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RESEARCH ARTICLE
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OPEN ACCESS
Citation: Xiong Y, Guo X, Huang X, Kang X, Zhou J,
Chen C, et al. (2023) Efficacy and safety of
tranexamic acid in intracranial haemorrhage: A
meta-analysis. PLoS ONE 18(3): e0282726. https://
doi.org/10.1371/journal.pone.0282726
Editor: Chinh Quoc Luong, Bach Mai Hospital, VIET
NAM
Received: October 14, 2022
Accepted: February 21, 2023
Published: March 31, 2023
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https://doi.org/10.1371/journal.pone.0282726
Copyright: © 2023 Xiong et al. This is an open
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Funding: The author(s) received no specific
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PLOS ONE | https://doi.org/10.1371/journal.pone.0282726 March 31, 2023
Efficacy and safety of tranexamic acid in
intracranial haemorrhage: A meta-analysis
Yu Xiong1☯, Xiumei Guo1,2☯, Xinyue Huang1☯, Xiaodong Kang1☯, Jianfeng Zhou1,
Chunhui Chen1, Zhigang Pan1, Linxing Wang2, Roland Goldbrunner3, Lampis Stavrinou4,
Pantelis Stavrinou3,5, Shu Lin6,7*, Yuping Chen1*, Weipeng Hu1*, Feng Zheng ID1*
1 Department of Neurosurgery, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, Fujian
Province, China, 2 Department of Neurology, The Second Affiliated Hospital, Fujian Medical University,
Quanzhou, Fujian Province, China, 3 Department of Neurosurgery, Center for Neurosurgery, Faculty of
Medicine and University Hospital, University of Cologne, Cologne, Germany, 4 2nd Department of
Neurosurgery, "Attikon" University Hospital, National and Kapodistrian University, Athens Medical School,
Athens, Greece, 5 Neurosurgery, Metropolitan Hospital, Athens, Greece, 6 Centre of Neurological and
Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China,
7 Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
☯ These authors contributed equally to this work.
* dr.feng.zheng@gmail.com (FZ); neurosurgery_fyey@163.com (WH); 503106356@qq.com (YC);
shulin1956@126.com (SL)
Abstract
Background
Although some studies have shown that tranexamic acid is beneficial to patients with intra-
cranial haemorrhage, the efficacy and safety of tranexamic acid for intracranial haemor-
rhage remain controversial.
Method
The PubMed, EMBASE, and Cochrane Library databases were systematically searched.
The review followed PRISMA guidelines. Data were analyzed using the random-effects
model.
Results
Twenty-five randomized controlled trials were included. Tranexamic acid significantly inhib-
ited hematoma growth in intracranial hemorrhage (ICH) and traumatic brain injury (TBI)
patients. (ICH: mean difference -1.76, 95%CI -2.78 to -0.79, I2 = 0%, P < .001; TBI: MD
-4.82, 95%CI -8.06 to -1.58, I2 = 0%, P = .004). For subarachnoid hemorrhage (SAH)
patients, it significantly decreased the risk of hydrocephalus (OR 1.23, 95%CI 1.01 to 1.50,
I2 = 0%, P = .04) and rebleeding (OR, 0.52, 95%CI 0.35 to 0.79, I2 = 56% P = .002). There
was no significance in modified Rankin Scale, Glasgow Outcome Scale 3–5, mortality, deep
vein thrombosis, pulmonary embolism, or ischemic stroke/transient ischemic.
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PLOS ONE Tranexamic acid in intracranial haemorrhage

Competing interests: The authors have declared Conclusion

that no competing interests exist.
Tranexamic acid can significantly reduce the risk of intracranial haemorrhage growth in
patients with ICH and TBI. Tranexamic acid can reduce the incidence of complications
(hydrocephalus, rebleeding) in patients with SAH, which can indirectly improve the quality of
life of patients with intracranial haemorrhage.

1. Introduction
Intracranial haemorrhage is a neurological disease with high morbidity and mortality [1]. It is
a serious form of stroke and a common cause of death and disability [2]. Early hemostasis is
key to treating patients with intracranial haemorrhage [3]. Hematoma enlargement is a power-
ful prognostic factor associated with neurological function in patients with intracranial haem-
orrhage. Therefore, preventing early hematoma growth is the main goal in the treatment of
acute intracranial haemorrhage [4].
Tranexamic acid is a widely used anti-fiber solvent [5]. It is a synthetic lysine analog that
competes with lysine residues on fibrin for the binding of plasminogen that effectively inhibits
the interaction between fibrinolytic enzymes and fibrin and prevents the dissolution of fibrin
clots [6]. In a randomized trial involving 2325 participants, tranexamic acid effectively reduced
hematoma expansion, but its hemostatic effect was not sufficient to translate into improved
functional outcomes [7]. In addition, the effect of tranexamic acid on improving neurological
function in patients with intracranial haemorrhage remains uncertain, and the safety of tra-
nexamic acid in reducing mortality and rebleeding complications in patients with intracranial
haemorrhage remains controversial [2, 4, 8–10]. Therefore, we conducted a meta-analysis to
evaluate the hemostatic effect of tranexamic acid and its safety in improving neurological func-
tion in patients with intracranial haemorrhage.

2. Methods
2.1 Search strategy
Two researchers (YX and FZ) conducted a comprehensive search of the PubMed, EMBASE,
and Cochrane Library databases. All clinical randomized controlled trials (RCTs) published
on tranexamic acid in patients with intracranial haemorrhage before September 2022 were
included. Keywords used in the retrieval strategy included “tranexamic acid”, “intracranial
haemorrhage”, “intracranial hemorrhage”, “subarachnoid hemorrhage”, “traumatic hemor-
rhage”, and “randomized controlled study”. The keywords used in this search strategy
included "Randomized Controlled Trial" AND (“Subarachnoid Hemorrhage” OR “SAH” OR
“Subarachnoid Hemorrhage, Aneurysmal” OR “Subarachnoid Hemorrhage, Spontaneous”
OR “Perinatal Subarachnoid Hemorrhage”OR “Subarachnoid Hemorrhage, Intracranial” OR
“Brain Injuries, Traumatic” OR “Trauma, Brain” OR “TBI” OR “Encephalopathy, Traumatic”
OR “Posterior Fossa Hemorrhage” OR “Brain Hemorrhage” OR “Intracranial Hemorrhages”)
AND (“AMCHA” OR “trans-4” OR “t-AMCHA” OR “AMCA” OR “Anvitoff” OR “Cykloka-
pron” OR “Ugurol” OR “KABI 2161” OR “Spotof” OR “Transamin” OR “Amchafibrin” OR
“Exacyl” OR "Tranexamic Acid"). The medical keywords database was used to identify syno-
nyms. Repetitive literature, case reports, conference summaries, animal experiments, experi-
mental designs, and ongoing experiments were excluded from the analysis. Before data

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analysis, literature retrieval was performed again to ensure that newly published eligible litera-
ture was included. The review was not registered.

2.2 Inclusion and exclusion criteria

The inclusion criteria of the eligible studies were as follows: (1) patients with intracranial
haemorrhage diagnosed by computed tomography or magnetic resonance imaging, including
intracranial hemorrhage (ICH), subarachnoid hemorrhage (SAH), and traumatic brain injury
(TBI); (2) intervention was tranexamic acid therapy (regardless of dose and injection time);
the controls employed a matching placebo or 0.9% saline according to the same administration
schedule; (3) outcome indicators included: modified Rankin scale (mRS), Glasgow Outcome
Scale (GOS), hematoma growth, hematoma expansion, and safety results, including mortality,
hydrocephalus, deep vein thrombosis (DVT), pulmonary embolism (PE), seizures, ischemic
stroke (IS) or transient ischemic attack (TIA), and rebleeding; and (4) the study was a clinical
RCT.
Additionally, the exclusion criteria were as follows: (1) interventions were non-tranexamic
acid treatment; (2) other diseases; (3) compared tranexamic acid with other blood-clotting
agents; (4) non-randomized controlled studies such as retrospective studies, case reports,
reviews, meetings, and letters; (5) ongoing studies; and (6) studies that were still in the early
design stage.

2.3 Selection of studies

Two researchers (YX and FZ) selected studies that met the inclusion criteria according to the
research title and abstract. The full text of the preliminary study was then retrieved to assess
whether they qualified for inclusion. For multiple results reported at different timepoints, we
used the last result reported at the longest follow-up time point. Discrepancies were resolved
through discussion.

2.4 Data extraction

A researcher (YX) used a pre-designed standardized form to extract data, and the data were
checked by a second researcher (FZ) to evaluate the risk of bias and evidence quality of indi-
vidual included studies. The extracted information included the type of study, type of intracra-
nial haemorrhage, sex ratio of subjects, details of interventions, outcome indicators, and other
data used to assess the risk of bias and quality of evidence. Whenever possible, missing data
were obtained via email from the study authors.

2.5 Quality of assessment

The Cochrane Risk Bias Assessment Tool was used to assess bias in each study. The degree of
bias risk (low, unknown, high) was evaluated from seven aspects (random sequence genera-
tion, allocation concealment, blinding of researchers and subjects, integrity of outcome data,
blind evaluation of research outcomes, selective reporting of research results, and other
sources of bias) to reflect the quality of each study.

2.6 Outcome measures

The outcome measures included hemostatic effects (hematoma growth, hematoma expan-
sion), efficacy outcomes (mRS and GOS), mortality, and safety outcomes (DVT, PE, IS or TIA,
hydrocephalus, seizures, and rebleeding). Hematoma expansion was defined as an increase of
>6 mL or >33% in hematoma volume on 24-h computed tomography scans compared with

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PLOS ONE Tranexamic acid in intracranial haemorrhage

the baseline hematoma volume [11]. The mRS and GOS are mostly used to evaluate the neuro-
logical function of patients with intracranial haemorrhage. An mRS score �2 is considered to
have a good prognosis, generally does not leave a disability after treatment, and does not affect
the quality of daily life of patients [12]. A GOS score 3–5 is generally considered a conscious
state that does not threaten the safety of life [13].

2.7 Statistical analysis

The meta-analysis of data was performed using REVMAN software (version 5.3 for Windows;
Cochrane Collaboration, Copenhagen, Denmark). We obtained 95% confidence intervals
(CIs) and P-values from each study by measuring the mean difference (MD) of continuous
variables and the odds ratio (OR) of binary variables. Q and I2 statistics were used to test the
heterogeneity of the studies. According to the recommendations of the Cochrane Statistical
Methods Group, the heterogeneity P-value was set to 0.1 and the I2 statistic was interpreted as
follows: 0–40%, low heterogeneity; 30–60%, moderate heterogeneity; 50–90%, substantive het-
erogeneity; 75–100%, obvious heterogeneity. Sensitivity analysis was performed to identify the
source of heterogeneity if the heterogeneity was substantial (I2�50%) [14].
For outcome indicators of more than 10 studies, researchers drew a funnel plot (RevMan
5.3) to evaluate publication bias [15]. We used Egger’s test and Begg’s test (STATAMP-64) to
evaluate the asymmetry of the funnel plot, and P>.05 was considered as no publication bias.

3. Results
3.1 Results of the search
A total of 207 studies were retrieved and 183 articles were included after removing duplicate
articles. Another 114 articles were excluded during primary screening (intervention without
tranexamic acid, study of disease without intracranial haemorrhage, meta-analysis and review,
conference summary, and animal experiments). After a full review of the remaining 69 studies,
29 ongoing studies and 13 studies that did not meet the inclusion criteria were excluded. The
retrieval strategy was repeated before data analysis, and no additional studies were identified
in the update. Finally, 25 studies involving 20146 patients were included. A flow chart of the
specific search strategy results is shown in S1 Fig. The overall characteristics of the 25 studies
and the specific information on the individual studies are shown in Table 1.

3.2 Risk of bias in included studies

The Cochrane Risk Bias Assessment Tool was used to assess the quality of the included 27
RCTs. Among them, 26 studies [3, 7, 11, 12, 16–20, 22–28, 30–32, 38] mentioned generating
random sequences, including through random number tables, computer random number gen-
eration, coin-throwing, and double-blind lottery. One study [21] did not specify the randomi-
zation process. Nineteen studies [3, 7, 11, 12, 17, 18, 27, 31, 38] were blinded for both subjects
and researchers, and one study [16] was only single-blinded. One study [25] was non-blinded
to the researchers or subjects (open label), and six studies [20–22, 24, 26, 28] did not elaborate
on blindness. The outcome measurement of one study [31] was completed by a research assis-
tant who knew the purpose and conditions of the study, while two studies [21, 24] did not
mention whether they conducted a blind evaluation of the outcome. In one study [17], two
patients who took tranexamic acid were lost to follow-up, and there were no 24-h follow-up
data. The results of the bias risk assessment are shown in S2 Fig.

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Table 1. The characteristics of the 29 included studies.

Author Year Design Type of TXA placebo Enrollment time after TXA Length of follow- Outcome
bleed bleed dose up
Arumugam [16] 2015 RCT ICH 15 15 Within 8 h 2g/day 1 day HG
Liu [17] 2021 RCT ICH 89 82 Within 8 h 2g/day 3 months HG mRS Mortality DVT Seizures
Meretoja [3] 2020 RCT ICH 50 50 within 4.5 h 2g/day 3 months mRS Mortality IS or TIA PE
Sprigg [18] 2014 RCT ICH 16 8 Within 24 h 2g/day 3 months HG mRS Mortality DVT IS or TIA
Sprigg [7] 2018 RCT ICH 1161 1164 Within 8 h 2g/day 3 months HG mRS Mortality
Chandra [19] 1978 RCT SAH 20 19 Within 7 days 6g/day 21 days Mortality
Fodstad [20] 1981 RCT SAH 30 29 Within 72 h 6g/day 42 days Mortality IS or TIA rebleeding
Gibbs [21] 1971 RCT SAH 25 22 NR 3g/day 2 months Mortality rebleeding
Hillman [22] 2002 RCT SAH 254 251 Within 48 h 4g/day 6 months GOS rebleeding
Kaste [23] 1979 RCT SAH 32 32 Within 72 h 6g/day 14 days Mortality rebleeding
Maurice [24] 1978 RCT SAH 25 25 Within 96 h 6g/day 3–33 months Mortality hydrocephalus
Post [25] 2021 RCT SAH 480 475 Within 24 h 3g/day 6 months mRS Mortality DVT Seizures
Hydrocephalus IS or TIA PE
rebleeding
Roos [26] 2000 RCT SAH 229 233 Within 96 h 6g/day 3 months GOS Hydrocephalus IS or TIA
rebleeding
Tsementzis [27] 1990 RCT SAH 50 50 Within 72 h 9g/day 6 months GOS Mortality rebleeding
Vermeulen [28] 1984 RCT SAH 241 238 Within 72 h 6g/day 3 months GOS Mortality DVT Hydrocephalus
IS or TIA PE rebleeding
CRASH 2 [29] 2012 RCT TBI 133 137 Within 8 h 2g/day 28 days HG IS or TIA rebleeding
CRASH-3 [30] 2019 RCT TBI 6359 6280 Within 3 h 2g/day 28 days DVT Seizures IS or TIA PE
Chakroun [13] 2018 RCT TBI 96 84 Within 24 h 2g/day 28 days GOS Mortality DVT PE rebleeding
Ebrahimi [31] 2019 RCT TBI 40 40 Within 8 h 2g/day 7 days Mortality
Fakharian [32] 2018 RCT TBI 74 75 Within 8 h 1g/day 3 months GOS Mortality rebleeding
Jokar [33] 2017 RCT TBI 40 40 Within 2 h 2g/day 2 days HG
Mousavinejad [34] 2020 RCT TBI 20 20 Within 8 h 2g/day 6h Mortality
Rowell [35] 2020 RCT TBI 657 309 Within 2 h 2g/day 6 months Mortality DVT Seizures
IS or TIA PE
Safari [36] 2021 RCT TBI 47 47 NR 4g/day 2 days HG
Yutthakasemsunt 2013 RCT TBI 120 118 Within 8 h 2g/day 1 days Mortality IS or TIA
[37]

ICH: intracranial hemorrhage; TBI: traumatic brain injury; SAH: subarachnoid hemorrhage; HG: hematoma growth; IS: ischemic stroke; mRS: modified Rankin Scale;
DVT: deep vein thrombosis; PE: deep vein thrombosis; TIA: transient ischemic attack; GOS: Glasgow Outcome Scale; RCT: randomized controlled trial; TXA:transamic
acid.

https://doi.org/10.1371/journal.pone.0282726.t001

3.3 Outcomes
3.3.1 ICH. 3.3.1.1 Hematoma growth. Four studies [7, 16–18] reported hematoma growth
at the end of follow-up, and the pooled data showed that the hematoma growth rate of the tra-
nexamic acid intervention group was lower than that of the control group (MD -1.78, 95%CI
-2.78 to -0.79, I2 = 0%, P < .001; Fig 1A) for ICH patients.
3.3.1.2 mRS. Three studies [3, 17, 18] reported mRS scores at the end of follow-up, and
pooled data showed that tranexamic acid had no significant benefit on the prognosis of
patients with ICH (MD 0.16, 95%CI -0.05 to 0.37, I2 = 0%, P = .13; Fig 1B).
3.3.1.3 mRS�2. Three studies [3, 7, 17] reported an mRS score�2 (non-disabling stroke
patients) at the end of follow-up. No significant difference was detected between the tranexa-
mic acid and control groups in ICH patients (OR 1.05, 95%CI 0.89 to 1.24, I2 = 0%; P = .58;
Fig 1C).

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Fig 1. Forest plot of the effect of tranexamic acid on hematoma growth (A), mRS (B), mRS�2 (C), and mortality (D)
in patients with ICH.
https://doi.org/10.1371/journal.pone.0282726.g001

3.3.1.4 Mortality. Four studies [3, 7, 17, 18] reported the number of deaths by the end of fol-
low-up. There was no significant difference in the incidence of deaths between the tranexamic
acid and control groups in ICH patients (OR 1.02, 95%CI 0.84 to 1.23, I2 = 0%, P = .84; Fig 1D).
3.3.2 SAH. 3.3.2.1 GOS 3–5. Four studies [22, 26–28] reported a GOS score of 3–5 at the
end of follow-up. There was no significant difference between the tranexamic acid interven-
tion and control groups in SAH patients (OR 1.13, 95%CI 0.91 to 1.41, I2 = 0%, P = .26;
Fig 2A).
3.3.2.2 Mortality. Eight studies [19–21, 23–25, 27, 28] reported the number of deaths by the
end of follow-up. There was no significant difference in the incidence of deaths between the
tranexamic acid and control groups in SAH patients (OR 0.84, 95%CI 0.54 to 1.31, I2 = 57%, P
= .83; Fig 2B).
3.3.2.3 DVT. Three studies [19, 25, 28] reported the occurrence of DVT at the end of fol-
low-up. No significant difference was detected between the tranexamic acid intervention
group and the control group in SAH patients (OR 1.08, 95%CI 0.51 to 2.30, I2 = 0%, P = .84;
Fig 2C).
3.3.2.4 IS or TIA. The occurrence of IS or TIA was reported in four studies [20, 25, 26, 28]
at the end of follow-up. No significant difference was detected between the tranexamic acid
and control groups in SAH patients (OR 1.20, 95%CI 0.83 to 1.72, I2 = 56%, P = .33; Fig 2D).
3.3.2.5 Rebleeding. Rebleeding was reported in nine studies [19–23, 25–28] at the end of fol-
low-up, and the data showed that the incidence of rebleeding in the tranexamic acid group was

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Fig 2. Forest plot of the effect of tranexamic acid on GOS 3–5 (A), Mortality (B), DVT (C), IS or TIA (D), and
Rebleeding (E) in patients with SAH.
https://doi.org/10.1371/journal.pone.0282726.g002

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PLOS ONE Tranexamic acid in intracranial haemorrhage

lower than that in the control group in SAH patients (OR 0.52, 95%CI 0.35 to 0.79; I2 = 56%, P
= .002; Fig 2E).
3.3.2.6 Hydrocephalus. Four studies [24–26, 28] reported hydrocephalus at the end of fol-
low-up, and pooled data showed that the incidence of hydrocephalus in the tranexamic acid
group was lower than that in the control group in SAH patients (OR 1.23, 95%CI 1.01 to 1.50;
I2 = 0%, P = .04; Fig 2F).
3.3.3 TBI. 3.3.3.1 Hematoma growth. Three studies [29, 33, 36] reported hematoma
growth at the end of follow-up, and the pooled data showed that the hematoma growth rate of
the tranexamic acid intervention group was lower than that of the control group (MD -4.86,
95%CI -8.06 to -1.58, I2 = 0%, P = .004; Fig 3A) for TBI patients.
3.3.3.2 Mortality. Six studies [13, 31, 32, 34, 35, 37] reported the number of deaths by the
end of follow-up. There was no significant difference in the incidence of deaths between the
tranexamic acid and control groups in TBI patients (OR 0.91, 95%CI 0.69 to 1.21, I2 = 0%, P =
.52; Fig 3B).
3.3.3.3 PE. Three studies [13, 30, 35] reported the occurrence of PE at the end of follow-up.
No significant difference was detected between the tranexamic acid intervention and control
groups in TBI patients (OR 1.22, 95%CI 0.45 to 3.27, I2 = 65%; P = .70; Fig 3C).
3.3.3.4 IS or TIA. The occurrence of IS or TIA was reported in four studies [29, 30, 35, 37]
at the end of follow-up. No significant difference was detected between the tranexamic acid
and control groups in TBI patients (OR 0.81, 95%CI 0.51 to 1.30, I2 = 23%, P = .39; Fig 3D).
3.3.3.5 Seizures. Two studies [30, 35] reported the occurrence of seizures at the end of the
follow-up. There was no significant difference between the tranexamic acid intervention and
control groups in TBI patients (OR 1.11, 95%CI 0.92 to 1.36, I2 = 0%, P = .28; Fig 3E).

4. Discussion
This meta-analysis involved 25 studies with a total of 20,146 participants, providing evidence
to evaluate tranexamic acid from three aspects: hemostatic effect, efficacy in improving neuro-
logical function, and complications. Compared with the control group, the tranexamic acid
group significantly reduced hematoma growth in ICH and TBI. For SAH patients, tranexamic
acid significantly reduced the probability of hydrocephalus and rebleeding. Mortality, IS or
TIA, DVT, PE, and risk of seizures were similar between the two groups.
Compared with patients without hematoma growth, those with hematoma growth have an
increased risk of neurological deterioration and mortality associated with intracranial haemor-
rhage [4]. Our data showed that tranexamic acid can inhibit hematoma growth, which is con-
sistent with a previous study [39, 40]. This may be because tranexamic acid is a synthetic lysine
derivative, which is an antifibrinolytic agent [41]. Tranexamic acid competitively inhibits the
adsorption of plasminogen on fibrin by binding to the lysine binding site on fibrin, thereby
inhibiting the activation of plasminogen and preventing the degradation of fibrinolytic pro-
teins by fibrinolytic enzymes, thus achieving antifibrinolytic and hemostatic effects [42, 43]. It
can also increase collagen synthesis in fibrin clots, thereby increasing the strength and stability
of clots and reducing bleeding [5, 44]. Normally, fibrinogen binds to lysine binding sites on
fibrin molecules and is converted to fibrinogenase in the presence of tissue plasminogen acti-
vator [45]. TXA blocks activation of plasminogen and prevents binding of plasmin to fibrin
[46].
Our results showed that tranexamic acid could significantly reduce the occurrence of hema-
toma growth in the brain, although no significant effect was detected on the recovery of neuro-
logical function (ICH: mRS, P = .69; mRS�2, P = .58. SAH: GOS 3–5, P = .26) or mortality
(ICH: P = .84; SAH: P = 0.43; TBI: P = 0.52). This may be because secondary brain injury is

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Fig 3. Forest plot of the effect of tranexamic acid on Hematoma growth (A), Mortality (B), PE (C), IS or TIA (D), and
Seizures (E) in patients with SAH.
https://doi.org/10.1371/journal.pone.0282726.g003

caused by inflammation; oxidative stress or cytotoxicity dominates when the hematoma vol-
ume is large, in addition to the mechanical compression of the surrounding brain tissue [47].
Therefore, it is difficult to improve neurological function in patients with intracranial haemor-
rhage. However, the presence or absence of hematoma growth is also associated with blood
pressure control, cerebral amyloid angiopathy, chronic kidney disease and lifestyle (smoking,
alcohol consumption), which may confuse the reported association [48–50]. Additionally, the
antifibrinolytic effect of tranexamic acid can promote the stability of thrombosis, and the effec-
tive benefits may be offset by the increase in ischemic events of IS or TIA [13]. Whether the
effective benefits of tranexamic acid can be offset by harm is still controversial. In addition, the
present meta-analysis shows that the incidence of hydrocephalus and rebleeding has been sig-
nificantly reduced compared to the control group in SAH patients. The reduction of hydro-
cephalus and rebleeding can decrease not only the occurrence of secondary surgery but also
the secondary injury of neurons caused by intracranial haemorrhage. Therefore, the use of

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PLOS ONE Tranexamic acid in intracranial haemorrhage

tranexamic acid may have a beneficial effect on the improvement of long-term neurological
function. However, the influencing factors of hydrocephalus and rebleeding are not only dis-
cussed, we needs to be more cautious about the results of data analysis [49].
The advantages of our study are as follows. First, we implemented a comprehensive search
strategy in multiple databases. Second, we included 25 studies with large sample size of 20,146
participants. Third, all 25 studies included in the present analysis were RCTs. Therefore, the
present meta-analysis may provide the highest-level evidence of evidence-based medicine on
this topic.
Our study had some limitations. First, in the 25 included studies, treatment time (2 h to 7
days), and disease severity may have led to deviation of outcome data. Second, the follow-up
time of each study was different, which may have affected the comparison between the tra-
nexamic acid interventional group and the control group. Subacute, chronic, and late compli-
cations were more likely to be reported in studies with longer follow-up periods. Third, the
location of intracerebral bleeding (intraventricular location, intraparenchymal location or
both) is an independent predictor for the development of secondary hydrocephalus. The stud-
ies we included and our analysis did not control for this potential effect modifier. In addition,
this association that tranexamic acid cannot improve the mRS score of ICH patients may also
be confused by the location of ICH, affecting the functional outcome of three months.

5. Conclusion
Our study shows that tranexamic acid significantly reduced the risk of intracranial haemor-
rhage growth in patients with ICH and TBI without increasing the incidence of ischemic
events when treating intracranial haemorrhage. Tranexamic acid intervention for SAH
patients can significantly reduce the occurrence of hydrocephalus and rebleeding, and indi-
rectly improve the quality of life of patients. ICH and TBI patients did not obtain the above
benefits, which is the focus of our future research. In addition, we should also focus on the
optimal time window and dose of tranexamic acid application to optimize patient treatment
strategies.

Supporting information
S1 Checklist. PRISMA checklist.
(DOCX)
S1 Graphical abstract. Schematic diagram of hemostatic mechanism of tranexamic acid (a)
and chemical structure of tranexamic acid (b).
(TIF)
S1 Fig. Flow chart describing the literature search.
(TIF)
S2 Fig. Risk of bias graph. (a) The judgment of each bias risk item is expressed in percentage
in all included studies. (b) Risk of bias summary.
(JPG)

Acknowledgments
We would like to thank Editage (www.editage.cn) for English language editing.

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Author Contributions
Data curation: Chunhui Chen.
Methodology: Xiaodong Kang, Jianfeng Zhou, Roland Goldbrunner.
Resources: Xinyue Huang.
Software: Xiumei Guo.
Supervision: Linxing Wang, Pantelis Stavrinou.
Validation: Zhigang Pan, Lampis Stavrinou.
Writing – original draft: Yu Xiong.
Writing – review & editing: Yu Xiong, Shu Lin, Yuping Chen, Weipeng Hu, Feng Zheng.

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