Haemophilia (2016), 22, e423–e426 DOI: 10.1111/hae.

13051

ORIGINAL ARTICLE Rare bleeding disorders

Efficacy of tranexamic acid for the prevention of bleeding

in patients with von Willebrand disease and Glanzmann
thrombasthenia: a controlled, before and after trial
A . E G H B A L I , * L . M E L I K O F , * H . T A H E R A H M A D I * and B . B A G H E R I †
*Department of Pediatric Hematology and Oncology, Arak University of Medical Sciences, Arak; and †Cancer Research
Center and Department of Pharmacology, Semnan University of Medical Sciences, Semnan, Iran

Introduction: Reducing bleeding episodes is very important in haematology disorders like von Willebrand disease
(VWD) and Glanzmann thrombasthenia (GT). Replacement factors are very expensive although prophylactic
drugs are affordable. Objective: To study the prophylactic effects of tranexamic acid (TXA) for reduction of
bleeding episodes in patients with VWD and GT in non-invasive conditions. Methods: A controlled, double-blind
before and after single-centre trial was performed in Amir-Kabir Hospital (Arak, Iran). The study was done on
17 patients with VWD and three patients with GT with minimum age of 2 years. Patients were received placebo
for 6 months to evaluate the frequency and severity of bleeding and also to record the frequency of use of factor
concentrates and platelet transfusion. After that, patients were given oral single dose of TXA 25 mg kg 1 day 1
for 6 months. The mentioned outcomes were studied and compared between two phases of study.
Safety assessment was done in all patients. Results: Tranexamic acid caused a significant reduction in number of
Grade 1 and Grade 2 bleeding episodes in VWD patients (P < 0.001 and P < 0.01 respectively). In addition,
TXA therapy was associated with significant decrease in the use of factor concentrates (P < 0.05). Number of
bleeding episodes decreased in GT patients who used TXA; however, difference between two phases of studies
was not significant (P = 0.1). TXA had no effect in the frequency of platelet transfusions in GT patients. TXA
therapy was associated with headache, back pain and musculoskeletal pain. No case of allergy or
thromboembolic events was seen following treatment. Conclusions: The results suggest that TXA is safe and
effective to reduce bleeding and use of factor concentrates in VWD patients. In addition, TXA therapy can
decrease bleeding in GT patients.

Keywords: bleeding, Glanzmann thrombasthenia, tranexamic acid, VWD

thrombasthenia (GT). GT is a rare and autosomal

Introduction
von Willebrand disease (VWD) is the most common
hereditary bleeding disorder in children [1]. The von
Willebrand factor (VWF) causes platelet adhesion to
thrombogenic surfaces. Bruising, menorrhagia and
postoperative haemorrhage are usually present in
patients with VWD. VWD is classified in three types:
in type 1, levels of VWF are reduced; in type 2, VWF
has abnormal function; in type 3, VWF is absent [1–
3]. Another inherited bleeding disorder is Glanzmann
Correspondence: Bahador Bagheri, PhD, Department of Pharma-
cology, School of Medicine, Semnan University of Medical
Sciences, Semnan, Iran.
Tel.: +982333448998; fax: +982333448999;
e-mails: bahadordvm@yahoo.com, bagherib@semums.ac.ir
Accepted after revision 25 June 2016
recessive disorder in which platelets contain defective
glycoprotein IIb/IIIa (GpIIb/IIIa). This integrin com-
plex is important for fibrinogen binding to platelets
and clot formation [4]. In GT, the bleeding time is sig-
nificantly prolonged. Mucosal bleeding, gingival bleed-
ing, menorrhagia and gastrointestinal bleeding are
seen in patients with GT [5]. Desmopressin is the drug
of choice in VWD. Desmopressin, a synthetic ana-
logue of vasopressin, causes a dose-dependent increase
in VWF from the patient’s endothelial cells. Type 1C,
most type 2 variants and type 3 are not responsive to
desmopressin [6]. In such cases, replacement therapy
is used. Current replacement therapy uses plasma-
derived VWF containing concentrates that also con-
tain factor VIII [7]. Platelet transfusion is the time-
honoured treatment for GT patients [8]. In addition,
recombinant activated FVII (rFVIIa) has been recently

© 2016 John Wiley & Sons Ltd e423

e424 A. EGHBALI et al.
approved for GT treatment in cases which are refrac-
tory to platelet transfusion. Antifibrinolytic drugs like
tranexamic acid (TXA) can be used with desmopressin
for the prevention of bleeding in VWD and GT.
Tranexamic acid is a lysine analogue that interferes
with plasminogen and plasmin and causes antifibri-
nolytic effects [9]. TXA is cost-effective and may mini-
mize the need for additional drugs for the
management of bleeding in trauma and surgical
patients and in patients with haematological disorders.
Despite accepted safety profile, TXA is associated with
concerns of an increased risk of thromboembolic
events [9,10]. Till now, evidence available for the use
of antifibrinolytics to prevent bleeding episodes in
non-invasive conditions is very limited. This was the
aim our study. With respect to efficacy and safety, we
have chosen a before and after trial to assess TXA
effects for the prevention of bleeding in patients with
VWD and GT in a 12-month study period.
Methods
Trial design
This placebo-controlled, double-blind, before and after
trial was conducted in Amir-Kabir Hospital, Arak,
Iran. Twenty-six children who had type 3 VWD with
recurrent bleedings and children with GT were
included in the study. The project was approved by
local ethics committee and written informed consent
was taken from parents of children. The study was
conducted in accord with the European directive
2001/20/EC. The registration number of this trial was
IRCT2015111525031N2. Patients were given placebo
for 6 months. Frequency and severity of bleeding, and
intervals of using plasma-derived concentrates were
monitored during 6 months by blinded paediatricians.
After 6 months, patients were administered oral TXA
25 mg kg 1 day 1 (TrancidTM; Amin Pharmaceuticals,
Tehran, Iran) for 6 months. During this period, bleed-
ing and intervals of using plasma-derived concentrates
were monitored. Diagnosis of VWD was done using
quantitative assay for VWF antigen, and testing for
VWF activity. GT diagnosis was confirmed by flow
cytometric analysis of platelet glycoproteins. Patients
were excluded if they had history of thromboembolic
events, hepatitis B and C, local bleeding lesions like
haemangioma, hepatic and renal failure and malignan-
cies. Patients were discontinued from the study for
these reasons: safety, lost to follow-up and voluntary
discontinuation. The World Health Organization
(WHO) standardized grading scale was used to mea-
sure the severity of bleeding [11]. According to this
grading scale, there are five grades of bleeding (0–4)
in different origins – Grade 0: no bleeding, Grade 1:
petechial bleeding, Grade 2: mild blood loss, Grade 3:
gross blood loss and Grade 4: debilitating blood loss.
Haemophilia (2016), 22, e423--e426
Bleeding is assessed in different sites; oral and nasal,
soft tissue and musculoskeletal, gastrointestinal, geni-
tourinary, pulmonary, body cavity, central nervous
system, invasive sites and haemodynamic instability.
Efficacy assessment
Efficacy endpoints were number of bleeding episodes,
severity of bleeding, site of bleeding episodes, platelet
transfusion requirements and the need for plasma con-
centrates. Patients were examined every month by
blinded paediatricians.
Safety assessment
Untoward effects, physical examination and vital signs
were monitored at baseline and every month by
blinded paediatricians. For the assessment of drug
adverse effects, patients were monitored for headache,
nasal and sinus symptoms, muscle pain, allergy and
gastrointestinal upset.
Data analysis
Data are shown as mean  SD. Data were analysed
using SPSS software version 18.0, Chicago, USA.
P < 0.05 was considered as statistically significant.
Comparisons between pre- and postintervention were
done using chi-square test and Mann–Whitney test.
Results
Baseline characteristics
Of the 26 patients who had been assessed for eligibility,
six patients did not enter the treatment. A total of 20
patients with established diagnosis were studied between
March 2014 and December 2015. Seventeen (85%)
patients had type 3 VWD and 3 (15%) patients had GT.
Clinical characteristics of study subjects are shown in
Table 1. The mean age was 25.9  14.6 months with an
excess of boys (60% vs. 40%). Patients had on-demand
therapy with factor concentrates and platelet transfusion.
Efficacy
As presented in Table 2, in the first phase of study in
VWD patients, there were 22 Grade 1 oropharyngeal
Table 1. Characteristics of patients.
Value
Age (month) 25.9  14.6
Age range (month) 27–54
VWD patients (number) 17 (85)
GT patients (number) 3 (15)
Male (number) 12 (60)
Data are shown as n (%) or mean  SD.
© 2016 John Wiley & Sons Ltd

bleeding episodes with mean of 7.76  4.94. In the
second phase of study, use of TXA caused a signifi-
cant decrease in Grade 1 oropharyngeal bleeding epi-
sodes; 13 episodes with mean of 4.2  3.7
(P < 0.001). In addition, a significant difference was
observed in Grade 2 oropharyngeal bleeding episodes
between two phases of study (5 episodes vs. 1 episode;
P < 0.01). As shown in Table 2, no significant differ-
ence was noted between two phases of study in Grade
3 bleeding. On the other hand, in the first phase of
study 74 factor concentrates were administered in 13
(75%) VWD patients; in the second phase of study it
significantly declined to 62 factor concentrates in eight
(47%) patients (P < 0.05). In GT patients, Grade 1
oropharyngeal bleeding was the most common bleed-
ing episodes. In spite of decrease in mean of bleeding
episodes between two phases of study, it failed to
reach a statistical significance in GT patients
(10.6  1.52 vs. 6.65  0.57, P = 0.1). In GT
patients, difference between frequencies of platelet
transfusions in the two phases of study was not statis-
tically significant.
Rate of response
From total of 17 VWD patients who underwent medi-
cal treatment, 3 (17.6%) patients did not respond to
treatment until the 6 months of treatment. All GT
patients were responsive to TXA therapy.
Safety
During treatment, none of patients showed allergic
skin reactions, anaphylactic shock, anaphylactoid
reactions and thromboembolic events. In addition,
long-term follow-up of the patients showed no case of
thromboembolic events. As shown in Fig. 1, headache
was seen in both groups of patients; however, rate of
headache was higher in VWD patients than GT
patients (P < 0.05). Back pain and musculoskeletal
pain were seen only in VWD patients (P < 0.01 and
P < 0.001 respectively).
Discussion
To the best of our knowledge, this is the first trial on
TXA efficacy for the prevention of bleeding in the
absence of invasive procedures. We showed that TXA
was effective and well tolerated for the reduction of
Table 2. Outcome data for patients’ treatment.
First phase of study
Grade Frequency of episodes Mean SD
1 22 7.76 4.94
2 5 0.94 1.5
3 3 0.17 0.72
© 2016 John Wiley & Sons Ltd
TRANEXAMIC ACID AND HAEMATOLOGY DISORDERS e425
Fig. 1. Untoward effects of TXA treatment; headache was the most com-
mon side effect in both groups of patients; *P < 0.05 vs. GT, **P < 0.01
vs. GT, *#P < 0.001 vs. GT.
bleeding in VWD patients. It reduced Grade 1 and
Grade 2 oropharyngeal bleeding in VWD patients. In
addition, TXA decreased the need for factor concen-
trates which is economically of great importance. In
Iran, the cost of TXA is 0.05$ for 250 mg tablets with
a total cost of 430$ for this study. The total estimated
cost of factor replacement (42 500 IU at 50$ per
500 U) used in this study is 6750$. A large Cochrane
review of 13 randomized trials suggests that there are
still very limited data about use of antifibrinolytics for
the prevention of bleeding in patients with haemato-
logical disorders. It also suggests that TXA may be
useful adjuncts to platelet transfusions [12]. In the
study by Davis, it was shown that oral TXA was
effective to reduce Grade 1 and Grade 2 bleeding in
patients with different hereditary bleeding disorders
who underwent endoscopy [13]. Of note, studied
patients did not receive replacement therapy. TXA
efficacy in elective and emergency operations has been
widely investigated. A work by Smit proved that peri-
operative administration of TXA was associated with
reduction in blood loss in patients who had total knee
arthroplasty without any history of haematological
disorders [14]. It was further supported by Gupta’s
work which showed that IV administration of TXA
could significantly reduce blood loss in radical surg-
eries [15]. CRASH-2 clinical trial proved that early
administration of TXA can significantly reduce mor-
tality in trauma patients although it has no effect on
transfusion requirements [16]. In our work, no severe
adverse event related to TXA was observed. TXA can
cause allergic reactions and more importantly it is
associated with increase in the risk of thromboembolic
Second phase of study
Number of patients Frequency of episodes Mean SD Number of patients P value
14 13 4.2 3.7 11 0.001
5 1 0.11 0.33 3 0.01
4 3 0.17 0.72 2 1
Haemophilia (2016), 22, e423--e426
e426 A. EGHBALI et al.

events and disseminated intravascular coagulation
[17]. This is of great importance in haematology
patients. It is noteworthy that in a Cochrane review of
over 25 000 patients, the use of TXA was not associ-
ated with an increased risk of mortality, myocardial
infarction, deep vein thrombosis and stroke [18]. In
addition, Avvisati did not report any side effects in
their treatment experience on TXA [19]. Despite
absence of significant differences, our trial showed
that TXA could reduce Grade 1 bleeding episodes in
GT patients. It should be noted that larger sample size
may provide more reliable data in GT patients. Plate-
let transfusion is the time-honoured treatment for GT.
Although very helpful, it may cause immune reaction
and transmit blood-borne pathogens. Bacterial con-
tamination of platelet concentrate is the most preva-
lent risk factor for infections [20]. Therefore, the use
of adjunct or alternative agent is helpful to minimize
the risk of such problems. Due to acceptable efficacy
and safety, TXA has the potential to be used as alter-
native agent for platelet transfusion. Of note, random-
ized control studies (RCT) with a large number of
patients are needed to ascertain clinical effects
of TXA in GT patients. However, because of rarity of
the disease, conduction of such trials is difficult.
Study limitation
As this was a single-arm study, further investigation
with a randomized control study is necessary. In addi-
tion, due to a small number of patients in our study,
efficacy and safety of antifibrinolytics should be tested
in large and high-quality randomized control trials.
Conclusion
This study emphasizes that prophylactic treatment
with TXA can cause a decrease in the number of
bleeding episodes and the need for factor concentrates
in patients with von Willebrand disease. Despite the
absence of significant difference, TXA therapy can
decrease bleeding in patients with GT. Furthermore,
TXA has an acceptable safety profile.
Acknowledgements
The author wish to thank the staff members of Amir-
Kabir Hospital for their help. Eghbali and Bagheri
designed the study; Melikof, Taherahmadi and Egh-
abli performed the research. Bagheri analysed data
and wrote the article.
Funding
The study was funded by a grant from the vice chan-
cellor of research of Arak University of Medical
Sciences.
Disclosures
The authors stated that they had no interests which might be perceived as
posing a conflict or bias.

References
1 Growe G, Vancouver BC, Akabutu J et al.
Hemophilia and von Willebrand’s disease.
Can Med Assoc J 1999; 153: 147–57.
2 Rodeghiero F, Castaman G, Dini E. Epi-
demiological investigation of the prevalence
of von Willebrand’s disease. Blood 1987;
69: 454–9.
3 Castaman G, Federici AB, Rodeghiero F
et al. Von Willebrand’s disease in the year
2003: towards the complete identification of
gene defects for correct diagnosis and treat-
ment. Haematologica 2003; 88: 94–108.
4 Franchini M, Favaloro EJ, Lippi G. Glanz-
mann thrombasthenia: an update. Clin
Chim Acta 2010; 411: 1–6.
5 French DL. The molecular genetics of
Glanzmann’s thrombasthenia. Platelets
1998; 9: 5–20.
6 Rodeghiero F, Castaman G, Di Bona E,
Ruggeri M. Consistency of responses to
repeated DDAVP infusions in patients with
von Willebrand’s disease and hemophilia A.
Blood 1989; 74: 1997–2000.
7 Pasi KJ, Collins PW, Keeling DM. Man-
agement of von Willebrand disease: a
guideline from the UK Haemophilia Cen-
tre Doctors’ Organization. Haemophilia
2004; 10: 218–31.
8 Poon MC, D’ Oiron R, Zotz RB. The inter-
national prospective Glanzmann Thrombas-
thenia Registry: treatment and outcomes in
surgical intervention. Haematologica 2015;
100: 1038–44.
9 Tengborn L, Blomb€ack M, Berntorp E.
Tranexamic acid–an old drug still going
strong and making a revival. Thromb Res
2015; 135: 231–42.
10 Federici AB, Castaman G, Mannucci PM.
Guidelines for the diagnosis and treatment
of von Willebrand disease in Italy. Italian
Association of Hemophilia Centers (AICE).
Haemophilia 2002; 8: 607–21.
11 Fogarty P, Tarantino DM, Brainsky A et al.
Selective validation of the WHO Bleeding
Scale in patients with chronic immune
thrombocytopenia. Curr Med Res Opin
2013; 28: 79–87.
12 Henry DA, Carless PA, Moxey AJ et al.
Anti-fibrinolytic use for minimizing periop-
erative allogeneic blood transfusion.
Cochrane Database Syst Rev 2011; 16:
CD001886.
13 Davis A, Walsh M, McCarthy P et al.
Tranexamic acid without prophylactic
factor replacement for prevention of
bleeding in hereditary bleeding disorder
patients undergoing endoscopy: a pilot
study. Haemophilia 2013; 19: 583–9.
14 Smit KM, Naudie DD, Ralley FE et al.
One dose of tranexamic acid is safe and
effective in revision knee arthroplasty. J
Arthroplasty 2013; 28: 112–5.
15 Gupta K, Rastogi B, Krishan A et al. The
prophylactic role of tranexamic acid to
reduce blood loss during radical surgery: a
prospective study. Anesth Essays and Res
2012; 6: 70–3.
16 Robrtes I, Shakur H, Afolabi A et al. The
importance of early treatment with tranexamic
acid in bleeding trauma patients: an explora-
tory analysis of the CRASH-2 randomised con-
trolled trial. Lancet 2011; 377: 1096–101.
17 Dunn CJ, Goa KL. Tranexamic acid: a
review of its use in surgery and other indi-
cations. Drugs 1999; 57: 1005–32.
18 Lethaby A, Farquhar C, Cooke I. Antifibri-
nolytics for heavy menstrual bleeding.
Cochrane Database Syst Rev 2004;
CD000249.
19 Avvisati G, ten Cate JW, B€ uller HR et al.
Tranexamic acid for control of haemor-
rhage in acute promyelocytic leukaemia.
Lancet 1989; 15: 122–4.
20 Blajchman MA, Beckers EA, Dickmeiss E,
Lin L, Moore G, Muylle L. Bacterial detec-
tion of platelets: current problems and pos-
sible resolutions. Transfus Med Rev 2005;
19: 259–72.

Haemophilia (2016), 22, e423--e426 © 2016 John Wiley & Sons Ltd
Copyright of Haemophilia is the property of Wiley-Blackwell and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.