [11-15]. The TREATT trial, targeting patients with hematologic malignancies and thrombocytopenia, is expected to offer insights into the prophylactic use of TXA in this high-risk population [16].

Summary of TXA dosing and clinical studies by condition

The clinical application of TXA varies depending on the type of bleeding and patient population. While its mechanism of action remains consistent, dosing regimens and administration routes differ across clinical contexts. The following table summarizes key studies involving TXA in settings such as trauma, cardiac and orthope-dic surgery, intracranial hemorrhage, and hematologic malignancies. These findings emphasize the importance of early administration— particularly within 3 hours—for optimal outcomes in trauma and intracranial bleeding (Table 1).

Safety and adverse effects of TXA

Although TXA is generally considered safe, caution is warranted in certain clinical settings. A notable adverse effect is seizures, particularly in high-dose intravenous regimens used in cardiac surgery (>50 mg/kg/day), likely due to central nervous system accumulation and GABA receptor antagonism [17].

Renal impairment increases the risk of TXA accumulation, necessitating dose adjustment based on estimated glomerular filtration rate (eGFR). Despite concerns regarding thromboembolic events (e.g., VTE, MI), large-scale trials such as CRASH-2 and WOMAN found no significant increase in such complications [14,15].

However, the HALT-IT trial observed a slight increase in thromboembolic and seizure events in patients with gastrointestinal bleeding, suggesting the need for caution in this population [18].

Topical or oral TXA is associated with fewer systemic side effects and may be preferable in lower-risk scenarios. Importantly, TXA does not interfere with the pharmacodynamics of antiplatelet or anticoagulant agents, allowing for safe co-administration.

In summary, TXA should be used with caution in:

• High-dose or cardiac surgery cases

• Patients with severe renal dysfunction (eGFR<30 mL/min/1.73 m²)

• Individuals with a history of seizures or neurologic disorders

• Acute GI bleeding, as per HALT-IT trial findings

Conclusion and future directions

TXA is a safe and effective antifibrinolytic agent widely used in trauma, surgery, and other bleeding scenarios. Among cardiovascular patients on antithrombotic agents, TXA reduces perioperative bleeding, transfusion needs, and reoperation rates without interfering with the mechanisms of antiplatelet or anticoagulant therapies. However, current evidence is limited by reliance on observational data in some settings and the scarcity of randomized trials in dual antithrombotic therapy populations.

Future research priorities include:

• Large-scale studies targeting dual therapy populations

• Optimization of dosing and timing in acute bleeding scenarios

• Long-term evaluation of thrombotic risk

• Assessment of indirect effects on platelet function

• Development of personalized protocols for high-risk groups (e.g., NOAC-related ICH, renal failure, neurocritically ill patients)

Ongoing global trials are expected to expand TXA’s clinical indications and guide future recommendations.

Fig. 1.

Mechanism of action of tranexamic acid (TXA). TXA binds to the lysine binding site of plasminogen, blocking fibrin–plasminogen interaction and preventing the conversion of plasminogen to plasmin by tPA. This stabilizes fibrin clots and inhibits fibrin degradation.

Table 1.

Summary of representative clinical studies involving tranexamic acid (TXA)

Study/Trial	Study design	Population/Setting	TXA dosing/Route	Main findings
Tian et al.	Meta-analysis	Cardiac surgery patients on antiplatelets	IV TXA (varied doses)	Decrease bleeding (~370 mL), decrease reoperation
Shi et al.	RCT	CABG patients on clopidogrel	IV TXA pre-op and intra-op	Decrease blood loss, transfusion, reoperation
Weber et al.	In vitro study	Platelet function in vitro	TXA in platelet-rich plasma	Partial restoration of platelet aggregation
TICH-2 trial	RCT	Spontaneous ICH (non-traumatic)	1 g IV bolus + 1 g over 8 hr	Decrease Hematoma expansion, no functional improvement
TICH-NOAC study	Observational (pilot)	NOAC-associated ICH	Within 6 hr of symptom onset	Trend toward bleeding control, no excess AE
Zak et al.	Observational cohort	Orthopedic surgery with CAD history	IV or topical TXA	Effective and safe in CAD patients
TREATT trial	RCT	Hematologic malignancy, thrombocytopenia	IV TXA prophylaxis	Ongoing evaluation for high-risk patients
HALT-IT trial	RCT	GI bleeding	1 g IV loading + 3 g over 24 hr	No benefit, Increases seizures and thrombosis
CRASH-2 trial	RCT	Trauma with bleeding risk	1 g IV bolus + 1 g over 8 hr (within 3 hr)	Decrease Mortality from bleeding, no excess thrombosis
WOMAN trial	RCT	Postpartum hemorrhage	Same as CRASH-2 protocol	Decrease Death from bleeding, safe profile

References

1. Lam T, Medcalf RL, Cloud GC, Myles PS, Keragala CB. Tranexamic acid for haemostasis and beyond: does dose matter?. Thrombosis journal 2023;21(1).94.

2. Cai J, Ribkoff J, Olson S, Raghunathan V, Al‐Samkari H, DeLoughery TG, et al. The many roles of tranexamic acid: an overview of the clinical indications for TXA in medical and surgical patients. European journal of haematology 2020;104(2).79-87.

3. Levy JH, Koster A, Quinones QJ, Milling TJ, Key NS. Antifibrinolytic therapy and perioperative considerations. Anesthesiology 2018;128(3).657.

4. Tian L, Li X, He L, Ji H, Yao Y; Group EiCA. Hemostatic effects of tranexamic acid in cardiac surgical patients with antiplatelet therapy: a systematic review and meta-analysis. Perioperative Medicine 2024;13(1).58.

5. Shi J, Ji H, Ren F, Wang G, Xu M, Xue Y, et al. Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: a multicenter randomized trial. JAMA surgery 2013;148(6).538-47.

6. Weber CF, Görlinger K, Byhahn C, Moritz A, Hanke AA, Zacharowski K, et al. Tranexamic acid partially improves platelet function in patients treated with dual antiplatelet therapy. European Journal of Anaesthesiology| EJA 2011;28(1).57-62.

7. Pszczolkowski S, Sprigg N, Woodhouse LJ, Gallagher R, Swienton D, Law ZK, et al. Effect of tranexamic acid administration on remote cerebral ischemic lesions in acute spontaneous intracerebral hemorrhage: a substudy of a randomized clinical trial. JAMA neurology 2022;79(5).468-77.

8. Polymeris AA, Karwacki GM, Siepen BM, Schaedelin S, Tsakiris DA, Stippich C, et al. Tranexamic acid for intracerebral hemorrhage in patients on non-vitamin K antagonist oral anticoagulants (TICH-NOAC): a multicenter, randomized, placebo-controlled, phase 2 trial. Stroke 2023;54(9).2223-34.

9. Sauter TC, Eberle B, Wuillemin WA, Thiele T, Angelillo-Scherrer A, Exadaktylos AK, et al. How I manage patients with anticoagulation-associated bleeding or urgent surgery. Swiss medical weekly 2018;148(1112).w14598-w.

10. Fischer K, Bodalbhai F, Awudi E, Surani S. Reversing bleeding associated with antiplatelet use: the role of tranexamic acid. Cureus 2020;12(9).

11. Zak SG, Tang A, Sharan M, Waren D, Rozell JC, Schwarzkopf R. Tranexamic acid is safe in patients with a history of coronary artery disease undergoing total joint arthroplasty. JBJS 2021;103(10).900-4.

12. Estcourt LJ, McQuilten Z, Powter G, Dyer C, Curnow E, Wood EM, et al. The TREATT Trial (TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia): safety and efficacy of tranexamic acid in patients with haematological malignancies with severe thrombocytopenia: study protocol for a double-blind randomised controlled trial. Trials 2019;20(1).592.

13. behalf of CRASH O. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. The Indian Journal of Neurotrauma 2012;9(1).3-14.

14. Roberts I, Edwards P, Prieto D, Joshi M, Mahmood A, Ker K, et al. Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms. Trials 2017;18(1).48.

15. Poeran J, Rasul R, Suzuki S, Danninger T, Mazumdar M, Opperer M, et al. Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. Bmj 2014:349.

16. Estcourt LJ, McQuilten ZK, Bardy P, Cole-Sinclair M, Collins GP, Crispin PJ, et al. Tranexamic acid versus placebo to prevent bleeding in patients with haematological malignancies and severe thrombocytopenia (TREATT): a randomised, double-blind, parallel, phase 3 superiority trial. The Lancet Haematology 2025;12(1).e14-e22.

17. Couture P, Lebon J-S, Laliberté É, Desjardins G, Chamberland M-È, Ayoub C, et al. Low-dose versus highdose tranexamic acid reduces the risk of nonischemic seizures after cardiac surgery with cardiopulmonary bypass. Journal of cardiothoracic and vascular anesthesia. 2017;31(5).1611-7.

18. Horton LC, Feuerstein JD. In adults with severe acute GI bleeding, tranexamic acid did not reduce death due to bleeding at 5 days. Annals of Internal Medicine 2020;173(8).JC46.