The Role of Tranexamic Acid (TXA) in Reducing Mortality in Trauma and Bleeding Patients

Introduction

An injury is any damage inflicted on the body, causing an imbalance in homeostasis, whether on purpose or not. (1). Accounting for 4.4 million deaths every year, as reported by the World Health Organization, trauma and injuries are considered the leading cause of mortality and Disability-Adjusted Life Years worldwide (2, 3). They are prevalent among people below 40 owing to road traffic injuries or unintentional self-inflicted violence in the form of suicide or homicide. Moreover, death attributed to post-partum hemorrhage accounts for the majority of maternal mortality rates. Studies report that trauma patients often die on site or within 48 hours of injury due to severe hemorrhage or head injury. However, severe uncontrollable hemorrhage can be prevented by blocking the process of Hyperfibrinolysis (4).

Fibrinolysis is the degradation of the fibrin coat of blood clots, which are formed following an injury. It is essential to maintain hemostasis and restore vascular blood flow. However, it might result in bleeding, particularly in veins with narrow to medium diameters, where the large amount of profibrinolytic agents around the fibrin mesh remodels the blood clot to ensure blood flow. Thus, patients who suffer from dysfunctional hemostasis (thrombosis or bleeding) often suffer from bleeding, which is attributed to an overactive fibrinolytic system (5, 6). Halting uncontrolled bleeding depends on identifying the location of injury and choosing a suitable agent to restore hemostasis (7).

There are several types of hemostatic agents, each of which acts on a different stage in the hemostatic process, whether through the intrinsic or extrinsic pathways. Thus, leading to the activation of factor X, prothrombin, fibrinogen, and Factor XIII into factor Xa, thrombin, fibrin, and factor XIIIa, resulting in the development of a fibrin clot. Current hemostatic agents include biologically active agents like thrombin, antifibrinolytics like TXA, and absorbable agents like gelatin. Moreover, the recent advancements in nanotechnology have led to the development of micro- and nano-based agents, which are site-specific and require low doses. However, traditional hemostatic agents, particularly Tranexamic acid, are still being widely used given their cost-effectiveness and rapid, aimable administration(8).

TXA is a lysine analog used as an antifibrinolytic agent. It prevents bleeding by inhibiting the binding of plasminogen to fibrin in the hemostatic pathway(9). TXA has a variety of treatment applications, including heavy menstrual bleeding, trauma, postpartum hemorrhage, traumatic brain injury, and perioperative bleeding. TXA was reported to reduce mortality caused by postpartum hemorrhage as well as trauma and brain injury by several landmark studies, such as WOMAN, CRASH 2, and CRASH 3 trials (10-12). However, its efficacy depends on the time of administration, where it should be administered immediately or within 3 hours of injury for high effectiveness (13). This review aims to demonstrate the mechanism of action of TXA as a hemostatic agent and to explore its safety and efficacy in reducing the mortality rates associated with trauma.

Methodology

This review is based on a comprehensive literature search including the most recent studies from 2015 to 2025 in the PubMed and Clinical Key databases, as well as Google Scholar. Utilizing MeSH (Medical Subject Headings) and relevant keywords, such as” Tranexamic acid” (TXA), “Fibrinolysis”, “Coagulation”, “Antifibrinolytic Agents”, “Hemorrhage”, “Post-partum Hemorrhage”, “Trauma Induced coagulopathy” (TIC). The search aimed to explore studies that explore the underlying mechanisms of the hemostatic system and how the antifibrinolytic action of tranexamic acid (TXA) contributes to halting hemorrhage associated with various fatal conditions. It also aims to demonstrate recent knowledge on the administration routes and dosage of TXA. The search was not restricted by publication date, language, or type of publication to ensure a broad exploration of the available literature.

Discussion

The Hemostatic System: Coagulation vs Fibrinolysis

Hemostasis is the body’s natural response to traumatic injuries. It is critical to stop bleeding and prevent blood loss. The occurrence of an injury activates the blood platelets at the site of injury, which in turn produce fibrin and form a plug along with the cells. Unlike the case of uncontrolled bleeding, where the cells are unable to form a plug (7, 14). Hemostasis is composed of 2 stages: a primary stage where platelets are activated by binding to the newly exposed vascular subendothelial components, like collagen. Then, upon activation, they release thromboxane and other mediators, attracting more platelets and forming a primary plug (7).

On the contrary, secondary hemostasis has two pathways, an extrinsic pathway with a rapid action in case of external vascular damage, in which tissue factor (TF) released from the vessel walls acts as a cofactor that activates a cascade leading to the activation of prothrombin to thrombin and the development of fibrin. On the contrary, the intrinsic pathway occurs in case of internal damage, and it starts with Hageman factor being activated by contact with exposed endothelium, collagen, high molecular weight kininogen (HK), prekallikrein, and Hageman factor (Factor XII). Both pathways end with the common pathway in which FX, prothrombin, fibrinogen, and Factor XIII are activated into Factor Xa, thrombin, fibrin, and Factor XIIIa.This eventually leads to the formation of a fibrin clot by thrombin (15, 16).

Following wound healing, the fibrin clot must be degraded to allow normal blood flow by a process known as fibrinolysis. (6). Fibrolysis is balanced by the action of plasminogen activators (tissue-type and urokinase-type) that convert plasminogen into plasmin to initiate fiber lysis and lytic inhibitors that impede this lysis (plasminogen fibrinolysis inhibitor)(17). During the process of fibrinolysis, damaged endothelial cells release tissue plasminogen activator, then plasminogen binds to fibrin at the lysin binding sites. The three of them form a complex that activates plasminogen into plasmin, which in turn degrades fibrin. Afterwards, plasmin inhibitors, such as C1-esterase inhibitor, block the action of plasmin. Thus, preventing further lysis. (6, 17).

Trauma-Induced Coagulopathy (TIC) and Antifibrinolytic Action of TXA

TXA is a synthetic analog of the amino acid lysine; it strongly binds to lysine-binding sites on plasminogen. Consequently, it protects fibrin from degradation by preventing its interaction with plasminogen. Thus, demonstrating an antifibrinolytic effect. Since TIC, linked to fibrinolysis, can elevate mortality rates in trauma cases, TXA could be beneficial for patients experiencing hemostatic irregularities in the initial stages of trauma. On the contrary, when administered in later stages, the subsequent rise in plasminogen activator inhibitor-1 levels leads to the complete suppression of fibrinolysis (18).

The prevalence of trauma-induced coagulation is approximately 25%, accounting for 35-50 % mortality rates. (19). TIC is mostly caused by trauma, severe injuries, or diminished blood flow.

Platelets play a vital role in the hemostatic system by aiding in the process of clotting factor assembly and the release of thrombin through interaction with the endothelium and the generation of fibrin, which forms a hemostatic plug. Injuries activate the endothelium, platelets, and the immune system simultaneously. Thus, resulting in the release of a group of mediators that impair the function of platelets, lower the concentration of fibrinogen, which in turn reduces the levels of thrombin, compromising clot formation and hemostasis (20).

The excessive generation of plasmin leads to hyperfibrinolysis and uncontrollable blood loss, which contributes to forming the lethal triad of trauma: hemodilution, metabolic acidosis, and hypothermia. In detail, excessive loss of blood leads to hypothermia, then large volumes of fluids are administered intravenously to compensate for blood loss and maintain blood pressure, resulting in hemodilution. In accordance with anorexia, lactic acid produced by anaerobic metabolism leads to acidosis. Finally, low concentrations of clotting factors owing to hemodilution, impaired enzyme function attributed to hypothermia, and reduced thrombin generation caused by acidemia develop severe coagulopathy, contributing to increased bleeding and adverse patient outcomes (21, 22). Given that injuries caused by trauma are the leading cause of mortality worldwide. Proper management of uncontrolled bleeding is highly urged. Several hemostatic agents are used in the treatment of uncontrolled hemorrhage. Among the most widely used agents for halting uncontrolled bleeding is the antifibrinolytic agent TXA.

TXA Indications

TXA in Trauma

Several clinical trials demonstrated the role of TXA in reducing hemorrhage caused by trauma with an administered dose of 1 gram. In CRASH 2, the landmark trial which enrolled more than 20000 trauma patients from 40 different countries, Roberts et al. (2013) reported that the efficacy of TXA to reduce the rate of death due to trauma depends on the time of administration, with optimal efficacy achieved on administration within 3 hours of injury. (23). On the contrary, Gruen, R. L. et al. (2023) reported that the prehospital administration of TXA followed by an infusion of the acid after 8 hours didn’t have a significant effect on survival (24). Moreover, Kaur et al. (2021) demonstrate TXA's ability to mitigate postoperative declines in hemoglobin and hematocrit levels at 24, 48, and 72 hours, in contrast to placebo. (25).

Strong evidence from systematic reviews further proves the efficacy of TXA in the treatment of hemorrhage associated with trauma. In detail, the systematic review by Augustinus et al. (2023) included 13 articles encompassing 54,843 patients undergoing hemiarthroplasty surgery and found that 14.1% (7733 patients) of these patients who received perioperative TXA experienced a significant decrease in transfusion rates, improved postoperative hemoglobin levels, reduced hospital stay lengths, and lower 30-day mortality (26). Similarly, a meta-analysis by Liechti et al. in 2023 involving 1139 mastectomy patients revealed that perioperative intravenous administration of TXA reduced the risk of hematoma and seroma formation (27). Furthermore, a meta-analysis by Liu et al. in 2022, covering 1497 patients undergoing spine surgery, demonstrated that TXA decreased total and perioperative blood loss, postoperative drainage, hospital stay duration, total blood transfusion volume, and international normalized ratio (28). TXA has also proven to be effective in the treatment of trauma under severe conditions

The resuscitation of trauma patients at high altitudes, as in military settings or harsh environments, poses a significant challenge. This is attributed to hypoxia and limited resources for blood transfusion. Nevertheless, a study by Brito (2021) demonstrated the beneficial use of TXA in such conditions, being a portable intervention. (29). Besides the use of TXA in trauma, it has been reported to be effective in the treatment of postpartum Hemorrhage (PPH), traumatic brain injury, and heavy menstrual bleeding.

Other Indications of TXA

Among the significant trials reporting the efficacy of TXA in the treatment of postpartum hemorrhage is the WOMAN’s trial in 2017, in which colaborators, 2017 reported that TXA is effective in reducing death due to postpartum hemorrage when adminstered at a dose of 1 gram articulary within 3 hours of giving birth, in a randomised, double-blind, placebo-controlled trial which recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries (30). However, in the recent WOMAN 2 study in 2024, TXA showed no efficacy compared to placebo in anemic pregnant women (31).

In addition to treatment of postpartum hemorrhage and heavy menstrual bleeding, the CRASH 3 trial, which encompassed 12,737 patients with TBI, proved TXA to be effective in traumatic brain injury patients when administered within 1 hour of injury (32). Given its various indications, TXA has several adverse effects if not administered at the appropriate time and dosage.

Disclosure

Conflict of interest

There is no conflict of interest.

Funding

No funding.

Ethical consideration

Non applicable.

Data availability

Data that support the findings of this study are embedded within the manuscript.

Author contribution

All authors contributed to conceptualizing, data drafting, collection and final writing of the manuscript.