CLINICAL-REGISTRY

Tranexamic acid in pediatric combat trauma requiring massive

transfusions and mortality

Mitchell Hamele, MD, James K. Aden, PhD, and Matthew A. Borgman, MD, Honolulu, Hawaii

BACKGROUND: Tranexamic acid (TXA) has been demonstrated to decrease mortality in adult trauma, particularly in those with massive transfusions
needs sustained in combat injury. Limited data are available for the efficacy of TXA in pediatric trauma patients outside of a single
combat support hospital in Afghanistan.
METHODS: The Department of Defense Trauma Registry was queried for trauma patients younger than 18 years from Iraq and Afghanistan requiring
40 mL/kg or greater of blood product within 24 hours of injury. Burns and fatal head traumas were excluded. Primary outcome was in-
hospital mortality. Secondary outcomes were hospital, ventilator, and intensive care unit–free days, as well as total blood product volume.
RESULTS: Among those pediatric patients receiving massive transfusions, those who received TXA were less likely to die in hospital (8.5% vs.
18.3%). Patients who received TXA and those who did not have similar hospital-free days (19 vs. 20), ventilator-free days (27 vs. 27),
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and intensive care unit–free days (25 vs. 24). Those who received TXA had higher 24-hour blood product administration (100 mL/kg
vs. 75 mL/kg). None of our results rose to the level of statistical significance. The TXA administration significantly reduced odds of
death on logistic regression (odds ratio, 0.35; 95% confidence interval, 0.123–0.995; p = 0.0488).
CONCLUSION: Use of TXA in pediatric patients with combat trauma requiring massive transfusions trended toward a significant improvement in
in-hospital mortality (p = 0.055). This mortality benefit is similar to that seen in adult studies and a less well characterized cohort in
another pediatric study suggesting TXA administration confers mortality benefit in massively transfused pediatric combat trauma
victims. (J Trauma Acute Care Surg. 2020;89: S242–S245. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
LEVEL OF EVIDENCE: Evidence (retrospective cohort), Level IV
KEY WORDS: Tranexamic acid; pediatric; trauma; massive transfusion; combat.

T he core tenets of hemostatic resuscitation for adult hemor-

rhagic trauma include balanced use of blood products,
avoidance of crystalloid fluids, and the use of tranexamic acid
(TXA).1,2 Though early coagulopathy in pediatric trauma has
been linked to increased mortality, hemostatic resuscitation has
predominantly been studied in adult patients.3 While some pedi-
atric providers now use TXA,4 there is very limited data to jus-
tify this. Tranexamic acid inhibits plasminogen activation
leading to decreased fibrinolysis and has been used with good
effect in pediatric surgery to reduce bleeding and need for blood
products.5 Just one small retrospective study has evaluated the
use of TXA in combat injury in children.6
The Clinical Randomisation of an Antifibrinolytic in
Significant Haemorrhage 2 (CRASH-2) trial demonstrated that
TXA use in adult civilian trauma could potentially improve mor-
tality without increased thromboembolic complications.7 The
Military Application of Tranexamic Acid in Trauma Emergency
Resuscitation (MATTERs) trial demonstrated that use of TXA
in adults who sustained combat trauma requiring massive trans-
fusion (MT) had an even greater positive survival effect.8
Submitted: January 31, 2020, Revised: March 9, 2020, Accepted: March 11, 2020,
Published online: April 6, 2020.
From the Department of Pediatrics-Critical Care (M.H.), Tripler Army Medical Cen-
ter, Honolulu, Hawaii; Brooke Army Medical Center Fort Sam Houston (J.K.A.,
M.A.B.), Houston, Texas; and Department of Pediatrics (M.H., M.A.B.),
Uniformed Services University, Services University, Bethesda, Maryland.
Presented at the 47th Annual Meeting of the Society of Critical Care Medicine,
February 25–28, 2018, in San Antonio, TX.
Address for reprints: Mitchell Hamele, MD, Department of Pediatrics, Tripler Army
Medical Center, Honolulu, HI 96859; email: Mitchell.t.hamele.mil@mail.mil;
mthamele@gmail.com.
DOI: 10.1097/TA.0000000000002701
S242
Tranexamic acid administration to pediatric trauma patients in
a combat setting: the pediatric trauma and tranexamic acid study
(PED-TRAX) demonstrated that at a single combat support hos-
pital, severely injured children who received TXA may have im-
proved survival.6
The purpose of this study is to evaluate the use of TXA in a
larger population of traumatically injured children requiring MT
in combat to see if there is an association with improved mortality.
METHODS
Following review and approval by the institutional review
board at Brooke Army Medical Center, we conducted a retro-
spective review of the Department of Defense Trauma Registry,
including trauma patients younger than 18 years treated from
2006 to 2013 who received MT as defined by 40 mL/kg of blood
products within 12 hours to 24 hours of presentation.9 The Depart-
ment of Defense Trauma Registry is the data repository for all pa-
tients (military and civilian) treated at fixed facilities (role 3) or
forward surgical teams (role 2b) within 72 hours of initial injury
with a trauma diagnosis from International Classification of Dis-
ease 9th Edition. Patients with burn injuries or fatal injury, deemed
to be secondary to head trauma, were excluded (Fig. 1). Our pri-
mary outcome was in-hospital mortality. Secondary outcomes were
24-hour mortality, hospital-free, ventilator-free, intensive care unit
(ICU)-free days reported with weighted average and interquartile
range and blood product administration volume (Table 1).
Descriptive analyses were performed to compare those
who received TXA (TXA+) with those who did not (TXA−).
Multivariate regression was utilized to determine the effect of
TXA, the factor of interest, on mortality. To account for
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J Trauma Acute Care Surg
Volume 89, Number 2, Supplement 2 Hamele et al.

associations with mortality, such as age and sex, were also in-
cluded in the full model based on previous literature.10 Variables
were not included if strong collinearity is present. Backward
elimination was performed to obtain the final model. Wilcox
rank-sum test was used for continuous variables and χ2 test
for categorical values. All statistical analyses were performed
using JMP version 13.2, SAS Corp. (Cary, NC).
Tranexamic acid use did not come into widespread use by
coalition forces in the combat theater until 2010. The TXA dose
was not recorded in the registry; however, the military protocol
for administering TXA calls for 1 g of TXA given within 3 hours
of injury, followed by 1 g over 8 hours at the discretion of the
treating team. No data on thromboembolic events or seizures
were included in the registry.

Figure 1. Patient inclusion and exclusion criteria and selection.
variables that might have influenced receiving TXA, variables
that differed by a p value of less than 0.2 in the univariate analysis
were included in the full model. Variables with historic strong
RESULTS
Table 1 shows the demographic, injury severity, and clin-
ical data for patients in the cohort who met the study criteria. All
data points were available for age, weight, sex, Injury Severity
Score (ISS), and mechanism of injury. Both cohorts were similar
in age, weight, sex, body temperature, ISS, head/neck Abbrevi-
ated Injury Scale (AIS), hematocrit, platelet counts, and Interna-
tional Normalized Ratio. Patients who received TXA were more
likely to have sustained blast injury (83% vs. 57%, p = <0.001)
and trended toward lower Glasgow Coma Scale (GCS) score
(7 vs. 11; p = 0.22). Base deficit (BD) in the TXA+ group

TABLE 1. Descriptive Univariate Analysis and Unadjusted Outcomes of Pediatric MT Patients Based on Receiving TXA
Characteristics TXA+ (n = 59) TXA− (n = 448) n = 507 p Value
Age, y 10 [5–13] 9 [5–12] 507 0.67
Weight, kg 25 [20–36] 26 [19–37] 507 0.97
Sex: male 48 (81%) 327 (73%) 507 0.21
ISS 17 [13–25] 17 [11–26] 507 0.66
Head AIS 0 [0–2] 0 [0–3] 507 0.15
Blunt 2 (3.4%) 49 (10.9%) 507 0.02
Blast 48 (83%) 255 (57%) 507 <0.001
Penetrating 8 (13.6%) 144 (32%) 507 0.003
GCS score 7 [3–15] 11 [3–15] 464 0.22
Temperature, °C 36.6 [34.9–37.6] 36.6 [36.1–37.5] 412 0.28
Hematocrit, mg/dL 32.3 [28.2–37.6] 29.6 [25.2–35] 443 0.2
BD 10 [5–15] 8 [5–12] 435 0.11
INR 1.7 [1.4–1.9] 1.4 [1.2–2.0] 323 0.57
Platelet count (100,000) 231 [163–335] 272 [170–383] 414 0.27
In-hospital Mortality 5 (8.5%) 83 (18.3%) 507 0.055
24 h Mortality 2 (3.4%) 30 (6.7%) 507 0.33
Hospital-free days, median [IQR] 19 [10–24] 20 [1–25] 507 0.96
Vent-free days, median [IQR] 27 [23–28] 27 [20–28] 507 0.99
ICU-free days, median [IQR] 25 [20–27] 24 [15.3–28] 507 0.56
pRBC, mL/kg 50 [29.2–72.2] 41.5 [28.2–57.6] 507 0.09
Platelet, mL/kg 9.7 [0–20] 0 [0–8.6] 507 <0.001
FFP, mL/kg 48.1 [25–64.3] 33 [20.9–50] 507 0.001
FFP/pRBC 1 [0.8–1.1] 1 [0.6–1] 502 0.07
Total blood product, mL/kg 100 [62.5–161] 75 [51.1–119] 507 0.015
Data presented as n (%) or median [IQR].
AIS, Abbreviated Injury Scale; IQR, interquartile range; INR, International Normalized Ratio; Vent, Ventilator.

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Hamele et al.
trended higher than the TXA− group (10 vs. 8; p = 0.11).
Other parameters were similar in both groups.
Table 1 also shows the primary and secondary outcomes.
In-hospital mortality was 17.4% for the entire cohort. Those
patients who received TXA were less likely to die in hospital
(8.5% vs. 18.3%) or within 24 hours of admission (3.4% vs.
6.7%), though values did not reach statistical significance.
Both groups had similar hospital, ventilator- and ICU-free
days. Both groups received similar amounts of packed red
blood cells (pRBCs) (50 mL/kg vs. 41.5 mL/kg) with a trend
toward more pRBC in the TXA group. The TXA group re-
ceived higher volumes of platelets (9.7 mL/kg vs. 0 mL/kg,
p = <0.001), fresh-frozen plasma (FFP) (48.1 mL/kg vs.
33 mL/kg; p = 0.001), and total blood product (100 mL/kg
vs. 75 mL/kg; p = 0.015) with a trend toward more balanced
FFP/pRBC administration in the TXA+ group.
Table 2 demonstrates logistic regression analysis of se-
lected variables impact on mortality. Included in the initial full
model were age, sex, head AIS, BD, mechanism of injury, FFP/
pRBC ratio, and TXA. Mechanism of injury and FFP/pRBC ratio
were eliminated in the final model due to lack of significance.
Tranexamic acid administration was independently associated
with reduced mortality (odds ratio [OR], 0.35; 95% confidence
interval [CI], 0.123–0.995; p = 0.0488).
DISCUSSION
We report the largest data set to date of the impact of TXA
on survival in pediatric combat trauma among patients who re-
quired MT. We found improved in-hospital mortality for those
patients who received TXA.
These results were similar to a less well-characterized sub-
set of the PED-TRAX study which evaluated the use of TXA in
combat injured children.6 After controlling for confounding fac-
tors, including mechanism, injury severity, BD, hypotension,
and GCS score, TXA administration was independently associ-
ated with reduced mortality (OR, 0.27; 95% CI, 0.85–0.89;
p = 0.03), which is very similar to our data with TXA indepen-
dently associated with reduced mortality (OR, 0.35; 95% CI,
0.123–0.995; p = 0.0488). A propensity analysis also indicated
a mortality benefit of TXA when controlling for blood product
ratios. They performed a subgroup propensity analysis on pa-
tients with large-volume transfusion, which was defined as
40 mL/kg of all blood products similar to our cohort, and also
identified a benefit of TXA. However, there were no descriptive
TABLE 2. Multivariate Logistic Regression for In-hospital Mortality
Full Model Final Model
(n = 400) (n = 435)
Variable OR p Value OR p Value
AIS (head) 1.47 (1.26–1.71) <0.0001 1.50 (1.29–1.74) <0.0001
Age 1.07 (1.00–1.15) 0.34 1.08 (1.01–1.15) 0.032
BD 1.15 (1.09–1.19) <0.0001 1.15 (1.11–1.19) <0.0001
Male 0.57 (0.30–1.08) 0.08 1.660 (0.89–3.1) 0.113
TXA+ 0.36 (0.12–1.02) 0.055 0.350 (0.12–0.995) 0.0488
Mechanism of injury 0.93 (0.38–2.23) 0.79
FFP/pRBC ratio 1.26 (0.81–1.96) 0.33
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J Trauma Acute Care Surg
Volume 89, Number 2, Supplement 2
details provided of this subgroup to compare with our study
population.6
The MATTERs study is the largest published data on
TXA in adult combat trauma. They reviewed 896 consecutive
admissions at a single combat support hospital in Afghanistan,
including a subset of 231 patients who received MT within
24 hours, 125 of those receiving TXA.8 When compared with
their cohort of MT patients receiving TXA, our patients had a
slightly lower ISS (17 vs. 26), were similarly likely to have
sustained blast trauma (83% vs. 76%), and tended to have lower
GCS scores. Their adult MT cohort mortality was similar to that
in our total population (17.4% vs. 22.7%).8 Among our patients
who received TXA, the absolute risk reduction of death was 9.8,
with a relative risk reduction of 53% and a number needed to
treat with TXA to prevent one death of 10.2. Similarly the MAT-
TERs MT subset found an absolute risk reduction of 13.7, a rel-
ative risk reduction of 49%, and a number needed to treat of
7.3.8 Though the mortality benefit in our study did not rise to
the level of statistical significance, the similarity to the MAT-
TERs adult data suggests a survival benefit from TXA adminis-
tration in pediatric patients requiring MTs.
The use of pRBC, platelets, and FFP as well as total blood
product utilization, was higher in the TXA+ group than in the
TXA− group in the unadjusted analysis. The FFP/RBC ratio
was also slightly higher in the TXA+ group. This may be a
signal that since TXA is an adjunct for hemostatic resuscita-
tion, the demonstrated improved mortality may have been
multifactorial. The TXA use, however, was independently as-
sociated with survival in the regression analysis. The survival
difference in the groups based on TXA treatment was noted
early (data not shown), as expected, given that the theoretical
benefit of TXA, and hemostatic resuscitation, is preventing
early deaths from hemorrhage.
Our study has several limitations related to its retrospec-
tive nature, limited data and lack of controlled protocols. Neither
the total amount nor timing of TXA dose was available. Data on
specific complications, such as thrombo-occlusive events, were
not available. Though large adult trials have shown no increased
thrombo-embolic complications a single study demonstrated in-
creased seizure risk with TXA administration in children.7,11
Some children are at increased risk for trauma-induced coagulop-
athy phenotype of fibrinolysis shutdown with TBI when com-
pared with adults.12 Here, aggressive use of TXA and plasma
might worsen the outcomes. There was no thromboelastography
data available to identify this phenomenon, which limits inter-
pretation. Common practice for selection of patients and admin-
istration of TXA as well as other practice habits changed over
time, though overall pediatric mortality did not significantly
change from 2006 to 2013.13 It is possible that TXA use was
simply a signal for those patients who received a more “hemo-
static” resuscitation, as well as benefited from other surgical ad-
vancements over time which could not be adjusted for in our
analysis, though we did adjust for FFP/pRBC ratio in the multi-
variate regression. Our study, like most other retrospective stud-
ies related to resuscitation strategies, may have also been
influenced by survival bias.14 In other words, those that received
TXA “self-selected” since they remained alive to receive it have
also been demonstrating a trend for the TXA+ group receiving
more blood products. While this may have biased our results,
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J Trauma Acute Care Surg
Volume 89, Number 2, Supplement 2
TXA is easily administered upon admission compared with
studies of FFP which needs to be thawed and is historically de-
layed in a resuscitation.
Finally, we had no long-term survival data, though based
on practice patterns during the time of the study, survival to dis-
charge is likely largely representative of long-term survival. Pe-
diatric patients in these treatment facilities were typically kept
until they were very stable prior to discharge home or transfer,
unless they died in hospital. Patients were not followed after dis-
charge. Therefore, no conclusions should be made on longer
term survival on this curve due to censuring as patients were
discharged or transferred.
Future avenues for study include optimal patient selection
for utilization of TXA in pediatric trauma. Tranexamic acid ap-
pears to benefit children requiring MTs but this benefit is less
clear in patients who required less or no blood products.6 The
optimal dose of TXA has yet to be elucidated for pediatric pa-
tients. A recent survey of US pediatric centers found a dose range
of 10 mg/kg to 40 mg/kg for TXA in trauma.4 A dose of 1 g may
have been used for patients in our study, as well as PED-TRAX,
the ideal dose for TXA in pediatric trauma and pharmacokinetics
in children remains unknown. A dosing guide for prehospital ad-
ministration of TXA in trauma would be beneficial, but should be
informed by data. Though it appears that initial dosing within
3 hours of injury is optimal in adult patients, there are no data
in pediatric patients.7 Finally, though complications are rare with
TXA administration, they were not recorded in this registry nor
was fibrinolysis shutdown data which could impact our interpre-
tation.12 Currently, the Pediatric Emergency Care Applied Re-
search Network is conducting a multicenter trial that will
hopefully start to answer some of these questions.15
Our data suggest a mortality benefit with utilization of
TXA in pediatric combat patients who have sustained significant
injuries and require transfusion greater than 40 mL/kg of blood
products. While more study is needed, it seems that early admin-
istration of TXA to pediatric combat trauma patients, who are
suspected of requiring MT, is warranted. Given the limitations
of our data, as discussed, we caution that application of our data
and conclusions to a broad cohort of pediatric trauma patients,
who do not match our population, is not warranted at this time.
Future pediatric research on appropriate patient selection (with
thromboelastography), timing, and dosing of TXA, as well as
further data on potential complications in this population, is
needed to help guide safe and effective usage.
AUTHORSHIP
M.H. analyzed the data, conducted the literature search and was the
primary author of the article. M.A.B. designed the study, collected
and analyzed the data and critically reviewed and revised the article
for important content. J.K.A. analyzed the data and critically reviewed
and revised the article of important content.
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Hamele et al.
DISCLOSURE
M.H. and M.A.B. are officers in the United States Army and J.K.A. is a
United State Government employee. The views in this article are those
of the authors and do not reflect the views of the United States Army, De-
partment of Defense, or the United States Government. None of the au-
thors received any funding for this work.
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