Neurosurgical Review

https://doi.org/10.1007/s10143-020-01324-0

REVIEW

Tranexamic acid in Neurosurgery: a controversy indication—review

José Luiz de Faria 1 & Josué da Silva Brito 1 & Louise Teixeira Costa e Silva 1 &
Christiano Tadeu Sanches Mattos Kilesse 1 & Nicolli Bellotti de Souza 1 & Carlos Umberto Pereira 2 &
Eberval Gadelha Figueiredo 3 & Nícollas Nunes Rabelo 1,3

Received: 13 January 2020 / Revised: 1 May 2020 / Accepted: 20 May 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Tranexamic acid (TXA) is one of the measures indicated to reduce bleeding and the need for volume replacement. However, data
on risks and benefits are controversial. This study analyzes the effectivity and risks of using tranexamic acid in neurosurgery. We
selected articles, published from 1976 to 2019, on the PubMed, EMBASE, Science Direct, and The Cochrane Database using the
descriptors: “tranexamic acid,” “neurosurgery,” “traumatic brain injury,” “subdural hemorrhage,” “brain aneurysm,” and “sub-
arachnoid hemorrhage.” TXA can reduce blood loss and the need for blood transfusion in trauma and spinal surgery. Despite the
benefits of TXA, moderate-to-high doses are potentially associated with neurological complications (seizures, transient ischemic
attack, delirium) in adults and children. In a ruptured intracranial aneurysm, the use of TXA can considerably reduce the risk of
rebleeding, but there is weak evidence regarding its influence on mortality reduction. The TXA use in brain surgery does not
present benefit. However, this conclusion is limited because there are few studies. TXA in neurosurgeries is a promising method
for the maintenance of hemostasis in affected patients, mainly in traumatic brain injury and spinal surgery; nevertheless, there is
lack of evidence in brain and vascular surgeries. Many questions remain unanswered, such as how to determine the dosage that
triggers the onset of associated complications, or how to adjust the dose for chronic kidney disease patients.

Keywords Tranexamic acid . Antifibrinolytic . Neurosurgery . Blood loss surgical . Brain injuries

Introduction patient’s head. Throughout the twentieth century, Cushing’s lat-

Neurosurgical procedures cause significant blood loss; thus,
demanding measures to restore volumes, such as crystalloids
and blood products, are necessary. However, the use of these
substances can result in hypokalaemia, anaphylactic reactions,
pulmonary trauma, infection, hemolytic reactions, cardiovas-
cular overload, and sepsis postoperative [1–5].
Modern neurosurgery has already deployed different methods
to control bleeding. Chemical, thermal, and mechanical methods,
and clinical measures were used, such as the elevation of the
eral ventricular puncture, bandages, clips, hydrogen peroxide,
caustic agents, adrenaline, thrombin, and fibrin were used [6].
Tranexamic acid (TXA), developed in the second half of
the twentieth century, is one of the alternatives for reducing
blood loss and the need for volume replacement. However,
data are controversial and there is uncertainty regarding the
recommended dosage, and associated risks [6–8].
This study seeks to review the literature by analyzing the
effectivity and risks of deploying TXA in neurosurgery and trau-
matic brain injury.

* Nícollas Nunes Rabelo

nicollasrabelo@hotmail.com
Methodology
1
Department of Neurosurgery, University Center UNiAtenas, We selected articles on the PubMed platform, EMBASE,
Paracatu, Minas Gerais, Brazil Science Direct, and The Cochrane Database using the terms:
2
Department of Neurosurgery of FBHC and Neurosurgery Service, “tranexamic acid,” “neurosurgery,” “traumatic brain injury,”
Aracaju, Sergipe, Brazil “subdural hemorrhage,” “brain aneurysm,” and “subarach-
3
Department of Neurosurgery, Hospital das Clinicas da Faculdade de noid hemorrhage” using the Boolean operator “OR” and
Medicina, University of Sao Paulo, Sao Paulo, Brazil “AND.” The search carried out by all the authors considered

articles published from 1976 to 2019 and resulted in 487 arti-
cles, 245 of which had their abstracts read. Meta-analysis,
randomized controlled trials, and cohort studies were includ-
ed. We excluded papers that were not in English, Spanish, or
Portuguese, as well as brief notes and case reports, articles not
related to the topic, or not available in full. After applying the
exclusion criteria, there were 57 articles left (Fig. 1).
Results and discussion
Patented by S. Okamoto in 1957 [9], TXA (trans-4-
aminomethyl-cyclohexane-1-carboxylic acid) is a synthetic
analog of lysine, which, by competition, inhibits the activation
of plasminogen into plasmin. At high concentrations, TXA
blocks non-competitive plasmin, inhibiting the dissolution
and degradation of fibrin clots.
Approximately 95% of TXA is excreted unchanged in the
urine, and excretion decreases with increasing plasma creatinine
levels. Dose-adjustment in patients with renal impairment re-
mains an unknown factor. Recently, TXA was shown to be
structurally similar to glycine, inhibiting competitively glycine
receptors in cortical and spinal cord neurons in rats, as well as
Fig. 1 Representation of identification, screening, eligibility, and inclusion and exclusion criteria in the review
Neurosurg Rev
GABA receptors in cortical and medullary neurons. Both inhib-
itory pathways of TXA cause an increased excitatory synaptic
stimulus, as evidenced by similar to convulsion-like events in-
duced at TXA concentrations of 31 μg mL−1 (200 μM). These
events are similar to those measured in the cerebrospinal fluid
(CSF) of patients undergoing extracorporeal circulation [2, 9, 10]
TXA crosses the blood-brain barrier and enters the eye,
reaching around 10% of the plasma concentration in the
CSF. This, in turn, can lead to changes in color vision, espe-
cially in patients who use the drug chronically. In conscious
patients, gastrointestinal side effects (nausea, vomiting, and
diarrhea) are more commonly reported [7, 9, 11]. The half-
life of TXA is approximately 80 min in patients with pre-
served renal function and can be administered orally, intrave-
nously, intramuscularly, or topically [4, 7, 12].
Despite the substantial discussion, there is yet no consensus
on either the minimum dose at which the drug generates ben-
efits or the maximum concentration at which complications
occur. TXA has been successfully administered in a number
of surgical procedures, such as orthopedic and cardiac surger-
ies, solid organ transplants, and gynecological and obstetric
interventions [3, 7, 13, 14]. TXA has also been successfully
used in non-surgical procedures with a high risk of bleeding in
Neurosurg Rev
order to reduce massive intraoperative blood loss and thus also
decrease the need for blood transfusion [1, 4, 9, 13, 15].
Spine surgery
Neurosurgery, especially spinal surgery, often involves signifi-
cant blood loss, thereby requiring blood transfusions.
Transfusion by-products can be detrimental to the patient due
to the risk of hemolytic and non-hemolytic reactions; infection;
and the dilution of plasma components, such as coagulation fac-
tors, by the replacement of red blood cells and crystalloids [1–3,
16]. In this regard, the use of antifibrinolytics may represent a
valuable strategy to control perioperative hemorrhage.
Studies (Table 1) on the application of TXA in spinal sur-
gery point the decision on the moment of application and the
dose that should be used as a first challenge. In most of the
analyzed, authors preferred to administer a dose ranging from
10 mg/kg (preferably in most studies) to 30 mg/kg immedi-
ately upon performing an incision, a maintenance dose of 0.5
to 2 mg/kg/h, followed by a preferable 1-mg/kg/h dose until
the end of the surgical procedure, obtaining satisfactory re-
sults. High TXA doses did not necessarily increase rates of
thromboembolism or convulsions in the case of ASA I and
ASA II patients, with no risk factors for thromboembolism or
significant renal changes [4, 8, 9, 13, 15–19].
Most studies have pointed out the beneficial potential of
TXA, including reduction in bleeding in the intraoperative and
postoperative periods, as well as the need for blood transfusion
[4, 8, 9, 13, 15–19]. There is increasing evidence showing TXA
can reduce intraoperative bleeding in spinal column surgery by
up to 49% (P < 0.007) [2, 7, 17]. Patients receiving intraoperative
TXA treatment also showed a decreased tendency to remain
hospitalized after surgery [7, 15, 17], although only a few
showed significant results [4, 15, 20]. In general, the studies were
limited due to the small sample number. Therefore, interpretation
for the general population must be done carefully.
Elwatidy et al. [7] obtained the most positive results. In
their study, high doses of TXA reduced total blood transfu-
sions by 80% and total blood loss by 49% (P < 0.007) in
laminectomy surgeries with posterior spinal fixation, as well
as laminectomy and the excision of spinal tumors. The blood
loss during surgery in the TXA group was 311.25 ± 412.49
mL versus 584.64 ± 797.30 mL in the placebo group (P =
0.03). Nevertheless, the study included only 64 patients.
Tsutsumimoto et al [18]. also reported that postoperative
blood loss in the first 16 h following surgery was significantly
lower in the TXA group than in the control group (P = 0.001).
The postoperative blood loss was 37% lower in the TXA
group in comparison with control group.
A retrospective study performed in 2012 included 106 pa-
tients (43 in the TXA group and 63 the in control group) and
evaluated the use of TXA in posterior spinal fusion for treat-
ment of adolescent idiopathic scoliosis (age in years, 15.2 ±
2.9 in the TXA group and 15.5 ± 3.0 in the control group).
They used a loading dose of 1 g, followed by an immediate
maintenance dose of 100 mg/h until the closure of the surgical
incision. There was a significant reduction in intraoperative
blood loss in the TXA-treated group (613 ± 195 mL) in com-
parison with the control group (1079 ± 421 mL; P < 0.001),
lower postoperative blood loss (155 ± 86 mL versus 263 ± 105
mL, respectively; P < 0.001), and decreased need for blood
transfusion during the procedure (258 ± 246 mL versus 377 ±
200 mL, respectively; P < 0.001). No major complications
were observed during the study [21].
In a meta-analysis [8] comprising 11 randomized controlled
trials (RCT) with a total of 644 patients, TXA successfully re-
duced intraoperative, postoperative, and total blood loss in spinal
surgeries. The major reduction was intraoperative blood loss by
an average of 219 mL, ranging from 116 to 322 mL compared
with placebo (P < 0.05). The meta-analysis also concluded that
the use of TXA leads to a reduction in the volume of blood
transfusions (risk ratio—RR—0.67 [0.54, 0.83], P < 0.05).
There was no association between thromboembolic events and
TXA. Zhang et al. [16] drew similar conclusions in another meta-
analysis, in addition to emphasizing the need for more accurate
studies to evaluate the risk of intravenous use of TXA. The TXA
use resulted lower risk of blood transfusion (odds ratio—OR—
0.56 [0.36, 0.87], P = 0.01) and was not associated with throm-
botic complications (OR 0.99 [0.06, 16.07], P = 0.99)
In the studies, there was no significant difference between
the TXA-treated group and the control group regarding com-
plications, thereby demonstrating the safety of TXA at differ-
ent dosages [4, 8, 9, 13, 15–19].
The studies were used for the adoption or use of tranexamic
acid in spinal surgery. Its blood loss reduction benefit is evi-
dent, although it is not possible to determine whether it is
greater before, during, or after the surgical procedure. Its po-
tential for mortality and hospital stay is not clear. However,
care should be taken with regard to the dosage adopted, with
low doses being preferable, since they have shown good re-
sults in recent studies. There is still no consensus on the pa-
tient who can use it. Therefore, general care should be taken
with elderly patients and patients with chronic renal failure or
decompensation. For them, the real impacts are not very clear
due to their non-inclusion in the studies or the small presence.
Therefore, an assessment of risks and benefits is necessary,
according to the practice of each neurosurgeon.
Brain surgery
The use of TXA in brain surgeries was analyzed in some RCT
and retrospective cohort studies (Table 2). The studies
adopted a variable dose of TXA. The initial dose ranged from
10 to 25 mg/kg and the maintenance from 1 to 10 mg/kg/h.
Despite the different doses, the results were similar and were
not associated with complications [1, 2, 24].
 Neurosurg Rev

Table 1 Key results of studies on TXA effects in spinal surgery

Study Type Number of patients Type of surgery Key results

of (TXA/P) and
study intervention

Seddighi [4] RCT 20/20 Major spine surgery The intraoperative blood loss (P = 0.139) and blood loss of the
L, 10 mg/kg 1st postoperative day (P = 0.067) did not show significant
M, 0.5 mg/kg/h differences, but a lower mean in the TXA group.
P: saline The mean of blood transfusion did not show a statistically
significant difference (P = 0.86).
The total blood loss in the TXA group was 669.5 mL versus
912.5 mL in the control group.
There were no complications.
Elwatidy [7] RCT 32/32 Laminectomy with posterior spinal Use of tranexamic acid in spine surgery is safe and effective.
Adults: fixation, and laminectomy and It reduced blood loss by 49% (P < 0.007) and need for blood
I, 2 g excision of spinal tumor transfusion by 80% (P < 0.008).
M, 10 0 mg/h There were no complications.
P: saline
Children:
I, 30 mg/kg
M,1 mg/kg/h
P: saline
Cheriyan [8] MA 325/319 All spinal surgery TXA reduced intraoperative, postoperative, and total blood loss.
I, 10 mg/kg to 2 g There was one case of myocardial infarction in the TXA group
M, 1–2 mg/kg/h not associated to TXA treatment.
P: saline
Multiple
interventions
Carabini [13] RCT 31/30 Multilevel spine fusion surgery Reduced total volume of RBC transfusion (1140 mL in the TXA
I, 10 mg/kg group versus 1460 mL in the control group, P = 0.034)
M, 1 mg/kg/h Reduced the cell saver transfusion (P = 0.042)
P: placebo There were no complications.
Shi [15] RCT 50/46 Lumbar spinal stenosis and lumbar Reduced perioperative blood loss (P < 0.005).
I, 30 mg/kg spondylolisthesis Total blood loss was reduced by 41% (P < 0.001).
M, 2 mg/kg/h The mean of blood transfusion did not show a statistically
P: saline significant difference (P = 0.191).
There were no complications in the TXA group.
Zhang [16] MA 208/203 Spinal surgery Reduced the amount of blood loss, the volume of blood
I, 10–100 mg/kg/h transfusion, and the transfusion rate
M, 1–10 mg/kg/h The TXA use resulted in 44% decline of risk of blood
P: saline transfusion compared with the placebo group with an OR of
Multiple 0.56 (95% confidence interval—CI—0.36 to 0.87)
interventions Further studies are needed.
Shakeri [17] RCT 25/25 Laminectomy and posterior spinal Reduced intraoperative blood loss (P = 0.0001)
I, 15 mg/kg fusion Total blood loss in the TXA group was 632.2 ± 193.1 versus
M: none 1037 ± 242.6 in the control group.
P: saline Reduced hospitalization time (P = 0.001)
Reduced need for transfusion (P = 0.001)
There were no complications.
Tsutsumimoto RCT 20/20 “French-door” cervical laminoplasty Perioperative blood loss, especially postoperative blood loss
[18] I, 15 mg/kg from C3 to C6 during the first 16 h, in the TXA group was significantly
M: none lower than that in the control group (P < 0.01).
P: saline The postoperative blood loss was reduced by 37% (132.0 ± 45.3
in the TXA group versus 211.0 ± 41.5 mL in the control
group).
There were no complications.
Raksakietisak RCT 39/39 Complex spine surgery Blood loss in the placebo group was higher than that in the TXA
[19] I, 15 mg/kg group (P = 0.014)
After 3 h, 15 mg/kg Postoperative period had lower blood loss (P = 0.014)
P: saline Reduced blood transfusion by 64.6%
Colomina [20] RCT 44/51 Major spine surgery Significant reduction in intraoperative blood loss (P = 0.01)
I, 10 mg/kg The mean of blood transfusion did not show statistically
M, 2 mg/kg/h significant difference (P = 0.06).
Neurosurg Rev

Table 1 (continued)

Study Type Number of patients Type of surgery Key results

of (TXA/P) and
study intervention

P: saline In the TXA group: one case of deep vein thrombosis and
pulmonary embolism, with no significant differences
between the TXA group and the control group.
Yagi [21] RS 43/63 Posterior spinal fusion for treatment of Intraoperative blood loss, mean of blood transfusion, and
I, 1 g adolescent idiopathic scoliosis postoperative blood loss were significantly reduced (P <
M, 100 mg/h 0.01) in the TXA-treated group.
P: saline TXA was not associated with major complications.
Xue [22] RS 20/22 Posterior laminectomy and Reduced the need and amount of blood transfusion
I, 15 mg/kg posterolateral bone graft fusion Can shorten the extubating time and shorten the length of
M, 1 mg/kg/h postoperative hospital stay without increasing the incidence
P: no intervention of postoperative coagulation dysfunction or postoperative
deep venous thrombosis
Lower intraoperative blood transfusion in the TXA group
963.64 ± 341.63 mL than 1680 ± 112.14 mL in the control
group
Lower postoperative hospital stay: 4.23 ± 1.02 days in the TXA
group versus 5.55 ± 1.28 in the control group
Damade [23] RS 36/47 Decompressive surgery associated No significant difference was found in intraoperative and
I, 15 mg/kg with bone fixation postoperative blood loss.
M, variable Significant reduction in postoperative bleeding was found in the
P: no intervention TXA group.
Multiple The volume of transfused blood was significantly reduced (P <
0.05) in the TXA-treated group.

RCT, randomized controlled trial; MA, meta-analysis; RS, retrospective study; I, infusion dose; M, maintenance dose; P, placebo; RBC, red blood cells

Hooda et al. [2] used TXA in excision of intracranial me-
ningioma, with N = 60 (30 in each group) with the following
results: significant reduction in heart rate, increase in mean
arterial pressure and plasminogen levels, intraoperative bleed-
ing reduction by 27% (RR 1.3 [1.1, 1.8], P = 0.03), and thus
improvement of hemodynamic maintenance accompanied by
a tendency to reduce the number of blood transfusions, but
without significant alteration (P = 0.89).
In a trial evaluating the use of TXA in elective craniotomy for
the excision of supratentorial tumors, Vel et al. [1] obtained
similar results as those described above, with a significant reduc-
tion in intraoperative bleeding (P = 0.012) yet without a corre-
sponding decrease in the need for blood transfusions (P = 0.109).
Mebel et al. [14] concluded that the use of TXA is safe,
with no significant differences in the rate of thromboembolic
events as compared with the control group. A retrospective
cohort study performed with 519 patients (245 of whom re-
ceived TXA) who had undergone complex neurosurgical pro-
cedures showed significantly lower transfusion rates (P =
0.04) in the TXA-treated group (13% versus 7% in the control
group).
Thromboelastography is one option for optimizing the se-
lection of patients who will benefit from TXA, since this
method allows for the rapid evaluation of hypofibrinogenemia
[26–28].
These studies are insufficient for conclusions, because
these are different procedures with a limited sample. Further
studies are needed. The TXA use may be negligible in brain
surgery.
Ruptured intracranial aneurysms
Risk of rebleeding is a major complication in rupture of intra-
cranial aneurysms occurring in 10 to 22% of affected patients.
Its highest incidence occurs in the first 24 h, peaking in the
first 6 h after the event [29, 30]. The prognosis for patients
experiencing rebleeding after the rupture of intracranial aneu-
rysms is quite poor, with 60% of these patients dying and
another 30% turning unable to perform daily activities, there-
by requiring care [29, 31–33].
The use of TXA can considerably reduce the risk of
rebleeding, but there is weak evidence for a decrease in the
overall number of deaths [31, 34–37]. In a Cochrane review
published in 2013 comprising 10 randomized controlled trials
regarding the effects of antifibrinolytics agents on hemorrhage
(RR 0.65, 95% CI 0.44 to 0.97, 78 per 1000 participants), the
overall mortality rate was unaffected (RR 1.00, 95% CI 0.85
to 1.18) [31].
In a meta-analysis performed with 2872 individuals, 1380
patients received antifibrinolytics agents for the management
 Neurosurg Rev

Table 2 Key points of studies on brain surgery

Study Type Number of patients Type of surgery Key points

of (TXA/P) and
study Intervention

Vel [1] RCT 50/50 Elective craniotomy for Saline group at 4, 6, and 8 h (P < 0.001)
I, 10 mg/kg excision of the Significant reduction in blood loss in the TXA group compared with the
M, 1 mg/kg/h supratentorial tumor saline group at 2, 4, and 6 h of surgery (P < 0.05)
P: saline There was no reduction in intraoperative blood transfusion requirements.
The mean total blood loss in the TXA group was 817.00 ± 423.3 mL and
1084.00 ± 604.8 mL in the saline group (P = 0.012)
There were no complications.
Hooda RCT 30/30 Excision of intracranial The amount of blood loss was significantly less in the tranexamic acid
[2] I, 20 mg/kg/ meningioma group compared with the placebo group (P = 0.03).
M,1 mg/kg/h The trend was towards lesser transfusion requirement in the tranexamic acid
P: saline group, even though it was not statistically significant.
There was no significant difference between the TXA group and the control
group, regarding complications.
Mebel RC 245/275 Complex skull base The rate of perioperative transfusion in patients who received tranexamic
[14] I, 10–25 mg/kg neurosurgical procedures acid was lower (7% versus 13%, P = 0.04).
M, 5–10 mg/kg/h There was no significant difference between the TXA group and the control
P: saline group, regarding complications.
Dadure RCT 19/21 Craniosynostosis surgery Volume of packed erythrocytes transfused was significantly reduced by
2011 I, 15 mg/kg 85% intraoperatively and by 57% throughout the study period (P < 0.05).
[24] M, 10 mg/kg/h Requiring blood transfusion was lower in the TXA group during surgery
45% versus 11% (P < 0.05) and during the whole study period 70%
versus 37% (P < 0.05).
Kurnik RC 23/30 Craniosynostosis surgery A 4-h postoperative infusion of TXA after open calvarial vault remodeling
[25] I, 10 mg/kg for craniosynostosis was as effective in reducing blood loss and trans-
M, 5 mg/mg/h per 24 fusion requirements as the 24-h infusion.
or 4 h

RCT, randomized controlled trial; RC, retrospective cohort; I, infusion dose; M, maintenance dose; P, placebo

of subarachnoid hemorrhage (SAH). It showed that TXA
treatment may be beneficial for diminishing rebleeding rate
in the short term, i.e., less than 3 days, which can be associated
with calcium channel blockers and hypervolemic therapies.
Furthermore, TXA treatment did not increase the risk of cere-
bral ischemic events, thereby constituting a potential strategy
to prevent poor functional outcomes [32].
Hillman et al. [37] analyzed the use of TXA in patients
immediately after the diagnosis of SAH within 48 h before
first hospitalization. A 1-g dose of TXA was administered
intravenously as soon as SAH was diagnosed at local hospitals
(before patient transport), followed by 1 g every 6 h until the
aneurysm was occluded, not exceeding 72 h of treatment. The
results showed a significant reduction in rebleeding rate, rang-
ing from 10.8 to 2.4%, and reduced mortality rate due to
rebleeding by 80% upon TXA treatment, with no increase in
drug-related ischemic and vasospasm events.
ULTRA [29] is a prospective, randomized, open-label,
multicenter study, which included 950 patients that evaluated
the effect of TXA on non-traumatic SAH adults 24 h after the
onset of headache. Patients in the TXA-treated group received
a TXA bolus dose (1 g intravenously) immediately after ran-
domization, followed by a continuous 1-g infusion for 8 h
until aneurysm initiation or, at most, for 24 h after the initia-
tion of medication. This paper will be important for assessing
the efficacy and safety of early TXA use in SAH patients.
The use of TXA in a ruptured intracranial aneurysm was
shown to be safe since it was not associated with worse out-
comes or thromboembolic events, according to more recent
studies on the topic [30, 32, 37]. However, the combination
with chlorpromazine can lead to worse outcomes [34]. Studies
performed before 2001 using high TXA doses often reported a
higher risk of thromboembolic complications [38, 39].
Despite the studies presented conflicting conclusions and
different protocols, the potential of TXA in reducing mortality
and rebleeding justifies its adoption as a protocol in hemor-
rhage stroke. Risks can be minimized by adopting short-term
intervention. More studies on the subject are needed in order
to establish unified guidelines (Table 3).
Traumatic brain injury
Traumatic brain injury (TBI) in Western countries is the lead-
ing cause of death among 15- to 29-year olds and is the third
leading cause of death among all age groups [42].
Neurosurg Rev

Table 3 Key points of studies on ruptured intracranial aneurysms

Study Type of Number of patients (TXA/P) and Key points

study intervention

Chandra RCT 20/19 Rebleeding and mortality were reduced by one-fourth and one-fifth, respectively (P
[40] 6 g per day, given 1 g every 4 h < 0.01).
intravenously for 3 weeks No side effects of tranexamic acid therapy were seen, such as pulmonary embolus
or renal artery thrombosis.
Fodstad RCT 30/29 TXA protects patients with ruptured aneurysms from rebleeding for 1 or 2 weeks.
[34] 6 g per day in the first week; Increased incidence of severe vasospasm, fatal delayed cerebral ischemia,
4 g per day in the second week; pulmonary embolism, and myocardial infarction among the tranexamic
6 g per day, per orally, in the third to sixth acid–treated patients in combination with chlorpromazine.
week
Fodstad RCT 21/20 TXA reduces rebleeding rate. TXA can increase the occurrence of cerebral
[38] 6 g per day in the first week; ischemia.
4 g per day in the second to fifth week
Vermeulen RCT 241/238 Reduces rebleeding from 24 to 9% in the TXA group (P < 0.001)
[39] 6 g per day in the first week Reduces mortality in 2.5%
4 g/day following 3 weeks Increases incidence of ischemic complications, 15% in the control group and 24%
Centers with oral administration used 6 in the TXA group (P < 0.001)
g/day on the third and fourth weeks
Wijdicks NRCT 119/238 Rate of rebleeding (24 of 119, 20%) was close with that in the placebo (56 of 238,
[35] 6 g per day for 4 weeks 24%).
Rate of cerebral infarction (33 of 119, 28%) was almost identical to that after
long-term tranexamic acid (59 of 241, 24%)
Treatment with tranexamic acid for 4 days fails to reduce the incidence of
rebleeding but still increases the rate of cerebral infarction.
Roos [41] RCT 229/233 Reduced the occurrence of rebleeding (RR, 0.58; 95% CL, 0.42–0.80)
6 g/day in the first week The occurrence of ischemic complications was the same in the two groups
6 g/day per orally in the second and third TXA combined with treatment to prevent cerebral ischemia does not improve
weeks outcome.
Hillman RCT 254/251 Reduction in the rebleeding rate from 10.8 to 2.4% and an 80%
[37] 1 g immediately on diagnosis Reduction in the mortality rate from early rebleeding
1 g every 6 h until the aneurysm was There was no predisposition to thromboembolic events.
occluded, not exceeding 72 h
Gaberel MA 1380/1492 Short-term use diminishes rebleeding rate.
[32] Multiple There was no predisposition to thromboembolic events.
Post [30] RCT 119/390 Did not reduce rebleeding rate in the TXA group
1 g immediately on diagnosis Mortality was significantly lower in the TXA group than that in the standard care
1 g every 8 h until the aneurysm was group.
occluded, not exceeding 36 h There was no predisposition to thromboembolic events.

RCT, randomized controlled trial; MA, meta-analysis; NRCT, non-randomized, placebo-controlled clinical trial

The CRASH-2 trial [43] was the first multicenter random-
ized controlled study to show efficacy and safety of TXA on
TBI patients. This study had N = 20,211 (10,096 in the TXA
group and 10,115 in the placebo group) and demonstrated
lower relative (RR = 0.85 [0.76, 0.96]) and all-cause mortality
(RR = 0.91 [0.85, 0.97]) after a loading dose of 1 g for 10 min,
followed by a maintenance dose of 1 g for 8 h in adult trauma
patients with or at risk of significant bleeding within 8 h of
injury. However, the author concluded that treatment beyond
3 h of injury is unlikely to be effective.
Analyzing the data obtained from the CRASH-2 study,
Roberts et al. [44] concluded that TXA reduced mortality
from bleeding in polytrauma patients, although this effect
seemed to be related to the time at which drug infusion was
initiated. In the group of patients treated within 3 h of trauma,
TXA reduced overall mortality and bleeding compared with
patients treated after 3 h of trauma, which led to increased
mortality due to bleeding. This suggests the use of
thromboelastography to discriminate those who need treat-
ment from those who do not.
In 2019, RCT analyzed the early use of TXA in patients
with subdural and epidural hemorrhage after TBI. Mean intra-
operative bleeding during surgery was significantly reduced in
the TXA group (P = 0.012) when compared with the placebo
group; however, no statistical significance was found in the
control of subdural and epidural hemorrhage [45].
Recent results from a meta-analysis showed that early treat-
ment with TXA is more effective in reducing bruising. TBI
patients treated with TXA exhibited reduced risk of hematoma
expansion, as well as favorable neurological outcomes due to
 Neurosurg Rev

lower mortality rate, without affecting the rate of thrombosis
events [46].
The 2016 European guidelines (4th edition) on the
management of major bleeding and coagulopathy fol-
lowing trauma [47] strongly recommends (grade 1A)
the early use of TXA in trauma patients who are bleed-
ing or at risk of significant bleeding. The guidelines
further recommend the use of TXA within the first
3 h after the trauma has occurred (grade 1B), with ad-
ministration of the first dose preferably in route to the
hospital (grade 2C).
The CRASH-3 trial [48] showed that treatment within 3 h
of the mild-to-moderate head injurie leads to a substantial
reduction in mortality in patients with TBI (RR 0.78 [0.64–
0.95]). It included adults presenting a score of 12 or lower on
the Glasgow Coma Scale, any intracranial bleeding on com-
puted tomography, and no major bleeding receiving a loading
dose of 1 g for 10 min, followed by a maintenance dose of 1 g
for 8 h. Thus, early treatment was shown to be more effective
than later treatment. In addition, there were no benefits of
TXA in terms of severe head injury (RR 0.99 [0.91–1.07]; P
value for heterogeneity 0.030).

Table 4 Key points of studies on traumatic brain injury

Study Type Participants Number of patients Key points

of (TXA/P) and
study intervention

CRASH-2 [43] RCT Adult trauma patients with, or at risk of, 10,096/10,115 TXA safely reduced the risk of death in bleeding trauma
significant bleeding who were within I, 1 mg patients.
8 h of injury M,1 mg over 8 h Treatment beyond 3 h of injury is unlikely to be effective.
P: saline Treatment after 3 h may increase the risk of death from
bleeding.
Roberts [44] RCT Crash-2 Trial similar patients 10,096/10,115 TXA treatment within the first 3 h of trauma reduced
I, 1 mg mortality.
M,1 mg over 8 h TXA treatment after 3 h of trauma increased bleeding
P: saline mortality.
Ebrahimi [45] RCT Patients with traumatic brain injury with 40/40 The TXA may reduce bleeding.
subdural and epidural hemorrhage I, 1 mg There was no statistical significance for subdural and
M,1 mg over 8 h subarachnoid hematoma reduction.
P: saline No complications were observed in any of the intervention
and control groups during the study as well.
Weng [46] MT Multiple patients with TBI 463/454 Significant effect on reducing the risk of hematoma
Multiple expansion.
Decreasing mortality rate
Improved favorable neurological outcomes
There was no increase in the rate of thrombotic events.
Chan [49] PS Patients with cerebral contusions or 81/570 Tranexamic acid was identified by univariate analysis to be
traumatic subarachnoid hemorrhage Multiple an independent factor associated with lower mortality.
Thromboembolic events were comparable in patients with
or without tranexamic acid.
El-Menyar [50] RS 102/102 Prehospital TXA administration is associated with less
Multiple in-hospital blood transfusion and massive transfusion
protocol.
There is no significant increase in the thromboembolic
events and mortality.
Chakroun-Walha PS All patients, aged at 18 years or older 96/84 The benefits of TXA in TBI without significant extracranial
[51] with TBI Multiple bleeding are to be considered.
The timing and indications of its use are still not defined
and the assessment of the outcome and the adverse
effects are still controversial.
Pulmonary embolism was statistically more frequent in
TXA group (11.5 versus 2.4%, P = 0.02).
CRASH-3 [48] RCT Adult trauma patients with, or at risk of, 6406/6331 Tranexamic acid is safe in patients with TBI treatment
significant bleeding who were within I, 1 mg within 3 h of injury reduces head injury-related death.
3 h of injury M,1 mg over 8 h Patients should be treated as soon as possible after injury.
P: saline Thromboembolic events were comparable in patients with
or without tranexamic acid.

RCT, randomized controlled trial; MA, meta-analysis; PS, prospective study; RS, retrospective study; I, infusion dose; M, maintenance dose; P, placebo
Neurosurg Rev

This study demonstrated that the effect of TXA ap-
pears to depend on the severity of TBI and the time
between injury and the initiation of treatment. Patients
with mild TBI (GCS score of 13–15 with intracranial
bleeding baseline on a CT scan) and patients with mod-
erate TBI benefited from TXA use, especially in the first
3 h after trauma with a considerable decrease in mortal-
ity. Patients with a GCS score of three with bilateral and
unilaterally unreacted pupils exhibited rapid expansion of
intracranial hemorrhage and did not have bleeding reduc-
tion, which did not improve outcome. There was no in-
creased risk of adverse events. In particular, the risk of
deep vein thrombosis, pulmonary embolism, stroke, and
myocardial infarction in the TXA-treated group was low-
er when compared with that in the placebo group, dem-
onstrating the safety of TXA among these patients [48].
The TBI with its devastating results associated with the use
by large RCTs justifies the use of TXA as a basic trauma
protocol. The use, however, must follow the guidelines al-
ready defined and be early. The mortality-reduced potential
cannot be ignored. In TBI, TXA use presents its best potential
(Table 4).
Risks and limitations of TXA use
Moderate-to-high doses (100 mg/kg/bolus and 10 mg/kg/h for
example) of TXA is potentially associated with neurological
complications (seizures, transient ischemic attack, delirium) in
adults and children [11, 52, 53].
A meta-analysis comprising 11,388 individuals showed no
association with increased risk of myocardial disease and mor-
tality, as well as weak association to neurological alterations.
However, there was a tendency to increase the risk of these
complications, suggesting the need for a deeper analysis in-
cluding a larger number of patients [54]. Similarly, another
meta-analysis based on 69 papers showed no significant asso-
ciation of TXA with an increased risk of thromboembolic
events [55].
In cardiac surgeries, the use of TXA was correlated with
higher mortality rates due to increased postoperative seizures.
The mechanism postulated for this effect was the binding of
TXA to GABA receptors, which abolished GABA-mediated
inhibition in the central nervous system [9, 56, 57].
There is currently no clinical evidence that the use of TXA
increases the risk of thromboembolic events, such as acute

Table 5 Benefits, risks, and

limitations of TXA use in Benefits and recommended Risks and limitations of
neurosurgery studies

Spine surgery Intraoperative bleeding reduction Different study protocols

Need for blood transfusion reduction Limited samples
Total blood loss reduction Larger doses do not enhance
TXA use is not linked to complications results
Low doses should be used Large doses may increase risk
of complications
Chronic patients need careful evaluation
Thromboembolic events are
rare
Brain surgery TXA use is not linked to complications Few studies on the topic
Use should be cautious Different study protocols
Use cannot be indiscriminate Limited samples
Chronic patients need careful evaluation New studies on the topic are
necessary
Ruptured Bleeding rate reduction Increase risk of cerebral
intracranial Mortality reduction infarction
aneurism Different study protocols
Low doses should be used
Chronic patients need careful evaluation Limited samples
Late use has no benefit
New studies on the topic are
necessary
Traumatic brain Mortality reduction Use after 3 h has no effect
injury TXA use is not linked to complications Larger doses do not
Treatment must be early recommended
Recommended use for severe and moderate TBI and
mild TBI in case of bleeding risk
Low doses are efficient

myocardial infarction, encephalic vascular accidents, deep
vein thrombosis, or pulmonary embolism [9, 52, 54]
(Table 5).
Conclusion
TXA in neurosurgeries is a promising method for the mainte-
nance of hemostasis in affected patients, as demonstrated by
its use in TBI and spine surgery; nevertheless, there is lack of
evidence in brain and vascular surgeries, and several points
remain unclear. There is still no consensus on the specific dose
at which TXA is beneficial or harmful, with conclusions re-
stricted for each study.
New studies are necessary to provide more accurate anal-
ysis of the possible benefits of TXA for chronic kidney dis-
ease patients. Larger sample studies are needed to investigate
the impact on brain surgery and intracranial aneurysm
surgery.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval For this type of study, formal consent is not required.
Animal experiments This article does not contain any studies with hu-
man participants or animals performed by any of the authors.
References
1. Udupi B, Siva Satya Prakash M, Adinarayanan S, Mishra S, Babu
L, Vel R (2014) Effect of low dose tranexamic acid on intra-
operative blood loss in neurosurgical patients. Saudi J Anaesth 9:
42. https://doi.org/10.4103/1658-354x.146304
2. Hooda B, Chouhan RS, Rath GP, Bithal PK, Suri A, Lamsal R
(2017) Effect of tranexamic acid on intraoperative blood loss and
transfusion requirements in patients undergoing excision of intra-
cranial meningioma. J Clin Neurosci 41:132–138. https://doi.org/
10.1016/j.jocn.2017.02.053
3. Choi HY, Hyun SJ, Kim KJ, Jahng TA, Kim HJ (2017)
Effectiveness and safety of tranexamic acid in spinal deformity
surgery. J Korean Neurosurg Soc 60:75–81. https://doi.org/10.
3340/jkns.2016.0505.004
4. Seddighi A, Nikouei A, Seddighi A, Zali A, Tabatabaei S,
Yourdkhani F, Naimian S, Razavian I (2015) The role of
tranexamic acid in prevention of hemorrhage in major spinal sur-
geries. Asian J Neurosurg 12:501–505. https://doi.org/10.4103/
1793-5482.165791
5. Meneghini L, Zadra N, Aneloni V, Metrangolo S, Faggin R, Giusti
F (2003) Erythropoietin therapy and acute preoperative
normovolaemic haemodilution in infants undergoing craniosynos-
tosis surgery. Paediatr Anaesth 13:392–396
6. Paulo D, Semonche A, Choudhry O, Al-Mufti F, Prestigiacomo CJ,
Roychowdhury S, Nanda A, Gupta G (2019) History of hemostasis
in neurosurgery. World Neurosurg 124:237–250. https://doi.org/
10.1016/j.wneu.2018.12.015
Neurosurg Rev
7. Elwatidy S, Jamjoom Z, Elgamal E, Zakaria A, Turkistani A, El-
Dawlatly A (2008) Efficacy and safety of prophylactic large dose of
tranexamic acid in spine surgery. Spine (Phila Pa 1976) 33:2577–
2580. https://doi.org/10.1097/brs.0b013e318188b9c5
8. Cheriyan T, Maier SP, Bianco K, Slobodyanyuk K, Rattenni RN,
Lafage V, Schwab FJ, Lonner BS, Errico TJ (2015) Efficacy of
tranexamic acid on surgical bleeding in spine surgery: a meta-anal-
ysis. Spine J 15:752–761. https://doi.org/10.1016/j.spinee.2015.01.
013
9. Ng WCK, Jerath A, Wasowicz M (2015) Tranexamic acid: a clin-
ical review. Anestezjol Intens Ter 47:339–350. https://doi.org/10.
5603/ait.a2015.0011
10. Lecker I, Orser BA, Mazer CD (2012) Saisir la chance de
comprendre les antifibrinolytiques. Can J Anesth 59:1–5. https://
doi.org/10.1007/s12630-011-9621-4
11. Goobie S (2013) The case for the use of tranexamic acid. Paediatr
Anaesth 23:281–284. https://doi.org/10.1111/pan.12093
12. Pisklakov S, Ibrahim H, Huang L (2017) Tranexamic acid and
major spine surgery: trends and controversies. J Surg Anesth 1:1–8
13. Carabini LM, Moreland NC, Vealey RJ, Bebawy JF, Koski TR,
Koht A, Gupta DK, Avram MJ, Zeeni C, Gould RW, Hemmer
LB, Sugrue PA, McClendon J (2018) A randomized controlled trial
of low-dose tranexamic acid versus placebo to reduce red blood cell
transfusion during complex multilevel spine fusion surgery. World
Neurosurg 110:e572–e579. https://doi.org/10.1016/j.wneu.2017.
11.070
14. Mebel D, Akagami R, Flexman AM (2016) Use of tranexamic acid
is associated with reduced blood product transfusion in complex
skull base neurosurgical procedures: a retrospective cohort study.
Anesth Analg 122:503–508. https://doi.org/10.1213/ANE.
0000000000001065
15. Shi H, Ou Y, Jiang D, Quan Z, Zhao Z, Zhu Y (2017) Tranexamic
acid reduces perioperative blood loss of posterior lumbar surgery
for stenosis or spondylolisthesis a randomized trial. Med (US) 96:
1–8. https://doi.org/10.1097/MD.0000000000005718
16. Zhang F, Wang K, Li FN, Huang X, Li Q, Chen Z, Tang YB, Shen
HX, Song QX (2014) Effectiveness of tranexamic acid in reducing
blood loss in spinal surgery: a meta-analysis. BMC Musculoskelet
Disord 15:1–9. https://doi.org/10.1186/1471-2474-15-448
17. Shakeri M, Salehpour F, Shokouhi G, Aeinfar K, Aghazadeh J,
Mirzaei F, Alavi SAN (2018) Minimal dose of tranexamic acid is
effective in reducing blood loss in complex spine surgeries: a ran-
domized double-blind placebo controlled study. Asian Spine J 12:
484–489. https://doi.org/10.4184/asj.2018.12.3.484
18. Tsutsumimoto T, Shimogata M, Ohta H, Yui M, Yoda I, Misawa H
(2011) Tranexamic acid reduces perioperative blood loss in cervical
laminoplasty. Spine (Phila Pa 1976) 36:1913–1918. https://doi.org/
10.1097/brs.0b013e3181fb3a42
19. Raksakietisak M, Sathitkarnmanee B, Srisaen P, Duangrat T,
Chinachoti T, Rushatamukayanunt P, Sakulpacharoen N (2015)
Two doses of tranexamic acid reduce blood transfusion in complex
spine surgery. Spine (Phila Pa 1976) 40:E1257–E1263. https://doi.
org/10.1097/BRS.0000000000001063
20. Colomina MJ, Koo M, Basora M, Pizones J, Mora L, Bagó J (2016)
Intraoperative tranexamic acid use in major spine surgery in adults:
a multicentre, randomized, placebo-controlled trial † †This Article
is accompanied by Editorial Aew470. Br J Anaesth 118:380–390.
https://doi.org/10.1093/bja/aew434
21. Yagi M, Hasegawa J, Nagoshi N, Iizuka S, Kaneko S, Fukuda K,
Takemitsu M, Shioda M, MacHida M (2012) Does the intraopera-
tive tranexamic acid decrease operative blood loss during posterior
spinal fusion for treatment of adolescent idiopathic scoliosis? Spine
(Phila Pa 1976) 37:16–20. https://doi.org/10.1097/BRS.
0b013e318266b6e5
22. Xue P, Yang J, Xu X, Liu T, Huang Y, Qiao F, Huang X (2018)
The efficacy and safety of tranexamic acid in reducing perioperative
Neurosurg Rev
blood loss in patients with multilevel thoracic spinal stenosis: a
retrospective observational study. Med (US) 97. https://doi.org/10.
1097/MD.0000000000013643
23. Camille D, Gaëtan T, Vianney G, Solène V, Emmanuel F, Rémi G,
Mourad O-S (2019) Blood loss and perioperative transfusions re-
lated to surgery for spinal tumors. Relevance of tranexamic acid.
Neurochirurgie. 65:377–381. https://doi.org/10.1016/j.neuchi.
2019.05.003
24. Dadure C, Sauter M, Bringuier S, Bigorre M, Raux O, Rochette A,
Canaud N, Capdevila X (2011) Intraoperative tranexamic acid re-
duces blood transfusion in children undergoing craniosynostosis
surgery: a randomized double-blind study. Anesthesiology 114:
856–861. https://doi.org/10.1097/ALN.0b013e318210f9e3
25. Kurnik NM, Pflibsen LR, Do A, Bristol R, Singh DJ (2018)
Craniosynostosis surgery and the impact of tranexamic acid dosing.
J Craniofac Surg 29:96–98. https://doi.org/10.1097/SCS.
0000000000004196
26. Huebner BR, Dorlac WC, Cribari C (2017) Tranexamic acid use in
prehospital uncontrolled hemorrhage. Wilderness Environ Med 28:
S50–S60. https://doi.org/10.1016/j.wem.2016.12.006
27. Na HS, Shin HJ, Lee YJ, Kim JH, Koo KH, Do SH (2016) The
effect of tranexamic acid on blood coagulation in total hip replace-
ment arthroplasty: rotational thromboelastographic (ROTEM®)
analysis. Anaesthesia 71:67–75. https://doi.org/10.1111/anae.
13270
28. Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE
(2013) Tranexamic acid in trauma. J Trauma Acute Care Surg 74:
1575–1586. https://doi.org/10.1097/TA.0b013e318292cc54
29. Germans MR, Post R, Coert BA, Rinkel GJE, Vandertop WP,
Verbaan D (2013) Ultra-early tranexamic acid after subarachnoid
hemorrhage (ULTRA): study protocol for a randomized controlled
trial. Trials 14:1–6. https://doi.org/10.1186/1745-6215-14-143
30. Post R, Germans MR, Boogaarts HD, Ferreira Dias Xavier B, Van
den Berg R, Coert BA, Vandertop WP, Verbaan D (2019) Short-
term tranexamic acid treatment reduces in-hospital mortality in an-
eurysmal sub-arachnoid hemorrhage: a multicenter comparison
study. PLoS One 14:1–9. https://doi.org/10.1371/journal.pone.
0211868
31. Baharoglu MI, Germans MR, Rinkel GJE, Algra A, Vermeulen M,
van Gijn J, Roos YBWEM (2013) Antifibrinolytic therapy for an-
eurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev
2013. https://doi.org/10.1002/14651858.CD001245.pub2
32. Gaberel T, Magheru C, Emery E, Derlon JM (2012)
Antifibrinolytic therapy in the management of aneurismal sub-
arachnoid hemorrhage revisited. A meta-analysis. Acta Neurochir
(Wien) 154:1–9. https://doi.org/10.1007/s00701-011-1179-y
33. Roos YBWE, Beenen LFM, Groen RJM, Albrecht KW,
Vermeulen M (1997) Timing of surgery in patients with aneurys-
mal subarachnoid haemorrhage: Rebleeding is still the major cause
of poor outcome in neurosurgical units that aim at early surgery. J
Neurol Neurosurg Psychiatry 63:490–493
34. Fodstad H, Forssell A, Liliequist B, Schannong M (1981)
Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid
hemorrhage: a consecutive controlled clinical trial. Neurosurgery 8:
158–165. https://doi.org/10.1227/00006123-198102000-00004
35. Wijdicks EFM, Hasan D, Lindsay KW, Brouwers PJAM, Hatfield
R, Murray GD, van Gijn J, Vermeulen M (1989) Short-term
tranexamic acid treatment in aneurysmal subarachnoid hemorrhage.
Stroke 20:1674–1679. https://doi.org/10.1161/01.STR.20.12.1674
36. Eastin TR, Snipes CD, Seupaul RA (2014) Are antifibrinolytic
agents effective in the treatment of aneurysmal subarachnoid hem-
orrhage? Ann Emerg Med 64:658–659. https://doi.org/10.1016/j.
annemergmed.2014.06.004
37. Hillman J, Fridriksson S, Nilsson O, Yu Z, Säveland H, Jakobsson
K-E (2002) Immediate administration of tranexamic acid and re-
duced incidence of early rebleeding after aneurysmal subarachnoid
hemorrhage: a prospective randomized study. J Neurosurg 97:771–
778
38. Fodstad H, Nilsson IM (1981) Coagulation and fibrinolysis in
blood and cerebrospinal fluid after aneurysmal subarachnoid haem-
orrhage: effect of tranexamic acid (AMCA). Acta Neurochir (Wien)
56:25–38. https://doi.org/10.1007/BF01400969
39. Vermeulen M, Lindsay KW, Murray GD, Cheah F, Hijdra A,
Muizelaar JP, Schannong M, Teasdale GM, Van Crevel H, Van
Gijn J (1984) Antifibrinolytic treatment in subarachnoid hemor-
rhage. N Engl J Med 311:432–437. https://doi.org/10.1056/
NEJM198408163110703
40. Chandra B (1978) Treatment of subarachnoid hemorrhage with
tranexamic acid (a double-blind clinical trial). Stroke 9:105
41. Roos Y (2000) Antifibrinolytic treatment in subarachnoid hemor-
rhage: a randomized placebo-controlled trial. Neurology 54:77–82.
https://doi.org/10.1212/wnl.54.1.77
42. Moreira MM, Adry RAR d C, Pereira CU (2019) Características do
Hematoma Epidural Contralateral após Craniectomia
Descompressiva para Tratamento de Trauma Cranioencefálico
Grave. Revisão Sistemática Jbnc - J Bras Neurocir 28:101–110.
https://doi.org/10.22290/jbnc.v28i2.1681
43. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L,
Cook L, Kawahara T, Perel P, Prieto-Merino D, Ramos M, Cairns
J, Guerriero C (2013) The CRASH-2 trial: A randomised controlled
trial and economic evaluation of the effects of tranexamic acid on
death, vascular occlusive events and transfusion requirement in
bleeding trauma patients. Health Technol Assess (Rockv) 17:1–
80. https://doi.org/10.3310/hta17100
44. Roberts I, Edwards P, Prieto D, Joshi M, Mahmood A, Ker K,
Shakur H (2017) Tranexamic acid in bleeding trauma patients: an
exploration of benefits and harms. Trials 18:1–6. https://doi.org/10.
1186/s13063-016-1750-1
45. Ebrahimi P, Mozaffari J, Bahrami R, Hanafi MG, Mousavinejad M
(2019) Intravenous tranexamic acid for subdural and epidural intra-
cranial hemorrhage: randomized, double-blind, placebo-controlled
trial. Rev Recent Clin Trials 14. https://doi.org/10.2174/
1574887114666190620112829
46. Weng S, Wang W, Wei Q, Lan H, Su J, Xu Y (2019) Effect of
tranexamic acid in patients with traumatic brain injury: a systematic
review and meta-analysis. World Neurosurg 123:128–135. https://
doi.org/10.1016/j.wneu.2018.11.214
47. Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J,
Fernández-Mondéjar E, Filipescu D, Hunt BJ, Komadina R,
Nardi G, Neugebauer EAM, Ozier Y, Riddez L, Schultz A,
Vincent JL, Spahn DR (2016) The European guideline on manage-
ment of major bleeding and coagulopathy following trauma: Fourth
edition. Crit Care 20:1–55. https://doi.org/10.1186/s13054-016-
1265-x
48. Crash T (2019) Articles Effects of tranexamic acid on death, dis-
ability, vascular occlusive events and other morbidities in patients
with acute traumatic brain injury ( CRASH-3 ): a randomised. 6736
49. Chan DYC, Tsang ACO, Li LF, Cheng KKF, Tsang FCP, Taw
BBT, Pu JKS, Ho WWS, Lui WM, Leung GKK (2019)
Improving survival with tranexamic acid in cerebral contusions or
traumatic subarachnoid hemorrhage: univariate and multivariate
analysis of independent factors associated with lower mortality.
World Neurosurg 125:e665–e670. https://doi.org/10.1016/j.wneu.
2019.01.145
50. El-Menyar A, Sathian B, Wahlen BM, Abdelrahman H, Peralta R,
Al-Thani H, Rizoli S (2019) Prehospital administration of
tranexamic acid in trauma patients: a 1:1 matched comparative
study from a level 1 trauma center. Am J Emerg Med. 38:266–
271. https://doi.org/10.1016/j.ajem.2019.04.051
51. Chakroun-Walha O, Samet A, Jerbi M, Nasri A, Talbi A, Kanoun
H, Souissi B, Chtara K, Bouaziz M, Ksibi H, Rekik N (2018)
Benefits of the tranexamic acid in head trauma with no extracranial

bleeding: a prospective follow-up of 180 patients. Eur J Trauma
Emerg Surg 45:1–8. https://doi.org/10.1007/s00068-018-0974-z
52. Sponseller PD, Johnson CC, Nami N, Wetzler JA, Frank SM,
Goobie SM, Johnson DJ (2016) High-dose versus low-dose
tranexamic acid to reduce transfusion requirements in pediatric sco-
liosis surgery. J Pediatr Orthop 37:e552–e557. https://doi.org/10.
1097/bpo.0000000000000820
53. Martin K, Breuer T, Gertler R, Hapfelmeier A, Schreiber C, Lange
R, Hess J, Wiesner G (2011) Tranexamic acid versus ε-
aminocaproic acid: efficacy and safety in paediatric cardiac surgery.
Eur J Cardio-thoracic Surg 39:892–897. https://doi.org/10.1016/j.
ejcts.2010.09.041
54. Ngaage DL, Bland JM (2010) Lessons from aprotinin: is the routine
use and inconsistent dosing of tranexamic acid prudent? Meta-
analysis of randomised and large matched observational studies.
Eur J Cardio-thoracic Surg 37:1375–1383. https://doi.org/10.
1016/j.ejcts.2009.11.055
55. Hariharan D, Mammi M, Daniels K, Petrucci K, Lamba N,
Cerecedo-Lopez CD, Doucette J, Papatheodorou S, Hulsbergen
Neurosurg Rev
A, Aglio LS, Smith TR, Mekary DR, Zaidi H (2019) The safety
and efficacy of tranexamic acid in adult spinal deformity surgery: a
meta-analysis. Value Health 22:S176. https://doi.org/10.1016/j.
jval.2019.04.757
56. Sharma V, Katznelson R, Jerath A, Garrido-Olivares L, Carroll J,
Rao V, Wasowicz M, Djaiani G (2014) The association between
tranexamic acid and convulsive seizures after cardiac surgery: a
multivariate analysis in 11 529 patients. Anaesthesia 69:124–130.
https://doi.org/10.1111/anae.12516
57. Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M (2010)
High-dose tranexamic acid is associated with nonischemic clinical
seizures in cardiac surgical patients. Anesth Analg 110:350–353.
https://doi.org/10.1213/ANE.0b013e3181c92b23
Publisher’s note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.