Tranexamic acid: A clinical review

Abstract

Blood loss and subsequent transfusions are associated with major morbidity and mortality. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, liver surgery and solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical diseases. The evidence of their efficacy has been mounting for years. Tranexamic Acid (TXA), a synthetic lysine-analogue antifibrinolytic, was first patented in 1957 and its use has been increasing in contrast to aprotinin, a serine protease inhibitor antifibrinolytic. This review aims to help acute care physicians navigate through the clinical evidence available for TXA therapy, develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening scope of applications. Many questions remain unanswered regarding other clinical effects of TXA such as anti-inflammatory response to cardiopulmonary bypass, the risk of thromboembolic events, adverse neurological effects such as seizures, and its morbidity and mortality, all of which necessitate further clinical trials on its usage and safety in various clinical settings.

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Tranexamic acid: a clinical review
Authors: William Chuk Kit Ng, Angela Jerath, Marcin Wasowicz
DOI: 10.5603/AIT.a2015.0011
Article type: Review articles
Submitted: 2015-02-10
Accepted: 2015-03-06
Published online: 2015-03-17
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Tranexamic acid: a clinical review
William Ng, Angela Jerath, Marcin Wasowicz
University of Toronto, UHN Department of Anesthesia, Toronto General Hospital, Canada
Abstract
Blood loss and subsequent transfusions are associated with major morbidity and mortality. The
use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, liver
surgery and solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical
diseases. The evidence of their efficacy has been mounting for years. Tranexamic Acid (TXA), a
synthetic lysine-analogue antifibrinolytic, was first patented in 1957 and its use has been
increasing in contrast to aprotinin, a serine protease inhibitor antifibrinolytic. This review aims to
help acute care physicians navigate through the clinical evidence available for TXA therapy,
develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening
scope of applications. Many questions remain unanswered regarding other clinical effects of TXA
such as anti-inflammatory response to cardiopulmonary bypass, the risk of thromboembolic
events, adverse neurological effects such as seizures, and its morbidity and mortality, all of which
necessitate further clinical trials on its usage and safety in various clinical settings.
Key words: anesthesia, tranexamic acid, antifibrinolytic, blood conservation
Blood loss and subsequent transfusions are associated with major morbidity and mortality
[1, 2]. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, liver surgery
and solid organ transplantation and non-surgical diseases. The evidence of their efficacy has been
mounting for years [3, 4]. Synthetic lysine-analogue Tranexamic Acid (TXA, trans-4-
aminomethylcyclohexane-1-carboxylic acid), along with ε-aminocaproic acid (ɛ-ACA), were first
patented by S. Okamoto in 1957 [5]. Many questions remain unanswered regarding other clinical
effects of TXA such as anti-inflammatory response to cardiopulmonary bypass (CPB), the risk of
thromboembolic events and adverse neurologic effects (seizures), as well as the morbidity and
mortality of TXA, all of which necessitate further clinical trials on its usage and safety in various
clinical settings. Therefore, this review aims to help acute care physicians navigate through the
clinical evidence available for TXA treatment, develop appropriate dose regimens whilst
minimizing harm, as well as understand its broadening scope of applications [5].
1

Mechanisms of action
TXA is a synthetic lysine-analogue antifibrinolytic [6] that competitively inhibits the
activation of plasminogen to plasmin; at high concentrations it non-competitively blocks plasmin,
thus TXA inhibits the dissolution and degradation of fibrin clots by plasmin. The binding of TXA
to plasminogen is 6 to 10 times more potent that of ɛ-ACA [7]. TXA has been shown to increase
thrombus formation in a dose-dependent fashion in animal models, in contrast to aprotinin, which
inhibits thrombus formation [8].
Evidence from numerous studies show that TXA inhibits plasmin-induced platelet
activation during extracorporeal circulation, such as cardiopulmonary bypass (CPB) used in
cardiac surgery [9−12]. There are multiple factors that lead to bleeding following CPB, and
fibrinolysis is one of the few that can be mitigated by pharmacological intervention. TXA also
reduces excessive bleeding after CPB by several other mechanisms. Firstly plasmin-platelet
interaction leads to the selective release of ADP-granules from platelets, which is triggered by
platelet surface contact with the extracorporeal circuit. Soslau et al. [13] found that platelet dense-
granule ADP content in patients loaded with TXA pre-CPB were higher compared to those loaded
with TXA post-CPB, with a strong inverse relationship to blood loss. The same investigators
estimated the EC50 (half maximal effective concentration) of TXA required for the inactivation
of plasmin-induced platelet aggregation during CPB to be ≤ 15 µg mL-1 in vitro; thrombin
activation of platelets was also inhibited by plasmin-TXA binding to platelet receptors. Thus, one
may conclude that there are several pathways explaining the preservation of platelet function by
TXA during CPB.
Thirdly, TXA possibly attenuates the inflammatory response and related hemodynamic
instability in patients undergoing CPB. Hyperfibrinolysis probably plays a significant role in this
inflammatory response. In a randomized controlled trial (RCT) of 50 patients undergoing CPB,
TXA reduced significantly several of the biochemical markers of inflammatory response [14]: IL-
6, fibrin separation products, creatine-kinase (CK) and plasminogen activator inhibitor. Patients
receiving TXA had reduced incidences of inflammatory response and vasoplegic shock, fewer
mean hours of norepinephrine use (1.2 vs 25.4 h) and fewer hours of mechanical ventilation (6.5
vs 12 h) in intensive care after CPB. In a larger RCT, IL-6 had a direct relationship with
temperature, D-dimer, troponin I, CK, and lactic acid after CPB [15]. Furthermore, giving
additional post-CPB TXA significantly reduced the relative risk (RR 2.5) of inflammatory
response compared to pre-CPB TXA dosing alone.
Fourthly, hyperfibrinolysis contributes to coagulopathy in trauma and has an estimated
incidence of 15% [16]. In trauma, tissue damage causes the release of tissue plasminogen
2

activator induced by tissue ischemia and endothelial injury [17]. Point-of-care testing by
rotational thromboelastometry allows rapid identification of patients with hyperfibrinolysis in
trauma — a state associated with greater INR derangements, lower fibrinogen and higher
mortality rates [18, 19] when compared to physiologic fibrinolysis. TXA use in trauma thus has
physiologic justification, but the diagnosis of hyperfibrinolysis is crucial before initiating
treatment.
Lastly, there is a beneficial interaction of TXA with desmopressin: if the fibrinolytic
activity of desmopressin via the transient release of tissue plasminogen activators [11, 20] is
abolished by TXA preparation, desmopressin exerts salutary effect on platelet activation,
significantly reducing postoperative blood loss and transfusion [21].
Clinical usage and efficacy
The main purpose of TXA is the reduction of perioperative bleeding and transfusion
requirements in both cardiac and non-cardiac surgery. There are clear benefits both from the
mortality-morbidity and economic-cost perspectives. In a recent meta-analysis of over 100 RCTs
that compared TXA vs no TXA or a placebo in more than 10,000 patients undergoing surgery
[22], there was overwhelming evidence that TXA reduces the probability of transfusion by 38%.
Moreover, a cumulative meta-analysis suggests that this evidence has been available for more
than 10 years. Although the same study showed that fewer deaths occurred in the TXA group (RR
0.61, 95% CI 0.38 to 0.98), this became uncertain when analysis was restricted to the trials with
adequate concealment. Similarly, the Cochrane Review of the effect of antifibrinolytics on blood-
loss and transfusion of allogeneic blood [3] found that TXA significantly reduced blood
transfusion by 39%, representing an absolute risk reduction of 18%. However, TXA was not
associated with decreased mortality in all surgeries.
Cardiac surgery
Since the publication of findings by Mangano et al. [23] and Karkouti et al.
antifibrinolytic choice in cardiac surgery has shifted from aprotinin to TXA and ɛ-ACA. This was
due to the concern that aprotinin may be associated with an increased risk of cardiovascular or
cerebral vascular events, as well as renal dysfunction or failure. In a propensity-score matched
analysis (n = 10870) of patients at high risk of blood loss in cardiac surgery, Karkouti et al. [2]
reported an increased risk of renal toxicity of aprotinin when compared with TXA with a
potential increase in mortality, whilst both antifibrinolytics had similar hemostatic effectiveness.
Subsequently, in a 5-year follow-up of (n = 4374) patients having CABG surgery [24], Mangano
3

et al. found aprotinin to be associated with increased mortality compared with a control, TXA and
ɛ-ACA.
The use of TXA was further propelled by the BART [25] trial (Blood Conservation Using
Antifibrinolytics in a Randomized Trial) published by Fergusson et al. [25], who compared the
use of aprotinin, TXA and ɛ-ACA in high-risk cardiac surgery patients. Alarmingly, the 30-day
mortality rate, was 6% for the aprotinin group vs 3.9% for TXA (RR 1.55) and 4.0% for ɛ-ACA
(RR 1.52); however, there was a modest reduction in the risk of massive bleeding in the aprotinin
group compared with the two lysine-analogues. This led to the withdrawal of FDA and Health
Canada approvals for aprotinin [26]. On the other hand, critics of BART have noted that in the
high-risk patient subset, aprotinin may possibly have a better benefit/risk profile [27]. Indeed, this
is supported by the propensity-score (n = 1544) matched study by Karkouti et al. [28]
Knowledge of the efficacy of TXA vs a control in reducing blood loss and transfusion in
cardiac surgery has been available for decades [29, 30]. Recent meta-analyses confirm this
notion. A report by Henry et al. [31] stated a relative risk of blood transfusion with TXA of 0.68
with ~300 mL of blood saved while Ngaage et al. [32] reported an odds ratio of 0.53 with ~298
mL of blood saved. Although a comparison of TXA with a placebo showed a reduction in the
number of reoperations caused by blood loss [3, 32], once again the benefit of reduced
reoperation numbers due to blood loss is even more convincing with high-dose aprotinin [3, 31].
Even though TXA is approximately 7-times more potent than ɛ-ACA, they were comparable in
relative risk and actual volume of blood loss in cardiac surgery [3]. Moreover, TXA did not show
a decreased risk of mortality in cardiac surgery in the aforementioned meta-analyses.
While the BART protocol TXA regimen — 30 mg kg-1 loading dose followed by 16 mg
kg-1 h-1 infusion during surgery with an added 2 mg kg-1 in the circuit is in the high-dose range
[33, 34], it has been nevertheless widely adopted by many cardiac surgical centers since the
publication of BART. Early dose-response studies in cardiac surgery by Horrow et al. [35] found
that a prophylactic loading dose of 10 mg kg-1 with infusion at 1 mg kg-1 h-1 was optimal, when
compared to six incremental loading doses from 2.5 to 40 mg kg-1 followed by 0.25 mg to 4 mg
kg-1 h-1 infusion. Later, several authors found inconsistent plasma concentrations [36, 37] with the
Horrow regimen when the pharmacokinetic influence of the circuit and patient renal function
were included in analysis. A recent RCT pitted the Horrow regimen against the higher BART
regimen in cardiac surgery patients [38], and it found that although a high dose of TXA does not
reduce the incidence of blood product transfusion up to day 7 (63% low dose vs 60% high dose),
it is more effective than a low dose of TXA in decreasing transfusion (2.5 vs 4.1 U), blood loss
(590 vs 820 mL), and repeat surgery (2.5% vs 6%). A subgroup analysis of high-risk patients with
4

dual antiplatelet therapy or having complex surgery showed a further reduced incidence of
transfusion and suggests that a high dose of TXA may be better in that group.
Many patients undergoing cardiac surgery receive aspirin and/or clopidogrel
preoperatively. There is evidence that TXA partially corrects arachidonic acid-induced (aspirin)
and ADP-induced (clopidogrel) platelet aggregation defects [39] detected by multiple electrode
aggregometry, in patients on dual-antiplatelet therapy, concurring with the plasmin-induced
platelet inhibition [10] by the redistribution and degradation of glycoprotein Ib and IIb/IIIa
receptors.
Ppediatric cardiac and non-cardiac surgery
The efficacy of TXA in major pediatric surgery reproduces what was found in the adult
population. In a meta-analysis of over 2,000 pediatric patients undergoing cardiac or scoliosis
surgery the authors found no evidence that TXA was inferior in the reduction of blood loss vs
aprotinin at 24 h. Indeed, TXA reduced blood loss by 11 mL kg-1 (95% CI 9 to 13 mL kg-1), and
reduced packed red cell transfusion by 4 mL kg-1 (95% CI 2 to 7 mL kg-1). In scoliosis surgery,
TXA significantly reduced blood loss by 682 mL (95% CI 214 to 1149 mL). A recent RCT
comparing TXA with a control (n = 150) in pediatric patients undergoing cardiac surgery [41]
demonstrated a reduction of blood loss but not the units of blood transfused at 24 h. Similarly, a
retrospective study (n = 231) of pediatric patients having cardiac surgery [42] found that TXA
significantly reduced blood loss and reduced the amount of blood transfused intraoperatively, as
well as at 48 h. Moreover, the authors found a reduction in the number of patients requiring blood
transfusion (45/103 vs 77/127, P = 0.012) at 48 hours. Interestingly, both studies did not find
differences between cyanotic and acyanotic subgroups. However, according to Faraoni et al. [43]
in their meta-analysis of pediatric cardiac surgery and TXA, there is much heterogeneity in the
data from RCTs: transfusion policies were ill-defined, with variability in regimens and data on
TXA effect on morbidity and mortality. However, these authors found that in the 848 patients
included in the analysis, the amount of red cells, platelet and fresh frozen plasma transfused
showed decreasing trends between TXA and the control. Despite recent pharmacokinetic studies
on pediatric populations [44, 45] the ideal dose regimen of TXA in pediatric cardiac surgery is
still unknown [46]. In vitro studies in neonates have shown a significantly lower plasma
concentration (~6.5 µg mL-1 vs ~17 µg mL-1) required to prevent hyperfibrinolysis when
compared to adults [45]; this would set the basis of future clinical trials on dosing regimens and
risk-benefit balance.
Faraoni and Goobie also performed a systematic review [47] on the use of
antifibrinolytics in pediatric non-cardiac surgery and concluded that in pediatric spine surgery
5

(mainly scoliosis correction) and craniosynostosis surgery, TXA did decrease blood loss and
transfusion requirements. An older Cochrane meta-analysis [48] found antifibrinolytics as a class
in scoliosis surgery reduced blood loss by 426 mL and the amount of blood transfused by 327
mL; no subgroup analysis on the effect of TXA alone was carried out. There are few RCTs
[49−51] on TXA use in pediatric scoliosis surgery. Thus, the safety profile of TXA use in
pediatric spinal surgery remains unresolved.
Basta et al. [52] conducted a separate systematic review on major pediatric surgery
(cardiac, spinal and craniofacial) and found that antifibrinolytics reduced blood loss and
transfusion volumes, particularly in craniofacial surgery. Craniosynostosis is not an uncommon
pediatric disease requiring early surgical intervention and is associated with considerable blood
loss [53]. There are two RCTs of TXA vs control in craniosynostosis surgery [54, 55]: Goobie et
al. showed significant decrease in blood loss of 54 mL kg-1 and decreased volume of blood
transfused by 23 mL kg-1; Dadure et al. [55] found a decrease in transfusion requirement by 85%
(11 to 1.6 mL kg-1) intraoperatively and by 57% (16.6 to 7.2 mL kg-1) postoperatively. Moreover,
Goobie et al. [44] describes a dose regimen for craniosynostosis using a two-compartment model,
suggesting a 10 mg kg-1 loading TXA followed by a 5 mg kg-1 h-1 infusion to produce a threshold
plasma concentration of 16 µg mL-1.
Orthopedic surgery
The reduction of blood loss in orthopedic surgery is of great importance, especially in hip
or knee arthoplasty and spinal surgery. Pharmacological treatment with TXA is making a
resurgence in orthopedic surgery. Indeed, antifibrinolytic use in orthopedic surgery is supported
by a meta-analysis by Kagoma et al. [56], which found a reduction in blood loss, relative risk of
transfusion (RR 0.52) and no increased risk of thromboembolism; the dose of TXA administered
ranged between 10−15 mg kg-1. A large retrospective analysis by Poeran et al. [57] studied the
perioperative use of TXA in knee or hip arthroplasty (n = 872416). Patients who received TXA
had lower rates of blood transfusion (7.7 vs 20.1%), fewer thromboembolic events (0.6 vs 0.8%),
and reduced incidence of acute renal failure (1.6 vs 1.8%) as well as combined complications (1.9
vs 2.6%). With an increasing dose of TXA (none, < 1 g, ~ 2 g and > 3 g), there were decreasing
odds (OR 0.31 to 0.38) of blood transfusion, and no significant increased risk of complications.
Moreover, its efficacy and safety profile in orthopedic surgery is further supported by two
meta-analyses of TXA use in primary hip [58] and knee [59] arthoplasty. In hip surgery, Sukeik et
al. [58] found that TXA reduced intraoperative blood loss by 104 mL and postoperative blood
loss by 172 mL (n = 350). There was also a proportional reduction of patients requiring blood
transfusion (risk difference −0.20). In total knee replacement, Alshryda et al. [59] found
6

significant reduction in blood loss by 591 mL (n = 763). It should be noted that there was
significant heterogeneity in the trials. Subgroup analysis of high dose TXA (> 4 g) showed a
reduction in transfusion requirements with homogeneity. In both meta-analyses there was no
evidence of increased risk of thromboembolic events due to TXA. In addition, the use of the
tourniquet in knee arthroplasty can activate local fibrinolysis apart from standard tissue trauma
[60] and adds justification for TXA use. A meta-analysis of intravenous TXA use (n = 581) in
spinal surgery by Yang et al. [61] had comparable findings to pediatric scoliosis surgery: there
was reduction in postoperative blood loss by 389.21 mL and the amount of blood transfused by
134.55 mL with TXA. A RCT of intravenous TXA use in cervical laminoplasty also found a
decrease in blood loss (264 mL) but not intraoperative blood loss [62]; again there was no
increase in complications.
Topical use
The topical use of TXA has been examined in a Cochrane review [63] by Ker et al.
Although the authors found reliable evidence that topical TXA reduces bleeding and blood
transfusion in surgical patients, the risk of thromboembolism is unclear, as many studies do not
report this complication or are underpowered. Topical administration results in a ten-fold less
plasma concentration of TXA when compared to intravenous administration [8, 64], with a
potential reduction in adverse effects. Although topical TXA has been studied in cardiothoracic
[65−68], orthopedic [64, 69−72], otorhinolaryngologic [73, 74] and orthognathic [75−77]
surgeries, high-quality trials are lacking.
Topical TXA in knee arthoplasty has been reviewed in a meta-analysis [78] while Panteli
et al. showed that topical TXA reduced postoperative drain output (−268 mL), total blood loss
(−220 mL), hemoglobin drop (−0.94 g dL-1) and transfusion risk (RR 0.47, 95% CI 0.26 to 0.84);
there was no increase in thromboembolisms. The authors examined the subgroup using > 2 g of
topical TXA and found that these patients had a significantly less transfusion requirement (RR
0.41, P = 0.05). Similarly in a separate review of RCTs [72], Zhang et al. [72] also found the
intra-articular injection of TXA in knee arthroplasty found a reduction of blood loss (396 mL),
relative transfusion risk (RR 0.22), drainage output and hemoglobin drop; there was no increased
risk of thromboembolism. Once again there was significant heterogeneity in these trials. Two
RCTs [69, 70] by Alshryda et al. found that intra-articular injection of TXA in primary total hip (n
= 161) and knee (n = 157) arthroplasty reduced the absolute risk of blood transfusion by 19.6%
and 15.4%, respectively, and reduced blood loss, hemoglobin drop, as well as decreased the cost
per episode by £ 305 and £ 333 respectively. Moreover, there was decreased length of stay in
7

knee surgery by 1.2 days without increased in thromboembolic events. All these findings
cumulatively support the topical use of TXA in orthopedic surgery.
In a meta-analysis of topical antifibrinolytic use in cardiac surgery (n = 622), Abrishami et
al. [79] found reduced postoperative blood loss and transfusion requirements in patients
undergoing on-pump cardiac surgery. Mahaffey et al. [80] (n = 160) found that combined
intravenous and topical TXA was associated with decreased chest drain output at 3, 6 and 12 h
postoperatively. Even though the total amount of TXA was higher in the combined group, less
TXA (4.1 g vs 5.1 g) was given intravenously compared with the control. In addition, there was
no increase in adverse events. Spegar et al. [81] studied the augmentation of systemic TXA by
topical application (2.5 g in 250 mL saline into pericardial cavity) in valvular surgery (n = 100)
and found intergroup variance on blood loss and fresh frozen plasma but a non-significant
decrease in the volume of blood loss in the augmented group. In contrast, Fawzy et al. [66] in
their RCT (n = 38) found a decrease in postoperative blood loss (−626 mL vs −1040 mL) and
platelet transfusion (median units 0 vs 2) using 1 g TXA in 100 mL saline into the pericardial
cavity. Similar regimens used in two other RCTs found that topical TXA did reduce postoperative
blood loss in cardiac surgery without increased risk of adverse events [67, 68].
Trauma
TXA application in trauma is supported by firm clinical evidence. The most convincing
multicenter RCT in trauma [82] to date is the comparison of TXA vs placebo in over 20,000
patients by the CRASH-2 collaborators. Patients were assigned to a placebo or IV loading of 1 g
TXA within 8 h of trauma then followed by IV infusion of 1 g TXA over 8 h. It showed that all-
cause mortality was reduced in the TXA group (RR 0.91), and death due to bleeding was
significantly reduced (RR 0.85). Subsequent analysis showed that early treatment (≤ 1 h from
injury) reduced the risk of death from bleeding (RR 0.68), while treatment given after 3h of
injury seemed to increase the risk of death due to bleeding [83].
It is important to remember that physiologic fibrinolysis and even fibrinolytic shutdown
occurs in trauma, and not just hyperfibrinolysis. In a recent study (n = 180) of patients with an
Injury Severity Score of ≥ 15, there was a sizeable portion (64%) of patients with fibrinolysis
shutdown per thromboelastometry at 30 min [84]. The distribution of mortality was U-shaped
relative to the fibrinolysis system, the physiologic group had lowest mortality (5%), and the
hyperfibrinolysis (44%) and shutdown (26%) groups had higher mortality. This supports the
employment of careful patient selection when using exogenous inhibition of fibrinolytic system.
The use of thromboelastometry will help prevent indiscriminate TXA therapy.
8

Neurosurgery
The use of antifibrinolytics in intracranial hemorrhage (ICH) and particularly aneurysmal
subarachnoid hemorrhage (SAH) has been investigated for decades, with earlier findings of
decreased re-bleeding rates but increased risk of stroke. New strategies were introduced for the
prevention of cerebral vasospasm with shorter antifibrinolytic intervention periods [85]. There is
renewed interest in TXA and ɛ-ACA for these patients. The earlier position is outlined in the
review of antifibrinolytics vs a control in ICH by the Cochrane Stroke Group [86]: the treatment
did not benefit patient outcome and death was not reduced. Treatment did reduce risk of re-
bleeding (OR 0.55) with some heterogeneity across the trials. However, there was an increased
risk of ischemic stroke (OR 1.39), again with heterogeneity in the trials. In drawing conclusions
from these results, the authors did not support the routine use of antifibrinolytics in aneurysmal
SAH. In contrast, a study [87] by Roos et al. [87] did not show rates of increased ischemic stroke,
namely delayed cerebral ischemia from vasospasm, probably because patients in this trial were
given calcium channel antagonist nimodipine and hypervolemic therapy concurrently.
Since this meta-analysis, new strategies using antifibrinolytics in short duration have
shown promise of reduced re-bleeding with fewer adverse events [88−91]. Although the
mechanism for re-bleeding is multifactorial, increased fibrinolysis and decreased platelet-plug
stability are implicated [92]. The risk of rebleeding is highest in the first 6 h after aneurysmal
SAH, with a poor prognosis as assessed by a reduction of the Glasgow Outcome Scale from 40%
to 80% and a mortality rate of 20% to 60% [92]. Hillman et al. [91] in their RCT (n = 505)
compared early intravenous TXA with a control in patients with SAH for short duration (up to 72
h) and found a significant reduction of early re-bleeding from 10.8% to 2.4% and an 80%
reduction in the mortality rate in the early rebleeders. Using evidence from transcranial Doppler
and clinical measurements, recent literature shows a resurgence of TXA as a part of protocol
therapy alongside other preventative strategies for vasospasm in the acute phase of aneurysm
SAH, prior to aneurysm closure [88, 93].
As traumatic ICH includes epidural, subdural and subarachnoid hemorrhage, the use of
TXA has been gaining increasing interest since CRASH-2 [82]. A nested RCT within CRASH-2
by Perel et al. [94] reviewed the rate of ICH growth in 270 patients, and they found no moderate
benefits (total hemorrhage growth and/or new ischemic lesions) nor harmful effects with certainty
in traumatic brain injury. More recently, Sprigg et al. [95] performed a pilot RCT comparing TXA
vs a control in spontaneous intracerebral hemorrhage — the first trial studying this application —
and found it feasible to use intravenous TXA early with good tolerability. As a result, two large
multicenter trials — namely TICH-2 (International) [95] and STOP-2 (Australia) [97] — are in
9

progress to evaluate the efficacy and safety of TXA in the setting of spontaneous intracerebral
hemorrhage.
Hepatic surgery
Orthotopic liver transplantation (OLT) is associated with significant blood loss and the
need for transfusion of blood products, with fibrinolysis being a major player in this [98, 99].
There has been clinical evidence for the use of antifibrinolytics in OLT for over three decades;
previously aprotinin was commonly used in OLT and trials demonstrated potential advantages
(antioxidant, anti-inflammatory) of aprotinin over TXA [100]. There is one meta-analysis which
has studied the use of antifibrinolytics including TXA and aprotinin in OLT (n = 1407), while
Molenaar et al. [101] found that both drugs reduced intraoperative blood and fresh frozen plasma
requirements.
There are several studies which have compared the efficacy of TXA with aprotinin in
OLT. In one RCT (n = 127), prophylactic TXA had similar efficacy to aprotinin [102] in terms of
blood and component transfusions both intraoperatively and at 24 h. There were neither
differences in mortality and complications nor in coagulation laboratory data collected
intraoperatively, except aPTT. Similar results were found by Ickx et al. [103] (n = 51), with the
additional finding of inhibition of fibrinolysis by both TXA and aprotinin vs a control. Gurusamy
et al. [104] addressed different strategies of decreasing blood loss in OLT in their Cochrane
review. Although with respect to aprotinin and TXA, they concluded that the clinical trials had
been biased, there were no differences in 60-day mortality rates, re-transplantation risk or
thromboembolic events in the TXA group vs the control and no difference between aprotinin and
TXA in mortality or thromboembolism risk. Massicotte et al. [105] analyzed 400 patients
undergoing OLT who had received antifibrinolytics and found no difference between TXA and
aprotinin in blood loss (1082 vs 1007 mL), blood transfused per patient (0.5 vs 0.5 U), final
hemoglobin (93 vs 95 g L-1), percentage of transfusion-free cases (80 vs 82%) or the 1-year
survival rate (85.1 vs 87.4%). Interestingly, preoperative hemoglobin correlated with 1-year
survival and transfusion requirements.
Görlinger [106] analyzed ROTEM® (rotational thromboelastometry) in 642 OLTs and
suggests using prophylactic administration only in fulminant liver failure or reduced maximal clot
firmness, which indicates a high-risk for hyperfibrinolysis. Although 60% of patients displayed
hyperfibrinolysis during OLT, only 40% who showed early hyperfibrinolysis during prehepatic
and anhepatic phases, required antifibrinolytics. In the neohepatic phase, only patients with
increased fibrinolysis and clinical bleeding were treated. This selection by point-of-care testing is
aimed at reducing iatrogenic prothrombotic risk.
10

TXA use has also been investigated for blood conservation in hepatectomy performed for
tumor resection. These studies showed promising efficacy, according to a RCT by Wu et al. [107]
(n = 214). Although a Cochrane review addressed use of pharmacological intervention for blood
conservation in liver resection, and found that aprotinin and TXA significantly reduced the risk of
allogeneic blood transfusion compared with a control [108], this review included a few small
RCTs. A survey of Canadian hepatobiliary surgeons showed that even though low central venous
pressure strategy was used commonly during liver resection, other conservation strategies
including TXA were rarely employed [109]. High quality RCTs on perioperative morbidity and
mortality are needed to assess pharmacological intervention for blood conservation in
hepatectomy.
Obstetric and gynecology
As Menorrhagia is a common illness affecting women’s health and quality of life, TXA
has been used as a form of treatment for over four decades. A recent review [110] placed its
efficacy in the reduction of menstrual blood loss by 34 to 59%. An earlier Cochrane review [111]
on the use of antifibrinolytics (TXA and its precursor) in heavy menstrual bleeding found that
TXA vs a placebo significantly reduced mean blood loss (mean difference −94 mL). TXA also
significantly reduced blood loss when compared to mefenamic acid, norethisterone and
etamsylate; there was no difference in adverse effects between TXA and the other agents. A
recent RCT also found reductions in menstrual blood loss by a new oral formulation of TXA that
was both statistically significant (> 50 mL) and clinically meaningful to patients, at doses > 3.9 g
day-1 for up to 5 days of the cycle [112]. This reinforced the findings of a greater quality of life
with TXA use in women with menorrhagia in an early uncontrolled study [113] (n = 849), who
were assessed by a questionnaire based on one designed by Edlund et al. [114].
A Cochrane review [115] analyzed two RCTs (n = 453) comparing TXA vs a control in
women having a caesarean section or vaginal delivery [116, 117], and the authors found that
blood loss of > 400 mL was less common and mean blood loss was lower in the TXA group vs
the control (mean difference −75 mL). A recent meta-analysis on TXA in pregnancy and
postpartum [118] by Peisidis et al. [118] included several quasi-blinded trials [119−121] excluded
from the above Cochrane review, and found a combined estimated decrease of blood loss by 32.5
mL in TXA pre-caesarean section vs a control. A similar effect of TXA was found in a separate
meta-analysis by Ferrer et al. [122] in a reduction of postpartum blood loss by 92 mL compared
with the control.
Ducloy-Bouthers et al. [123] (n = 144) demonstrated that a high-dose TXA (4 g infusion
over 1 h followed by 1 g h-1 for 6 h) vs a control — in women with greater than 800 mL
11

postpartum hemorrhage — was effective in reducing blood loss (173 vs 221 mL). Moreover, the
TXA group had a shorter duration of hemorrhage, less progression to severe postpartum
hemorrhage and less incidence of transfusion. This trial was underpowered to detect rare adverse
effects. A RCT (n = 439) by Gungorduk et al. [124] showed that TXA — 1 g given intravenously
over 5 min at the delivery of the anterior shoulder — reduced blood loss during the 3rd and 4th
stage of labor compared to the control (261.5 vs 349.98 mL), significantly higher hematocrit and
hemoglobin levels on day one, with no major complications at a three week follow-up.
Gungorduk et al. [125] also performed a RCT (n = 660) of pre-caesarean intravenous TXA vs
control, and found a significantly lower mean blood loss, a lower proportion of women with
severe postpartum hemorrhage (> 1000 mL blood loss) and a lower risk of additional uterotonics
used. Finally, three new RCTs [126−128] comparing pre-caesarean section intravenous TXA vs a
control have shown a reduction of intraoperative and post-caesarean blood loss without increased
adverse events such as thromboembolism. Determining the different obstetric and gynecological
settings in which TXA may be beneficial remains a critical question for future research.
Other usages
A common minor surgery where post-operative bleeding remains a big issue is
tonsillectomy. A meta-analysis of the use of TXA in tonsillectomy [129] (n = 180), showed a
reduced volume of blood loss but not the number of patients with post-tonsillectomy hemorrhage.
Albirmawy et al. [73] found that post-resection topical TXA in pediatric adenoidectomy led to a
reduction of blood loss during surgery, decreased postoperative bleeding and transfusion.
Lastly, several old trials support the use of TXA in hereditary angioneurotic edema [130,
131]. The biological mechanism involves the inhibition of the complement system by TXA in the
presence C1 esterase deficiency and partial normalization of plasma kinin activation [130]. In
Japan, TXA is approved for conditions such as urticarial swelling, itch, eczema, drug eruptions or
toxicoderma [8], in which local hyperfibrinolysis and inflammation are involved [131].
The use of TXA in upper gastrointestinal bleeding was reviewed in a Cochrane meta-
analysis, and although TXA use vs a control reduced mortality risk, the effect was lost in a
subgroup analysis stratified for bias control and in an sequential analysis [132]. No such benefit
was demonstrated in TXA vs other anti-ulcer therapy. Although five serious cases of
thromboembolic events occurred in the TXA group, this was not statistically significant. No
RCTs were found assessing TXA use in upper gastrointestinal bleeding in liver disease [133]. The
use of TXA in hemoptysis from any cause was reviewed by the Cochrane Collaboration [134],
and TXA vs a control significantly reduced bleeding time (mean difference −19.47 h), without
any difference in side-effects.
12

Adverse effects and dosing
Topical administration of TXA to the central nervous system of animals has been shown
to cause seizures in a dose-related fashion [135, 136], this correlates with human reports of
seizures induced by accidental intrathecal injections of TXA [136−138]. Recently a dose-
response relationship of TXA has been proposed as a modifiable risk factor for seizures for
patients undergoing cardiac surgery [139]. TXA crosses the blood-brain barrier and penetrates the
eye, and produces cerebrospinal fluid concentration levels around 10% of the plasma
concentration [8]. Likewise, it diffuses into and out of synovial membranes and joint fluid. It is
now clear from current literature that moderate to high doses of TXA in cardiac surgery are
associated with an increased risk of seizures [139, 140]. In a multivariate analysis of over 11,000
patients after cardiac surgery, Sharma et al. [142] found TXA to be a strong independent predictor
for the development of postoperative generalized seizures [141] (OR 14.3); in addition, patients
with seizures had a 2.5 times higher mortality rate. Similarly, in a propensity-score adjusted
analysis (n = 4883) Koster et al. [143] showed that moderate dosing of TXA in cardiac surgery
doubled the rate of post-CPB seizure and in-hospital mortality. Similar concerns over the
increasing trend of post-CPB seizure in pediatric patients have led to the substitution of TXA by
ɛ-ACA in a major European center for pediatric cardiac surgery.
The postulated mechanism was TXA binding to GABAA receptors, subsequently blocking
GABAA-mediated inhibition in the CNS [144, 145]. Recently, Lecker et al. [145] have
demonstrated that TXA is structurally similar to glycine, and competitively inhibits glycine
inhibitory receptors in the cortical and spinal cord neurons in rats; TXA also inhibited the
GABAA receptors in cortical and spinal cord neurons. Both TXA dis-inhibitory pathways cause
increased excitatory synaptic drive evidenced by seizure-like events in cortical slices induced at
TXA concentrations of 31 μg mL-1 (200 μM), similar to that measured in CSF of patients
undergoing CPB. Finally, peak CSF TXA concentrations occurred when the infusions were
stopped after CPB, later than peak serum levels. When taken together, this explains the late-onset
of unexpected seizures in patients emerging from anesthesia after CPB. Moreover, ɛ-ACA had
10-fold less potency in glycine receptor inhibition, and aprotinin had no inhibitory potency.
There are various dose regimens for different indications cited by clinical trials; initially
an effective plasma concentration of TXA for antifibrinolysis was reported to be 5−10 μg mL-1
[147] or 10−16 μg mL-1 [13, 147, 148]. Subsequently, Dowd et al. [37] proposed the dosing
scheme later adopted in the BART study, in order to ensure plasma levels which would achieve
complete inhibition of fibrinolysis for cardiac patients undergoing CPB, namely a loading dose
30 mg kg-1, maintenance infusion at 16 mg kg-1 h-1with an additional 2 mg kg-1 in the circuit [25,
13

37]. Sharma et al. [150] conducted a pharmacokinetic study of the BART regimen in cardiac
surgery and demonstrated that plasma TXA concentrations were consistently higher than
suggested levels aiming to achieve 100% (>100 μg/mL) and 80% inhibition (> 10 μg mL-1) of
tissue plasminogen activator and these levels remained high for up to 6 hours postoperatively.
Approximately 95% of TXA is excreted via the urine unchanged, and excretion decreases with
increasing plasma creatinine levels. The dosage adjustment for renal-impaired patients remains an
unknown; Jerath et al. [151]used the 2 compartment model to guide a simulated reduction of the
maintenance infusion rate according to the GFR of patients during CPB to achieve > 100 μg mL-1
threshold plasma concentrations.
Despite the fact that TXA is minimally metabolized in the body, precautions should be
taken with prothrombotic medications [152] used concomitantly. According to the Cyklokapron®
product information [6], these medications include a combination hormone contraceptives, factor
IX, Xa and VIIa complex concentrates, anti-inhibitor coagulant concentrates, thrombin,
batroxobin or hemocoagulase.
There is currently no clinical evidence that the use of TXA increases the risk of
thromboembolic events, namely myocardial infarction, stroke, deep vein thrombosis or
pulmonary embolism according to meta-analyses and clinical trials cited in the general [22, 63],
trauma [82], orthopedic [48, 56, 58, 59, 78], cardiac [25, 32, 153] or obstetric & gynecological
[111, 112, 119, 123] settings. However, there are reports of catastrophic intracardiac or
intrapulmonary thromboses [154], whose putative cause was antifibrinolytic use, albeit none
involved TXA. The meta-analysis of antifibrinolytics in OLT (n = 1407) by Molenaar et al. [101]
found no increased risk of hepatic artery thromboses or thromboembolism. Ngaage et al. [32] in
their meta-analysis of TXA in cardiac surgery noted that thromboembolic events (myocardial
infarction and neurologic complication) and mortality observed were few but not increased
compared to non-treatment groups; the authors still warn against the indiscriminate use of TXA.
In patients with menorrhagia, TXA was not associated with an increased thromboembolism risk
in a nested case-control study [155] (n = 686), whereas other therapy groups had a significantly
increased risk, suggesting that menorrhagia is prothrombotic. Finally, Perel et al. [63] were
uncertain about the increased risk of thromboembolism and stroke in a Cochrane review of TXA
in emergency surgery; only three trials met the criteria for inclusion and the number of events
observed were small.
Overall, the cumulative evidence shows that TXA is a well-tolerated drug when delivered
orally, intravenously and/or topically. Gastrointestinal disturbance, allergic skin reaction, visual
disturbance occur more commonly [8] and seizures less commonly at high concentrations.
14

Unanswered questions
There are still important questions of mortality and morbidity of TXA use in surgery. One
may expect that a reduction of transfusion would translate into reduction in mortality and
morbidity. As mentioned above, Ker et al. [22] found fewer deaths (RR 0.61) occurred in the
TXA group in their meta-analysis, albeit with uncertainty of adequate concealment. The overall
potential for increased thromboembolism risk with TXA remains uncertain. The safety profile and
dose regimens of TXA in cardiac and non-cardiac surgeries in the pediatric population requires
further investigation, as previous studies are underpowered to detect differences in adverse effects
[47].
The adjustment of TXA in renal impairment warrants further investigation, especially
given the at-risk patient group undergoing cardiac surgery. There is no universally accepted dose
regimen despite definite concerns of seizure risk of high-dose TXA.
Given the link between inflammatory response and coagulation-fibrinolysis systems and
the likely attenuation of inflammatory response by TXA in CPB [14, 15], clinicians ought to
identify at-risk patients who may benefit from its treatment.
There are several case reports of young, healthy individuals developing ischemic cerebral
events after TXA use, especially those with heterozygous MTFR C677T genes (methylene
tetrafolate transferase) [156]. In the meta-analyses and large clinical trials, the risk of stroke,
pulmonary thromboembolism and deep venous thrombosis with TXA use remains uncertain. The
interaction of pharmacology with genetic factors is an exciting field for research.
Several ongoing multicenter RCTs on TXA are worth following. The STOP-AUST trial
[98] is comparing early (≤ 4.5 h of stroke onset) intravenous TXA use with a placebo in patients
with confirmed intracerebral hemorrhage by CT angiography contrast extravasation — a
biomarker of likely hematoma growth. The hypothesis is that TXA will reduce intracerebral
hematoma growth at 24 h. CRASH-3 is an international pragmatic trial quantifying the effect of
early TXA (the same regimen as CRASH-2) on mortality and morbidity in 10,000 patients with
traumatic brain injury [157]. Lastly, Shakur et al. [158] is leading an international pragmatic trial,
a.k.a. the WOMAN trial, on the use of TXA in 15,000 women with a clinical diagnosis of
postpartum hemorrhage, with the authors hypothesizing a reduction of mortality and/or
hysterectomy. This trial has a large third world representation with an obvious contextual
relevance. In view of the thrombotic and bleeding complications of cardiac surgery [5], Myles et
al. is leading a multicenter RCT (ATACUS, n = 4600) investigating aspirin and TXA in CABG
surgery [159]. It is a 2 × 2 factorial trial assessing whether aspirin, TXA, or both can reduce
15

mortality and/or morbidity after elective CABG. Ischemic (renal, cerebral, bowel) complication is
a secondary endpoint. This will yield important data on TXA in cardiac surgery.
Summary
TXA as an antifibrinolytic treatment applied in a perioperative setting has strong
pharmacological and clinical grounds. Although there are other situations in which the use of
TXA is desirable, these require definitive trials on morbidity and mortality. TXA administration
should be based on clinical judgment, guided by patient history, thromboelastometry, laboratory
and radiologic investigation, and tailored to the treatment location and capacity for intervention
and transfusion. Future reviews should include guidelines on TXA dose regimens minimizing
seizure risk, and conclusions regarding the thromboembolic risk. The ongoing research outlined
will help answer these questions.
Ackowledgements
1. The authors declare no financial disclosure.
2. 2. The authors declare no conflict of interest.
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157. Dewan Y, Komolafe EO, Mejía-Mantilla JH, Perel P, Roberts I, Shakur H: CRASH-3 —
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Corresponding author:
Marcin Wasowicz, MD
Department of Anesthesia EN3-438,
Toronto General Hospital, 200 Elizabeth St,
Toronto, ON M5G2C4, Canada
Tel.: 1 (416) 340-3567, fax: 1 (416) 340-3698
e-mail: Marcin.Wasowicz@uhn.ca
Received: 10.02.2015
Accepted: 22.02.2015
28

Table 1 − Major studies of tranexamic acid in cardiac surgery surgery
Study LOE n & population Intervention & Comparator Relevant Outcome
Mangano et al.
[23] 2b 4374 adults for
CABG AP, TXA & ACA vs control
All antifibrinolytics reduced blood loss. AP doubled
risk of renal failure, increased risk of stroke or
myocardial infarction
Karkouti et al.
[2] 2b
898 propensity
matched adults for
high − risk CS
AP vs TXA
TXA and AP have similar hemostatic effectiveness;
AP group had higher rates of renal dysfunction (24%
vs 17%, P = 0.01)
Mangano et al.
[24] 2b 4374 adults after
CABG
AP vs control, TXA vs
control, ACA vs control
AP increased mortality risk 20.8% vs 12.7% at 5
years. TXA/ACA did not show increased risk
BART trial,
Fergusson et
al. [25]
1b 2331 adults for
high − risk CS AP vs TXA vs ACA
AP group had higher mortality 6% vs TXA 3.9% and
ACA 4.0%; AP showed modest decrease in massive
bleeding vs TXA/ACA
Henry et al.
[31, 30] 1a
25000+ adults for
major surgery
including 3006 CS
subgroup
TXA vs control, AP vs
control, ACA vs control
In CS subgroup: TXA vs had RR 0.68 for BTx,
perioperative BL − 300 mL
Ngaage et al.
[32]
1a,
2a
10000+ adults for
CS
TXA vs control, AP vs
control, TXA vs AP
RCTs alone: TXA had OR 0.53 for BTx, BL 298 mL
less. Combined RCT & OS: TXA BL − 283 mL
Schouten et al.
[40] 1a 1893 children for
CS
TXA vs control, AP vs
control, ACA vs control
TXA group had BL 11 mL/kg less and reduced BTx
by 4 mL/kg. TXA not inferior to AP
n − number of patients, LOE − Level of evidence, TXA − tranexamic acid, AP − aprotinin, ACA − aminocaproic acid, CS −
cardiac surgery CABG − coronary arterial bypass grafts, HR − hazard ratio, OR − odds ratio, RR − relative risk, BTx −
blood transfusion, BL − blood loss, RCT − randomized controlled trials, OS − observational studies

Table 2 − Major studies of tranexamic acid in orthopedic surgery
Study LOE population & n Intervention & Comparator Outcome
Kagoma et al.
[56] 1a
Patients for THR or
TKA. 1432 for BL,
1557 for BTx, 1637
for VTE meta −
analysis
ATF vs control
ATF group had BTx RR 0.52 (p <0.00001) and less
BL 1.1 SMD vs control. No increased risk of VTE.
TXA group had less BL 393 mL vs control.
Poeran et al.
[57] 2b 872416 patients for
THR or TKA
TXA ≤ 1g, 2g or ≥ 3g vs
None
TXA group had lower rates BTx 7.7 vs 20.1%, RD
1.2 vs 1.6%. Decreasing OR 0.31 − 0.38 (p<0.001)
as TXA dose increased. No increase in VTE or other
complications.
Sukeik et al.
[58] 1a 350 patients for
THR TXA vs control
Less intraoperative BL by 104 mL, postoperative BL
by 172 mL, decrease RD for BTx − 0.20
(p<0.0001).
Alshryda et al.
[59] 1a
Patients for TKA,
763 for BL, 824 for
BTx analysis
TXA vs control BL reduced by 591 mL, RR of BTx 2.56 (95% CI
2.1 − 3.1) in favour of TXA.
Yang et al.
[60] 1a 581 patients for
spinal surgery TXA vs control BL reduced by 389 mL. No increase in VTE.
Schouten et al.
[40] 1a 207 children for
scoliosis surgery
TXA vs control, AP vs
control BL reduced by 682 mL. Not inferior to AP.
n − number of patients, LOE − Level of evidence, THR − total hip replacement, TKA − total knee arthroplasty, ATF −
antifibrinolytic, TXA − tranexamic acid, AP − aprotinin, ACA − aminocaproic acid, BTx − blood transfusion, BL − blood
loss, SMD − standardized mean difference, VTE − venous thromboembolism, RD − renal dysfunction, RR − relative risk,
RD − risk difference
Table 3 − Major studies of topical tranexamic acid use in surgery
Study LOE population & n Intervention Outcome
Panteli et al.
[78] 1a
Patients for TKA.
512 in BTx, 257 in
BL, 178 in DO meta
− analyses
Topical TXA in NS vs
control
RR of BTx 0.41 (P = 0.05), reduced postoperative
BL by 220 mL, and DO by 268 mL. Higher dose > 2
g TXA further significantly reduced BL. No increase
VTE
Alshryda et al.
[69] 1b 161 patients for
THR
Intra − articular injection
TXA vs control
Reduction AR by 19.6%, CPE by £305, reduced BL
by 129 mL, Hb drop by 0.84g dl-1
Alshryda et al.
[70] 1b 157 patients for
TKA
Intra − articular injection
TXA vs control
Reduction AR by 15.4%, CPE by £333, LOS by
1.2d, reduced BL by 168 mL, Hb drop by 0.83g dl-1
Abrishami et
al. [79] 1a 622 patients for CS Topical TXA/AP vs control
Reduced chest DO BL at 24h by 220 mL, overal
reduction of 1 unit PC per patient (95% CI − 1.54 to
− 0.53, P < 0.0001)
n − number of patients, LOE − Level of evidence, TXA − tranexamic acid, AP − aprotinin, ACA − aminocaproic acid, TKA
− total knee arthroplasty, THR − total hip replacement, CS − cardiac surgery, BTx − blood transfusion, BL − blood loss, DO
− drain output, VTE − venous thromboembolism, RR − relative risk, AR − absolute risk, CPE − cost per episode, Hb −
hemoglobin, LOS − length of stay in days (d), PC − packed red blood cells
Table 4 − Major studies of tranexamic acid in obstetrics & gynecology

Study LOE population & n Intervention Outcome
Lethaby et al.
[111]
1a,
2a*
Women of
reproductive age
with MN: 84 in
TXA vs placebo
analysis, 171 in
TXA vs alternative
analysis.
TXA or precursor vs
placebo, TXA vs alternative
therapy NSAID, ETM, PRO
WMD in BL of 94 mL in favour of TXA. TXA
reduced BL compared to alternatives
Novikova et
al. [115] 1a 453 women for CS
or VD TXA vs control BL of > 400 mL less common in TXA group. WMD
− 75 mL
Gungorduk et
al. [125] 1b 660 women for CS Pre − CS intravenous TXA
vs control
Lower mean BL (500 vs 600 mL). RR of PPH 2.7
(95% CI 1.1−6.3), and RR of additional uterotonics
1.7 (95% CI 1.1−2.6) in favour of TXA
n − number of patients, LOE − Level of evidence, TXA − tranexamic acid, AP − aprotinin, ACA − aminocaproic acid, MN
− menorrhagia or heavy menstrual bleeding, CS − cesarean section, VD − vaginal delivery, PPH − post − partum
hemorrhage, VTE − venous thromboembolism, BL − blood loss, WMD − weighted mean difference, NSAID − non −
steroidal anti − inflammatory mefenamic acid, ETM − ethamsylate, PRO − oral luteal phase progestagen norethisterone, RR −
relative risk, RCT − randomized controlled trial
*3 single RCT analyses of TXA vs NSAID, TXA vs ETM,and TXA vs
PRO therapies
Table 5 − Major studies on tranexamic acid in trauma and neurosurgery
Study LOE population & n Intervention & Comparator Outcome
CRASH − 2
by Shakur et
al. [82]
1b 20211 adult trauma
patients
1 g TXA on admission then
1g over 8h vs placebo
All cause mortality reduced, RR 0.91 (95% CI
0.85−0.97). Death from bleeding reduced, RR 0.85
(95% CI 0.76−0.96).
Roberts et al.
[83] 2b 20211 adult trauma
patients
Same as CRASH − 2.
Exploratory analysis of
treatment ≤ 1h, 1−3h, ≥ 3h
from injury
Early (< 1h) TXA had RR of death 0.68 (95% CI
0.57−0.82) and intermediate (1−3h) TXA had RR of
death 0.79 (95% CI 0.64−0.97). Late TXA > 3h had
increased RR of death 1.44 (95% CI 1.12−1.84)
Hillman et al.
[91] 1b 505 patients with
aneurysmal SAH
TXA 1g on diagnosis, then
1g every 6h until aneurysm
clipped, (max 72h) vs
control
Reduction in bleeding rate 10.8% to 2.4%, 80%
mortality reduction. No increased risk of ischemic
events by TCD
n − number of patients, LOE − Level of evidence, TXA − tranexamic acid, AP − aprotinin, ACA − aminocaproic acid, SAH
− subarachnoid hemorrhage, RR − relative risk, TCD − transcranial doppler studies