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BMJ: first published as 10.1136/bmj-2023-075720 on 4 January 2024. Downloaded from http://www.bmj.com/ on 5 January 2024 at Medical Genetics Research Center. Protected by
1 Department of Transfusion Medicine THERAPEUTICS
and Hematology, Carlo Poma
Hospital, Mantova, Italy

2 North-Western Tuscany Blood Bank,

Efficacy and safety of tranexamic acid in acute haemorrhage
Pisa University Hospital, Italy Massimo Franchini, 1 Daniele Focosi, 2 Marco Zaffanello, 3 Pier Mannuccio Mannucci4
3 Department of Surgical Sciences,
of severe blood loss include major surgery (especially
Dentistry, Gynecology and Pediatrics, What you need to know cardiovascular, liver, and orthopaedic interventions),
University of Verona, Verona, Italy
• Tranexamic acid is a synthetic haemostatic drug that traumas, and the peripartum period.2 Postoperative,
4 Fondazione IRCCS Ca’
inhibits fibrinolysis
peripartum, and trauma related bleeding often
Granda-Ospedale Maggiore Policlinico requires blood transfusions which are lifesaving but
and University of Milan, Angelo • It is effective in reducing bleeding and mortality,
Bianchi Bonomi Hemophilia and
have drawbacks, such as scarcity of units, the risk of
although to different extents in trauma, peripartum,
Thrombosis Center, Milan, Italy mismatched transfusion, allergic reactions,
and surgical settings
Correspondence to M Franchini
transfusion related acute lung injury, and transfusion
• It is generally safe and inexpensive with few adverse
[email protected] associated circulatory overload.2 To minimise the
reactions, although further studies are needed to
Cite this as: BMJ 2024;384:e075720 need for transfusions in patients with acute bleeding,
assess its safety in settings of high thromboembolic
http://dx.doi.org/10.1136/bmj-2023-075720 risk several surgical procedures, anaesthetic techniques,
Published: 04 January 2024 and haemostatic medications have been developed.
Among the haemostatic medications, tranexamic acid
A 33 year old woman in the fourth month of pregnancy
is one of the most commonly used.
is referred to the emergency department because of
spontaneous massive antepartum haemorrhage. On What is tranexamic acid?
admission her haemoglobin level has dropped to 7 g/dL
Tranexamic acid is a synthetic lysine related
and she is transfused with three packed red blood cell
anti-fibrinolytic amino acid which binds reversibly
units. Her coagulation parameters are normal but
to the lysine receptor sites of plasminogen, thereby
sonography of the fetus reveals a formerly unknown
inhibiting the interaction with formed plasmin and
placenta praevia. Bleeding stops immediately after
fibrin.2 3 As a result, fibrin degradation is prevented,
placement into the vagina of a cotton swab soaked
and the framework of the fibrin’s matrix structure is

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with a 1000 mg vial of tranexamic acid. In addition,
preserved.3 -5 Tranexamic acid is more commonly
on-demand oral therapy with tranexamic acid (1000
used than the other lysine derivative ε-aminocaproic
mg every eight hours) is prescribed at home during
acid (EACA) as it has a 10-fold greater potency.3
minor bleedings for the rest of the pregnancy, enabling
successful delivery by caesarean section at week 31. Because of its ability to inhibit fibrinolysis and clot
degradation, tranexamic acid has been used
Acute haemorrhage successfully to prevent or reduce blood loss in various
Haemorrhage is historically defined as the loss of clinical conditions characterised by excessive
20% or more of the total blood volume (albeit recent bleeding6 7 in adults and in children over the age of
definitions are more focused on haemodynamics1), 1.8 9 Characteristics of tranexamic acid are presented
which is associated with an increased risk of in table 1.
morbidity and mortality. The most common causes

Table 1 | Characteristics of tranexamic acid

Tranexamic acid
Chemical name trans-4-aminomethylcyclohexanecarboxylic acid
Mechanism of action Anti-fibrinolytic agent. Competitive inhibitor of plasminogen activation
Dosage forms 250-500 mg tablets; 500 mg/5 mL vials; 1000 mg/10 mL vials
Route of administration Oral, topical, or intravenous
Dose 15 mg/kg every 6-8 hours. Dose adjustment in patients with renal failure
according to serum creatinine levels. Tranexamic acid is approved in children
from 1 year of age. Dosages are calculated based on children’s weight
Adverse events Changes to vision (with prolonged treatment). Gastrointestinal symptoms
and allergic reactions (skin rash). Concomitant use with oral contraceptives
or oestrogens may potentiate a hypercoagulable state. Uncertain risk for
venous thromboembolism

The drug is not a magic bullet, however.10 Since its have taken a more balanced view of its safety and
enthusiastic reception in the 1960s,11 researchers efficacy.12 13

This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with
important new indications or concerns. To suggest a topic, please email us at [email protected]

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BMJ: first published as 10.1136/bmj-2023-075720 on 4 January 2024. Downloaded from http://www.bmj.com/ on 5 January 2024 at Medical Genetics Research Center. Protected by
How well does tranexamic acid work in acute surgery, gastrointestinal bleeding, and peripartum haemorrhage.
haemorrhage? Key points are presented in the following sections and major trials
summarised in table 2. This article primarily focuses on the use of
Trials of tranexamic acid have been conducted in acute trauma, intravenous tranexamic acid in the acute inpatient setting.

Table 2 | Clinical results of the largest randomised controlled trials on the use of tranexamic acid for the treatment of acute bleeding
Trial Design Patients/controls (n) Results
CRASH-221 Trauma patients randomised to receive 10 096/10 115 Reduction of all-cause of death (placebo 16%
tranexamic acid or placebo v tranexamic acid 14.5%; absolute mortality risk
reduction=1.5%; NTT=67; RR 0.91, 95% CI 0.85
to 0.97, P=0.0035) and bleeding-related death
(placebo 5.7% v tranexamic acid 4.9%;
absolute mortality risk reduction=0.8%;
NTT=125; RR 0.85, 95% CI 0.76 to 0.96,
P=0.0077)
CRASH-314 Patients with recent traumatic brain injury 6406/6331 Reduction of the risk of head injury-related
randomised to receive tranexamic acid or death with tranexamic acid versus placebo in
placebo patients treated within 3 hours of injury
(placebo 19.8% v tranexamic acid 18.5%;
absolute mortality risk reduction=1.3%;
NTT=77) and in patients with mild-to-moderate
head injury (RR 0.78, 95% CI 0.64 to 0.95)
WOMAN15 Women with postpartum haemorrhage 10 051/10 009 Death caused by bleeding: placebo 1.9% v
randomised to receive tranexamic acid or tranexamic acid 1.5% (RR 0.81; 95% CI 0.65 to
placebo 1.00; P=0.045); absolute mortality risk
reduction=0.4%; NTT=250, and death if
tranexamic acid within 3 hours: placebo 1.7%
v tranexamic acid 1.2% (RR 0.69; 95% CI 0.52
to 0.91; P=0.008); absolute mortality risk
reduction=0.5%; NTT=200, and laparotomy to

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control bleeding: placebo 1.3% v TXA 0.8%
(RR 0.64; 95% CI 0.49 to 0.85; P=0.002);
absolute mortality risk reduction=0.5%;
NTT=200, and no significant differences in
composite primary endpoint (death from all
causes or hysterectomy): placebo 5.5% v
tranexamic acid 5.3% or hysterectomy: placebo
3.5% v tranexamic acid 3.6%; RR 1.02, 95%
CI, 0.88 to 1.07; P=0.84
HALT-IT16 Patients with acute gastrointestinal bleeding 5994/6015 Tranexamic acid did not reduce death from
randomised to receive tranexamic acid or gastrointestinal bleeding
placebo (RR 0.99, 95% CI 0.82 to 1.18)
PATCH17 Trauma patients randomised to receive 661/646 Tranexamic acid led to reduced mortality at 1
tranexamic acid or placebo month (RR 0.79) and 6 months (RR 0.83), but
no difference in functional outcome at 6
months
TRAAP218 Women undergoing caesarean delivery 2086/2067 Prophylactic tranexamic acid significantly
randomised to receive tranexamic acid or reduced postpartum haemorrhage incidence
placebo (adjusted RR 0.84, 95% CI 0.75 to 0.94; P=
0.003) compared with placebo
RR=risk ratio; NNT=number needed to treat

Trauma CRASH-320 found a significant reduction in head injury-related

death (modified primary endpoint), but not in overall mortality
Two randomised controlled trials (RCTs) (n=20 451) have assessed
which was the original primary endpoint (only when patients with
the effect of tranexamic acid in acute trauma. The larger of these
poorer prognosis were excluded in a sensitivity analysis).21 The
(CRASH-2, n=20 211)15 was conducted in 40 countries and included
international placebo controlled PATCH RCT which included 1310
patients with a variety of trauma; the other (CRASH-3, n=240)16 was
adults with major trauma found that pre-hospital administration
restricted to those with traumatic brain injury. These trials found a
of 1 g bolus tranexamic acid followed by 1 g infusion over eight
lower mortality rate in patients with acute traumatic injury receiving
hours led to reduced mortality at one month (relative risk, RR, 0.79;
tranexamic acid compared with the placebo group. In CRASH-2
95% CI 0.63 to 0.99) but no difference in favourable functional
(which, within eight hours of injury, infused 1 g tranexamic acid
outcome at six months.17 22
over 10 minutes followed by 1 g over eight hours19), however, 65%
of all deaths and 55% of deaths within one hour were not related A recent systematic review of tranexamic acid use in paediatric
to bleeding, and the bleeding-related absolute reduction of mortality trauma found that children treated with tranexamic acid had longer
of 0.8% connotes a number needed to treat of 125. In addition, survival despite more severe injuries and worse prognostic

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predictors compared with those who did not receive tranexamic mode of birth, and without increasing the risk of thromboembolic
acid.23 The European Medicine Agency’s recommended dose of events.39
tranexamic acid for children is generally 15 mg/kg of body weight
In the TRAAP2 RCT, among 4551 women who underwent caesarean
given by intravenous injection every 8-12 hours until bleeding is
delivery and received prophylactic uterotonic agents, prophylactic
controlled.9
administration of tranexamic acid resulted in a statistically
Surgery significantly lower incidence of calculated estimated blood loss
>1000 mL or red cell transfusion by day two than placebo (reduction
Tranexamic acid has been used successfully to reduce blood loss
of blood loss of 107 mL (-63 to -152 mL).40 41 In contrast, a double
in several surgical specialties, especially in cardiac and major
blind RCT of 10 995 women undergoing caesarean section found no
orthopaedic surgery.15 16 24 25 It is considered fundamental to blood
reduction in red blood cell transfusions but a modest decrease in
management programmes in transfusion medicine, which aim to
the use of uterotonics when delivering 1 g intravenous tranexamic
minimise perioperative blood loss and thus exposure to allogeneic
acid immediately after cord clamping. Prophylactic intravenous
blood in elective surgeries.14 26 27 In the ATACAS RCT that included
tranexamic acid did not improve blood loss-related outcomes in
4662 patients undergoing cardiac surgery, those randomised to
another RCT on 4079 women with single pregnancy and vaginal
receive tranexamic acid had half the number of major haemorrhages
delivery.42 Finally, an overview including 14 systematic reviews of
or episodes of cardiac tamponade (1.4% v 2.8%, P=0.001) compared
tranexamic acid after caesarean section concluded that prophylactic
with those receiving placebo.28
tranexamic acid may reduce blood transfusion, but rigorous well
In the POISE-3 RCT, tranexamic acid (1 g intravenously at the start designed research is still needed due to the limitations of the
and end of surgery) was compared with placebo in 9535 patients included studies.43
having non-cardiac surgery who were at risk for bleeding and
cardiovascular events and were receiving one or more long term What are the harms?
antihypertensive medications. The trial found a significantly lower Serious adverse events
incidence of composite bleeding (life threatening bleeding, major
The main perceived risk of tranexamic acid is the onset of thrombotic
bleeding, or bleeding into a critical organ) at 30 days (9.1% v 11.7%,
complications owing to its inhibition of fibrinolysis, which is a
hazard ratio, HR, 0.76, 95% CI 0.67 to 0.87, equivalent to a number
natural mechanism of defence against thrombus formation. Most
needed to treat of 38), but not of cardiovascular events (14.2% v
publications do not systematically search for thromboembolic
13.9%, HR 1.02, 95% CI 0.92 to 1.14) in the tranexamic acid-treated
complications or even exclude patients at risk, and this
group than in the placebo group.29
between-studies clinical heterogeneity could represent a serious

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Gastrointestinal and other acute haemorrhages limitation for meta-analyses. Evidence is conflicting and often
In the HALT-IT RCT conducted in patients with acute gastrointestinal lacking, but we believe there is an increased risk for those already
bleeding, tranexamic acid did not reduce deaths (risk ratio 0.99, at high risk of thrombosis. For example, a meta-analysis of 216
95% CI 0.82 to 1.18)30 and showed an increased risk of venous clinical trials including 125 550 participants did not find an
thromboembolic events (RR 1.85, 95 CI 1.15 to 2.98) and seizures (RR association between intravenous tranexamic acid treatment and
1.73, 95% CI 1.03 to 2.93),31 potentially because of the high thromboembolic events, and no increased risk of vascular occlusive
tranexamic acid dose (4 g) or late treatment initiation. Similarly, events in patients with a history of previous thromboembolism.44
no beneficial effect was seen in patients with haematological The TRAAP-2 trial, which evaluated the effect of tranexamic acid
malignancy in the A-TREAT study,32 in patients with intracerebral in preventing blood loss in 4153 caesarean deliveries, found an
haemorrhage in the STOP-AUST study,33 or those with subarachnoid adjusted risk ratio (aRR) for deep vein thrombosis or pulmonary
haemorrhage in the ULTRA study.34 For hyperacute primary embolism of 4.01 (95% CI 0.85 to 18.92) three months after delivery
intracerebral haemorrhage, the TICH-2 study did not show a better and an aRR for arterial embolisation, emergency surgery, or
functional outcome after 90 days for tranexamic acid compared hysterectomy of 1.84 (95% CI 0.73 to 4.62).40 In trauma, tranexamic
with placebo.35 acid is a potential adjunctive thromboembolic risk factor,45 and a
recent meta-analysis found an odds ratio (OR) of 2.60 (95% CI 1.7
Peripartum haemorrhage to 4.1; P<0.001) for the development of thromboembolic events after
The WOMAN RCT was conducted in women with postpartum tranexamic acid administration.46 Another meta-analysis found a
haemorrhage (PPH) after vaginal delivery or caesarean section (table pooled incidence of in-hospital thrombotic events of 5.9% (95% CI
2) and found a marginal but statistically significant effect of 1 g 3.3% to 8.5%), about three times higher than that reported in the
intravenous tranexamic acid (followed by another 1 g if bleeding CRASH-2 trial (2.0%, 95% CI 1.8% to 2.3%).47 Nevertheless, a recent
continued) on reduction of death caused by bleeding (RR 0.81, 95% systematic review and meta-analysis, including 73 RCTs and
CI 0.65 to 1.00; P=0.045).36 This absolute reduction was 0.4% (death evaluating the safety of tranexamic acid in the setting of orthopaedic
caused by bleeding) or 0.5% (death if tranexamic acid was given surgery (a procedure carrying an increased thromboembolic risk),
within three hours of delivery), implying a number needed to treat found a similar incidence of venous thrombotic events in tranexamic
of 250 and 200, respectively, to prevent one death.37 In the recent acid -treated patients and controls.48
E-MOTIVE RCT recruiting 210 132 women undergoing vaginal The profound toxicity of inadvertent intrathecal tranexamic acid
deliveries in southern Africa, a holistic multi-component administration in place of obstetric spinal anaesthesia resulted in
intervention (which included tranexamic acid) reduced major a 50% mortality owing to neurotoxicity and seizures across case
bleeding and maternal mortality following postpartum haemorrhage reports and series.49
compared with usual care (1.6% v 4.3%, risk ratio, 0.4, 95% CI 0.32
to 0.50, P<0.001).38 A Cochrane systematic review on three RCTs Minor adverse events
involving 20 412 women concluded that tranexamic acid Other side effects of tranexamic acid use include visual changes or
administered intravenously reduces mortality caused by bleeding involve the gastrointestinal tract, and are typically dose dependent.
in women with primary postpartum haemorrhage, irrespective of Gastrointestinal symptoms, which include nausea, vomiting,

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BMJ: first published as 10.1136/bmj-2023-075720 on 4 January 2024. Downloaded from http://www.bmj.com/ on 5 January 2024 at Medical Genetics Research Center. Protected by
dyspepsia, and diarrhoea, often subside with dose reduction. Advisers to this series are Robin Ferner and Patricia McGettigan.
Hypotension and bradycardia may occur with excessively rapid
Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial
intravenous infusion. Seizures have been reported with tranexamic companies. The authors declare the following other interests: none.
acid administration, especially at high doses.3 Hypersensitivity
reactions, such as rash and rarely anaphylaxis, may occur. Provenance and peer review: commissioned; externally peer reviewed.
Tranexamic acid is contraindicated in patients with haematuria
because blood from the upper urinary tract can provoke painful 1 Stanworth SJ, Dowling K, Curry N, etalTransfusion Task Force of the British Society for
Haematology. Haematological management of major haemorrhage: a British Society for
clot retention.3 Haematology Guideline. Br J Haematol 2022;198:-67. doi: 10.1111/bjh.18275. pmid: 35687716
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requirements). Tranexamic acid is about 1000 times cheaper per bleeding. Haematologica 2020;105:-5. doi: 10.3324/haematol.2020.250720. pmid: 32336684
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haemorrhage.50 A head-to-head cost effectiveness analysis between 7 Cai J, Ribkoff J, Olson S, etal. The many roles of tranexamic acid: an overview of the clinical
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Tranexamic acid at vaginal delivery has a 65-73% probability of 8 European Medicines Agency (EMA). Assessment report. Antifibrinolytics containing aprotinin,
saving costs from hospital resources51 and is likely to be cost aminocaproic acid and tranexamic acid. Tranexamic acid. 2012https://www.ema.europa.eu/en/doc-
effective in countries in sub-Saharan Africa and southern Asia that uments/referral/assessment-report-antifibrinolytic-medicines-tranexamic-acid_en.pdf
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How does tranexamic acid compare with other
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treatments? hemorrhageObstet Gynecol 2017;130:.
Tranexamic acid is usually preferred to the other authorised doi: 10.1097/AOG.0000000000002384. pmid: 29189683
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antifibrinolytic agent EACA because it is 10 times more potent and
new synthetic fibrinolytic inhibitor. Br J Haematol 1965;11:-45.

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