The Effect of Tranexamic Acid and

Gender on Intraoperative Bleeding in

Orthognathic Surgery—A Randomized
Controlled Trial
Jesper Jared Secher, DDS,* Johannes Jakobsen Sidelmann, PhD,y Janne Ingerslev, DDS,z
Jens Jørgen Thorn, DDS, PhD,x and Else Marie Pinholt, DDS, MSc, DrOdontk
Purpose: The purpose of this randomized trial was to measure the effect of intravenously administered
tranexamic acid (TXA) on intraoperative blood loss (IOB) in patients undergoing bimaxillary orthognathic
surgery (OS).
Materials and Methods: The authors designed and implemented a double-blinded placebo-controlled
trial composed of patients eligible for OS at the Hospital of South West Denmark (Esbjerg, Denmark) from
August 2014 through September 2016. The primary predictor variable was a single intravenous dose of
TXA 1 g administered preoperatively or an equivalent saline placebo. The primary outcome was IOB deter-
mined by milliliters of blood in the suction canister and gauzes deducted from the volume of saline used
intraoperatively.
Results: The study population consisted of 96 patients. The TXA group (n = 51) and the placebo group
(n = 45) showed a median IOB of 275 and 403 mL (P = .005), respectively. A significant effect of TXA was
detected in women (median IOB, 153 mL [96 to 233 mL] in TXA group vs 329 mL [185 to 582 mL] in pla-
cebo group; P < .001), whereas no significant effect of TXA on IOB was detected in men (median IOB,
367 mL [275 to 472 mL] in TXA group vs 429 mL [275 to 655 mL] in placebo group; P = .23). No corre-
lations were found between IOB and procedure length, procedure type, or hematologic markers (platelets,
hemoglobin, and hematocrit).
Conclusion: In contrast to other studies, this double-blinded randomized controlled trial found a hemo-
static effect of TXA in women and none in men who underwent bimaxillary OS. To focus on the specific
effect of TXA in men, future studies should include larger male samples.
Ó 2017 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 76:1327-1333, 2018

Orthognathic surgery (OS) carries an innate risk of such surgery. Blood transfusions are performed from
intra- and postoperative bleeding because of the richly time to time, although increasingly infrequently in
vascularized tissues of the facial skeleton involved in OS because of hemostatic advancements and

*PhD Student, Department of Oral and Maxillofacial Surgery,
Hospital of South West Denmark, Esbjerg; Department of Regional
Health Research, Faculty of Health Sciences, University of
Southern Denmark, Esbjerg, Denmark.
yAssociate Professor, Unit for Thrombosis Research, Department
of Regional Health Research, University of Southern Denmark,
Esbjerg, Denmark.
zConsultant, Department of Oral and Maxillofacial Surgery,
Hospital of South West Denmark, Esbjerg, Denmark.
xConsultant, Department of Oral and Maxillofacial Surgery,
Hospital of South West Denmark, Esbjerg, Denmark.
kProfessor, Department of Regional Health Research, Faculty of
Health Sciences, University of Southern Denmark, Esbjerg, Denmark.
Conflict of Interest Disclosures: None of the authors have a rele-
vant financial relationship(s) with a commercial interest.
Address correspondence and reprint requests to Dr Secher:
Department of Oral and Maxillofacial Surgery, Hospital of South
West Denmark, Finsensgade 35, DK-6700 Esbjerg, Denmark;
e-mail: jesperjaredolsen@gmail.com
Received June 15 2017
Accepted November 13 2017
Ó 2017 American Association of Oral and Maxillofacial Surgeons
0278-2391/17/31435-0
https://doi.org/10.1016/j.joms.2017.11.015

1327
1328
optimized surgical protocols.1 Because OS consists of
an elective group of procedures, and morbidity can
evolve from anemia and allogenic blood transfusions,2
procedures that aim to decrease surgical bleeding are
clinically relevant.3 Hypotensive anesthetic regimes,
surgical techniques, and the use of antifibrinolytics,
including tranexamic acid (TXA), are the methods of
choice.4-9
TXA is a synthetic lysine analogue with antifibrino-
lytic abilities because of its reversible binding to
lysine-binding sites on plasminogen molecules. By
this binding, plasminogen cannot bind to the fibrin
clot, thereby decreasing the subsequent activation
of plasminogen to plasmin induced by tissue-type
plasminogen activator10 (Fig 1). The decreased fibri-
nolytic susceptibility of the clot lessens bleeding.
The clinical effect of TXA is well documented and
meta-analyses have shown TXA decreases overall in-
traoperative bleeding (IOB) by one third across
various surgeries, including cardiac, orthopedic,
head and neck, obstetrics and gynecology, urologic,
breast cancer, and OS.11,12 Similar decreases in IOB
have been reported in OS, but the total number of
trials is limited.7,13-17 Furthermore, no information
FIGURE 1. Theoretical model of the antifibrinolytic action of tranexamic acid. T, tranexamic acid; tPA, tissue plasminogen activator. Adapted
from Dunn and Goa.10
Secher et al. Tranexamic Acid and Intraoperative Bleeding. J Oral Maxillofac Surg 2018.
TRANEXAMIC ACID AND INTRAOPERATIVE BLEEDING
exists on the effect of TXA according to patient
gender within the respective patient populations.12
Most previous OS studies focused on the intravenous
(IV) administration of TXA,7,13-15 although decreased
bleeding by topically administered TXA has been
reported.16
The length and extent of surgery and the experience
level of the surgeon are other factors influencing IOB
in OS,4 whereas gender and age have not been consid-
ered relevant in these instances.12 However, recent
research by the authors showed a gender-specific vari-
ation in IOB during bimaxillary OS performed without
TXA. In that study, men displayed markedly higher IOB
levels compared with women, which correlated to an
increased fibrin turnover in women.18
The primary aim of the present trial was to test the
effect of IV-administered TXA compared with saline
placebo on IOB in patients undergoing bimaxillary
OS and secondarily to investigate the effect of gender
on IOB.
To address this matter, the following null hypothesis
was investigated: administering IV TXA or saline in pa-
tients undergoing bimaxillary OS would result in no
meaningful difference in IOB.
SECHER ET AL
Materials and Methods
STUDY DESIGN AND SAMPLE DESCRIPTION
A double-blinded randomized controlled trial was
designed and executed from August 2014 through
September 2016 at the Department of Oral and Maxil-
lofacial Surgery at the Hospital of South West Denmark
(Esbjerg, Denmark). The study was approved by the
national competent authorities and classified as a
phase IV drug trial (ID number 2013-005473-52) and
monitored by and conducted according to the regula-
tions of Good Clinical Practice.
Patients with a diagnosis of maxillary or mandibular
deficiency, excess, or asymmetries and in need of treat-
ment with bimaxillary OS with or without maxillary
segmentation or additional genioplasty were screened
for inclusion. Patients were excluded as study subjects
if the following criteria were present: younger than
18 years; pregnancy; history of thromboembolism,
cramps, diabetes, connective tissue disorders, or can-
cers; known allergy to TXA; ocular complications; kid-
ney deficiency; or intake of u-3 fatty acids, garlic,
ginseng, and gingko biloba up to 10 days preoperatively.
A power calculation was considered from previ-
ously reported data, which stated that a mean IOB
of 436 mL (standard deviation, 208 mL) was to be ex-
pected in the placebo group.4 The desired difference
in blood loss to be detected between the TXA and
placebo groups was at least 100 mL4 and the antici-
pated dropout frequency was 10%. To fulfill these as-
sumptions and reach a power of 0.8 and an a of 0.05,
a minimum of 80 patients had to complete the trial
(40 in TXA group; 40 in placebo group). Study sub-
jects were allocated by block randomization to
blindly receive IV TXA 1 g or the equivalent IV
dose of saline placebo.
The trial drug was prepared by the hospital phar-
macy and delivered to the anesthesiologist who admin-
istered it from the onset of anesthesia to the start of
surgery. Patients and anesthetic and surgical teams
were kept blinded to the type of intervention drug.
The primary predictor variable was intervention
type (TXA vs placebo) and the primary outcome vari-
able was IOB measured in milliliters (Table 1).
Secondary predictor variables were patient’s
gender, age, and weight, procedure type according
to the extent of osteotomies performed, and hemato-
logic markers of platelets, hemoglobin, and hematocrit
at baseline (Table 1). Secondary outcome variables
were length of surgery and hematologic markers at
5 hours after the start of surgery.
SURGICAL AND ANESTHETIC PROCEDURE
The patients were medicated preoperatively with
acetaminophen 1 g orally (Panodil 500-mg tablet;
1329
Table 1. STRATIFICATION OF STUDY VARIABLES
Primary predictor Intervention type (TXA vs
variable control)
Secondary predictor Age (yr)
variables
Male vs female gender
Weight
Oral contraceptive use
Platelet count at t0 (109/L)
Hemoglobin at t0 (mmol/L)
Hematocrit at t0
Procedure type: bimaxillary
sectioned vs un-sectioned
maxilla
Primary outcome Intraoperative bleeding (mL)
variable
Secondary outcome Procedure duration (minutes)
variables
Platelet count at t5 (109/L)
Hemoglobin at t5 (mmol/L)
Hematocrit at t5
Abbreviations: t0, baseline; t5, 5 hours after start of surgery;
TXA, tranexamic acid.
Secher et al. Tranexamic Acid and Intraoperative Bleeding. J Oral
Maxillofac Surg 2018.
Alternova, Skaelskør, Denmark), cefuroxime 1.5 g (B.
Braun, Melsungen, Germany), metronidazole 1 g
(5 mg/mL; Baxter A/S, Søborg, Denmark), and dexa-
methasone phosphate 8 mg (Dexaven 4 mg/mL;
KRKA, Novo Mesto, Slovenia) administered intrave-
nously at induction of anesthesia and cefuroxime
1.5 g and metronidazole 500 mg once more after 3
and 11 hours. Cefuroxime was continued with
750 mg 3 times a day for the next 2 days. Dexaven
4 mg was continued after 3, 9, and 15 hours. Two
hours preoperatively, the patients received low-
molecular-weight heparin 3,500 IU subcutaneously
(Innohep; Leo Pharma, Ballerup, Denmark). Throm-
bosis prophylaxis included compression stockings
on the day of surgery. Participants received controlled
hypotensive anesthesia (mean arterial pressure,
60 mmHg measured invasively). Anesthesia was
induced by sufentanil 0.25 to 0.30 mg/kg (Sufenta;
Janssen-Cilag A/S, Birkerød, Denmark), propofol
1.5 to 2.5 according to patient response (10 mg/mL
by injection, infusion fluid, or emulsion; Fresenius
Kabi, Bad Homburg, Germany), and remifentanil 3 to
4 mg/kg administered over 30 seconds followed by
an initial maintenance dosage of 0.1 to 0.2 mg/kg per
minute (Ultiva 50 mg/kg; GlaxoSmithKline Pharma
A/S, Brøndby, Denmark) until surgery was started.
All patients were intubated with an endotracheal
tube through the nasal route. Before surgery, another
dose of sufentanil 0.15 mg/kg was given, and
1330
anesthesia was maintained by desflurane (inhaled con-
centration, 5 to 7%; minimum alveolar concentration,
1%; Suprane; Baxter A/S), remifentanil 0.3 to 0.4 mg/
kg per minute, and sufentanil 0.75 to 1.0 mg/
kg (50 mg).
No antifibrinolytics were administered aside from
the possibly active intervention drug. The patients
were placed in a reverse Trendelenburg position
with the head positioned 30 above the rest of the
body. Local anesthesia consisted of Marcaine (bupiva-
caine hydrochloride and epinephrine injection)
20 mL with 0.5% epinephrine (AstraZeneca, Copenha-
gen, Denmark) administered as infiltrations and nerve
blocks immediately before the start of the mandibular
procedure and another 20 mL before the maxillary
procedure. A bilateral modified Obwegeser sagittal
mandibular split osteotomy and a standardized Le
Fort I osteotomy were performed with sectioning of
the maxilla in 4 parts in most instances. Osteotomy
lines were consistently mended with particulate autol-
ogous bone or bone blocks harvested from the
mandibular rami during sagittal splits from the tooth-
bearing segment of the lower jaw, from the bottom
of the nasal cavity in cases of impaction, and from
the pterygoid plates during maxillary procedures. An
additional genioplasty was performed in a few cases.
All operations were performed by 1 of 2 experienced
surgeons (J.I. or J.J.T.) occasionally attended by resi-
dent trainees.
Assessed for eligibility (n= 115)
Randomized (n= 104)
Allocated to TXA (n=52)
Received allocated intervention (n= 51 )
Did not receive allocated intervention due to
technical error (n= 1)!
Analysed (n= 51)
Male (n=26)
Female (n=25)
FIGURE 2. Consolidated Standards of Reporting Trials (CONSORT) flowchart. TXA, tranexamic acid.
Secher et al. Tranexamic Acid and Intraoperative Bleeding. J Oral Maxillofac Surg 2018.
TRANEXAMIC ACID AND INTRAOPERATIVE BLEEDING
CALCULATION OF INTRAOPERATIVE BLEEDING
The bleeding volume was calculated by deducting
the weight of the contents of the suction canister and
soaked gauzes from the weight of saline used during sur-
gery. This included weighing the tubing from the water-
cooling systems, the plastic bags of saline, and the
empty suction canister taking into account the weight
of the dry units of gauze, tubing, and plastic bags.
The weight of blood in grams was considered equal
to the volume in milliliters because of the negligible
difference between blood and water mass volume.
DATA HANDLING AND ANALYSES
Statistical calculations were performed using SPSS
21.0 (IBM Corp, Armonk, NY). The c2 test was used
for comparison of dichotomous variables. The
Kolmogorov-Smirnov test was used for the evaluation
of distribution of data. The Mann-Whitney U test was
applied to compare differences between men and
women with respect to the primary and secondary
outcome variables. Spearman correlation analysis
was used for determination of correlations between
the primary outcome variable and the secondary
outcome variables.
Results
One hundred four patients were included in the
study and 96 completed the trial according to the
Excluded due to
Pre-existing conditions (n= 1)
Withdrawal of participation
after initial consent (n= 1)
Delays due to protocol
amendment (n= 9)
Allocated to control (n=52)
Received allocated intervention (n=45)
Did not receive allocated intervention due to
logistic difficulties (n=6) and late withdrawal
from study subject (n=1)
Analysed (n= 45)
Male (n=22)
Female (n=23)
SECHER ET AL 1331

protocol (TXA, n = 51; placebo, n = 45). Twenty-six

men and 25 women received the active drug, and 22
men and 23 women received the placebo. The main
reason for subject exclusion was challenges related
to intermediate protocol amendments (Fig 2). Results
are presented as median and interquartile range.
A significant difference in IOB was found between
the intervention groups, with an IOB of 275 mL (143
to 408 mL) in the TXA group and 403 mL (215 to
609 mL) in the placebo group (P = .005; Fig 3A), con-
trary to the null hypothesis.
A significant difference in IOB was found in women,
with a median IOB of 153 mL (96 to 233 mL) in the
TXA group and 329 mL (185 to 582 mL) in the placebo
group (P < .001; Fig 3B).
No significant difference in IOB was found between
the TXA and placebo groups for men (367 mL [275 to
472 mL] vs 429 mL [275 to 655 mL]; P = .23; Fig 3B).
In the placebo group, the IOB in men was 100 mL
lower (329 mL; 185 to 582 mL) than in women
(429 mL; 275 to 655 mL; P = .21). A significant differ-
ence in IOB was detected between men and women in
the TXA group (367 mL [275 to 472 mL] vs 153 mL [96
to 233 mL]; P < .001; Fig 3B).
Age, gender, body mass index, platelet count, hemo-
globin, hematocrit, and the distribution of sectioned
versus un-sectioned osteotomies were comparable in
the TXA and placebo groups (P > .1; Table 2). Oral con-
traceptive (OC) use (n = 10) did not appreciably affect
IOB compared with OC nonuse (n = 36; 167 mL [67 to
417 mL] vs 202 mL [143 to 414 mL], respectively).
No significant effect of TXA versus placebo was
seen for any of the secondary outcome variables
(P > .1; Table 3).

Discussion
The primary finding of this study was a general
decrease in IOB in patients undergoing bimaxillary
OS concomitantly receiving TXA 1 g versus placebo
preoperatively. The secondary finding was that TXA
notably decreased IOB in women, whereas a minor
trend toward a lower IOB was observed in men. More-
over, women treated with TXA bled considerably less
than men receiving TXA. Therefore, the null hypothe-
sis was rejected.
The primary finding is in agreement with results ob- FIGURE 3. A, Intraoperative blood loss according to intervention
group. B, Intraoperative blood loss according to patient gender
tained in studies in other fields of surgery11 and in the and intervention group. Kruskal-Wallis 1-way analysis of variance
orthognathic setting.12 However, the present trial on ranks showed no effect of oral contraceptive use on intraopera-
included a larger sample with an equal gender distribu- tive bleeding compared with nonuse. TXA, tranexamic acid.
tion and a fixed TXA dosage as opposed to the variable Secher et al. Tranexamic Acid and Intraoperative Bleeding. J Oral
dosages used in other studies.7,13-15 Maxillofac Surg 2018.
Factors, such as the length of OS and the experience
of the surgeon,5 can contribute to IOB in OS. However, experience because 2 experienced surgeons per-
the present study showed no meaningful association formed all procedures. Resident trainees routinely at-
between the length of surgery and IOB or surgeon tended operations, but this did not influence IOB.
1332 TRANEXAMIC ACID AND INTRAOPERATIVE BLEEDING

Table 2. SECONDARY PREDICTOR VARIABLES ACCORDING TO INTERVENTION GROUP

TXA (n = 51) Placebo (n = 45) P Value

Age (yr) 21 (19.0-28.8) 22 (20.0-27.5) .45

Men/women 26/25 22/23 .85
Weight (kg) 75 (65.5-82.8) 73.5 (61.0-83.0) .78
Platelet count at t0 (109/L) 216 (174-250) 208 (170-258) .72
Hemoglobin at t0 (mmol/L) 8.3 (7.7-8.8) 8.3 (7.5-8.9) .55
Hematocrit at t0 (1) 0.39 (0.37-0.42) 0.39 (0.36-0.41) .14
Osteotomy sectioned/un-sectioned 45/6 42/3 .50*

Abbreviations: t0, baseline; TXA, tranexamic acid.

* By Fisher exact test.
Secher et al. Tranexamic Acid and Intraoperative Bleeding. J Oral Maxillofac Surg 2018.

Moreover, patients receiving TXA were comparable to
patients receiving placebo for age, weight, hematolog-
ic variables, and surgical procedures performed.
Fibrin formation and fibrin stability are important
determinants in wound healing. The effect of TXA
on the interaction between plasminogen and fibrin
has a major influence on the stability of the fibrin by
ensuring delayed fibrin degradation and efficient tissue
repair after surgery. Thus, the pronounced effect of
TXA observed in the present study shows that IOB in
OS is meaningfully affected by the efficacy of the
fibrinolytic system, and that decreased fibrinolytic
susceptibility of the fibrin clot is an important determi-
nant of IOB.
TXA has a profound effect on bleeding in women; it
is used to decrease heavy menstrual bleeding19 and to
decrease bleeding after cesarean section. Rajesparan
et al20 investigated the efficacy of IV TXA 1 g in
patients undergoing total hip replacement on bleeding
and found a similar bleeding pattern, with a pro-
nounced decrease in bleeding in female TXA recipi-
ents and an overall male tendency to bleed more.
The OS trials concerned with TXA7,13-15 used
dosages set according to the weight of the patients
and no gender-specific differences in IOB were found
between intervention groups. Gender-specific IOB
within the respective intervention groups was not
reported in any of the OS trials of TXA. The
gender-specific differences in IOB observed in the pre-
sent study could have been caused by the fixed dose of
TXA used in all patients regardless of body weight.
This explanation is unlikely, because no correlation
was seen between IOB and weight (P = .25; Table 2).
The mechanism behind the gender-related effect of
TXA on IOB remains elusive, although female sex hor-
mones have been suggested to influence bleeding
levels in hepatic surgery through a protective effect
on vascular integrity.21 Thus, attention should be
drawn to the fact that women receiving OCs were
included in the study. The hemostatic system is mark-
edly affected by OC use, and in particular the plasma
concentration of plasminogen is clearly affected by
OC, suggesting an upregulation of the fibrinolytic sys-
tem.22 In the present study, the authors did not
observe a noteworthy effect of OC on IOB.
The study shows that preoperatively administered
IV TXA decreases IOB in OS by approximately one
third as reflected in previous studies. TXA decreased
IOB considerably in women, whereas no clear effect
was seen in men. Because the authors cannot rule
out the possibility of a type II error for the male sample
or a dosage-related response, further trials are needed.
These should include a larger male sample and prefer-
ably TXA dosages according to weight.

Table 3. SECONDARY OUTCOME VARIABLES ACCORDING TO INTERVENTION GROUP

TXA (n = 51) Placebo (n = 45) P Value

Procedure length (minutes) 240 (219-272) 254 (218-270) .40

Platelet count at t5 206 (174-252) 198 (169-265) .92
Hb at t5 8.0 (7.4-8.8) 7.9 (7.3-8.6) .27
Hct at t5 0.39 (0.35-0.41) 0.37 (0.35-0.40) .15
Abbreviations: Hb, hemoglobin; Hct, hematocrit; t5, 5 hours after start of surgery; TXA, tranexamic acid.
Secher et al. Tranexamic Acid and Intraoperative Bleeding. J Oral Maxillofac Surg 2018.
SECHER ET AL
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