Tranexamic acid: An emerging depigmenting agent

Abstract

Tranexamic acid (TXA), an antifibrinolytic drug, is now gaining popularity as a depigmenting agent. It is a synthetic
lysine amino acid derivative which mainly blocks the conversion of plasminogen to plasmin by inhibiting plasminogen
activator. This results in less free arachidonic acid production, and hence a reduction in the prostaglandin (PG) levels
as well. Thus, by reducing PG production, TXA reduces the melanocyte tyrosinase activity and plays an important role
in the treatment of melasma, ultraviolet‑induced hyperpigmentation, and other postinflammatory hyperpigmentation.
It has been tried topically, orally, and intradermally in the management of melasma with minimal adverse effects.
However, more randomized trials are needed to fully elucidate the exact mechanism of action, ideal route, frequency,
and duration of administration of the drug, along with its potential to treat other pigmentary disorders.

Full text

66 © 2016 Pigment International | Published by Wolters Kluwer - Medknow
INTRODUCTION
Tranexamic acid (TXA) is primarily an antifibrinolytic drug,
whose effects have traversed multiple systems and finally
embarked upon the skin. It is a synthetic lysine derivative and
was first described in 1966. The drug came as a boon in the
treatment of menorrhagia in 1968 and mainly acts by blocking
the lysine site on plasminogen, thereby inhibiting fibrinolysis.
Since then the indications have become innumerable, and
it has proved to be highly useful in controlling bleeding in
various coagulation defects such as hemophilia, surgeries
like cardiopulmonary bypass and arthroplasty.[1]
Besides coagulation disorders, TXA can ameliorate the
necessity for a surgical intervention in menorrhagia or
dysfunctional uterine bleeding and in upper gastrointestinal
hemorrhage. It reduces the postoperative need for blood
transfusion and hence mortality rates, with a good cost
benefit and tolerance factor.[2]
It is worth mentioning that this old drug not only
holds the position of an antifibrinolytic but also an
adjuvant in pigmentary disorders like melasma and
ultraviolet (UV)‑induced hyperpigmentation.[3]
TRANEXAMIC ACID IN MELASMA
Melasma is an acquired hypermelanosis affecting the
sun‑exposed areas of skin, most commonly the face and neck.
The exact etiopathogenesis is unknown; however, various
etiological factors have been proposed in the literature.
These include sun exposure, pregnancy, hormonal therapy,
genetic factors, and vascular factors.[4] Innumerable studies
evaluating melasma treatments are available; however, only
a statistically minor proportion of the subjects have shown a
complete clearance of melasma. The relapsing tendency and the
deep dermal component in melasma are other hurdles in the
treatment besides the adverse effects of commonly used topical
triple combination regimens. The skin‑whitening effects of TXA
were incidentally found when it was used in the treatment of
aneurysmal subarachnoid hemorrhage. TXA was reported to be
useful in the treatment of melasma in 1979 by Nijor in Japan.[5,6]
Tranexamic acid: An emerging depigmenting agent
ABSTRACT
Tranexamic acid (TXA), an antibrinolytic drug, is now gaining popularity as a depigmenting agent. It is a synthetic
lysine amino acid derivative which mainly blocks the conversion of plasminogen to plasmin by inhibiting plasminogen
activator. This results in less free arachidonic acid production, and hence a reduction in the prostaglandin (PG) levels
as well. Thus, by reducing PG production, TXA reduces the melanocyte tyrosinase activity and plays an important role
in the treatment of melasma, ultraviolet‑induced hyperpigmentation, and other postinammatory hyperpigmentation.
It has been tried topically, orally, and intradermally in the management of melasma with minimal adverse effects.
However, more randomized trials are needed to fully elucidate the exact mechanism of action, ideal route, frequency,
and duration of administration of the drug, along with its potential to treat other pigmentary disorders.
Keywords: Antibrinolytic, depigmenting agent, intradermal, melasma, tranexamic acid
Review Article
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DOI:
10.4103/2349-5847.196295
Anju GeorGe
Department of Dermatology, Bangalore Baptist Hospital,
Bengaluru, Karnataka, India
Address for correspondence: Dr. Anju George, “Anjanam,”
Chitatumukku P. O., Trivandrum ‑ 695 301, Kerala, India.
E‑mail: dranjugeo@gmail.com
This is an open access arcle distributed under the terms of the Creave Commons
Aribuon-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak,
and build upon the work non-commercially, as long as the author is credited and the new
creaons are licensed under the idencal terms.
For reprints contact: reprints@medknow.com
How to cite this article: George A. Tranexamic acid: An emerging
depigmenting agent. Pigment Int 2016;3:66‑71.
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Pigment International / Jul-Dec 2016 / Volume 3 / Issue 2
George: Tranexamic acid as a depigmenting agent
The drug tackles mostly the vascular component of melasma
and is now widely used as an adjuvant with significant results.[7,8]
PHARMACOLOGY AND MECHANISM OF ACTION AS A
DEPIGMENTING AGENT
TXA (trans‑4‑aminomethylcyclohexane carboxylic acid)
is a synthetic lysine amino acid derivative which controls
and diminishes the dissolution of hemostatic fibrin. TXA
exerts its antifibrinolytic effects by reversibly blocking
lysine binding sites on plasminogen. This prevents plasmin
from interacting with lysine residues on the fibrin polymer,
leading to subsequent fibrin degradation. The native
human plasminogen has 4–5 lysine binding sites. However,
their affinity for TXA is low. The high‑affinity lysine site of
plasminogen is involved in its binding to fibrin. Plasminogen
gets displaced from the surface of fibrin once the high‑affinity
binding site gets saturated with TXA. Although plasmin may
be formed due to conformational changes in plasminogen,
binding to and dissolution of the fibrin matrix is inhibited.
TXA extends and disseminates throughout the intracellular
and extracellular compartments and is finally excreted
unchanged in the urine.[8,9]
Inhibition of ultraviolet‑induced plasmin activity
UV exposure increases plasminogen activator production by
epidermal keratinocytes in situ.[10] TXA is a natural plasmin
inhibitor which blocks the conversion of plasminogen to
plasmin. The drug accomplishes this through the inhibition
of plasminogen activator by creating a reversible complex
with plasminogen.[2,11]
TXA also prevents the binding of plasminogen to the
keratinocytes and thus inhibits UV‑induced plasmin activity
in keratinocytes.[12] Plasmin is a protease that enhances
the intracellular release of arachidonic acid (AA) and
alpha‑melanocyte‑stimulating hormone (α‑MSH). AA and
α‑MSH have the property of stimulating melanogenesis by
melanocytes. Tranexamic acid being a plasmin inhibitor
depletes the keratinocyte pool of AA involved in UV‑induced
melanogenesis.[6,8,13,14] The topical application of TXA has
shown reduction in UV‑induced hyperpigmentation. An
empirical study demonstrates the effective usage of
TXA on guinea pigs where the pigmentation is explicitly
developed by the application of topical AA in a controlled
manner.[11,15,16]
Reduction in prostaglandin production
Following UV exposure, prostaglandins (PGs) activate
signaling pathways involved in growth, differentiation, and
apoptosis of melanocytes. PG E2 is released abundantly by
keratinocytes following UV radiation (UVR). This stimulates
the formation of dendrites in melanocytes and melanocyte
tyrosinase activity. TXA inhibits PG production and thus
reduces the melanocyte tyrosinase activity. This particular
characteristic of TXA is successfully applied in the treatment
of melasma, UV‑induced hyperpigmentation, and other
postinflammatory hyperpigmentation.[11,15,17]
Reduction of vascularity in melasma
A common speculation is that UVR stimulates the production
of angiogenic factors such as vascular endothelial growth
factor (VEGF), basic fibroblast growth factor (b‑FGF), and
interleukin‑8. VEGF interacts with VEGF receptors present
in epidermal keratinocytes which release metabolites of AA
and plasminogen from the proliferated vessels. This enhances
melanogenesis. TXA targets the vascular components of
the skin and hence adds support to the vascular theory of
melasma.[18‑20]
Plasmin plays an important role in the release of b‑FGF, which is
a potent melanocyte growth factor and promotes melanocyte
proliferation.[21] TXA indirectly reduces b‑FGF production.
It also suppresses angiogenesis and neovascularization
induced by b‑FGF. Experimental studies have shown a
reduction in lesional mast cells, which might suppress
various pathogenetic factors that initiate the development
of melasma.[22] These mechanisms point to the fact that TXA
may be tried for other conditions like periorbital melanosis
and even early keloids, where the vascularity component
can be targeted.
Effects on melanogenesis
Tyrosinase‑related protein (TRP‑1) and TRP‑2 are important
enzymes in the Raper mason pathway of melanogenesis.
TXA not only reduces tyrosinase levels but also decreases
the levels of TRP‑1 and TRP‑2. Activation of the signaling
pathway extracellular signal‑regulated kinase (ERK) induces
microphthalmia‑associated transcription factor (MITF)
degradation, resulting in reduced melanogenesis. MITF
is the key transcription factor regulating these enzymes
involved in melanogenesis. TXA stimulates the ERK
signaling pathway and downregulates MITF protein level.
This reduces inflammation‑induced melanogenesis by
decreasing tyrosinase protein expression. TXA is also capable
of suppressing melanogenesis by regulating tyrosinase
transcription in addition to an anti‑inflammatory action.[11,14,23]
These mechanisms may pave the way for TXA being a potential
drug in treating postinflammatory hyperpigmentation. More
experimental studies are however needed to prove the exact
mechanism and efficacy of the drug in treating the same.
Li et al. studied TXA intradermally on guinea pigs and found
that at the basal layer of exposed epidermis, the number of
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68 Pigment International / Jul-Dec 2016 / Volume 3 / Issue 2
George: Tranexamic acid as a depigmenting agent
melanocytes remained the same, but the melanin content was
significantly lowered. This highlights the fact that TXA has
no effect on the number of melanocytes but affects melanin
expression.[24,25]
It has been over four decades since TXA has been in use
both orally and intravenously as a fibrinolytic inhibitor.[26]
For depigmentation, the drug may be administered orally,
topically, intradermally, or intravenously. However, literature
lacks comprehensive studies on the efficacy of different
modes of administration of the drug under diverse conditions.
ORAL TRANEXAMIC ACID
In the prospective, randomized controlled trial (RCT) study
conducted by Karn et al. in Nepal, oral TXA was administered
to melasma patients in a dose of 250 mg twice daily for
3 months. A statistically significant decrease in the mean
melasma assessment severity index (MASI) from the baseline
was observed. The authors concluded that it provides a rapid
and sustained improvement in the treatment of melasma.[13]
Another descriptive study conducted on 65 melasma patients
in Pakistan, the drug was prescribed at the same dose for
6 months. Sixty‑three percent had a good response and 23%
had an excellent response after 6 months.[27] The dose of oral
TXA used in melasma is far less than that prescribed for its
hemostatic action.
In many situations, it is used as an adjuvant with other drugs
or procedures. Cho et al.[28] studied 51 melasma patients,
where TXA was administered at a dose of 500 mg/day for
8 months. This was combined with intense pulsed light
and Q‑switched neodymium: yttrium‑aluminum‑garnet (Qs
Nd‑YAG) (four sessions). The combination treatment showed a
better response when compared to laser therapy alone. In the
randomized trial by Shin et al.,[29] TXA at a dose of 750 mg/
day (for 8 weeks) was combined with low‑fluence Qs Nd‑YAG
laser therapy. The combination showed a superior reduction
in mean MASI score compared with laser therapy alone.
However, in the study by Wu et al., a recurrence of melasma
was observed in 9.5% after 6 months of treatment.
Nonetheless, these were effectively treated with repeated
administration of TXA. Another notable observation in this
study was the differential response of TXA on melasma
patients having coexisting freckles and senile lentigo. The
treatment was unresponsive to freckles and senile lentigo,
whereas the melasma responded well.[14]
Padhi and Pradhan concluded that oral TXA at a dose of
250 mg twice daily along with fluocinolone containing
topical triple combination cream for 8 weeks, produced
a significant and faster improvement in melasma, and also
saved patients from the adverse effects of long‑term use of
steroids and hydroquinone.[30]
TOPICAL TRANEXAMIC ACID
Epidermal melasma has a better prognosis and hence
topical TXA may show some efficacy in this variant, rather
than the dermal and mixed melasma variants, which carry
a poor prognosis.[15,31] Exogenous ochronosis, guttate
hypomelanotic macules, colloid milia, erythema, and
stinging and burning sensation are few of the common
side effects of hydroquinone.[27] As a result, patients often
tend to discontinue such topical medications, and further
seek alternative treatment modalities. Topical TXA shows
rapid and more sustained results with very minimal adverse
effects as far as epidermal melasma is concerned, and the
drug has been proven to have almost similar cumulative
effects of hydroquinone and dexamethasone.[3] A better
probe is however needed to find out the efficacy of TXA as a
combination therapy with other medications and with other
methods used in the treatment of melasma.
In the study by Wu et al.,[14] patients with freckles were
unresponsive to oral administration of TXA. On the contrary,
Kondou et al.[32] successfully employed topical TXA emulsion
for the treatment of melasma and freckles for 5–18 weeks.
Here, the topical TXA also prevented the appearance of
new lesions. A combination of oral and topical TXA showed
both significant declines in epidermal pigmentation and
improvement of dermal melasma.[33] However, the rationale
of combination therapy is not very clear as oral TXA should
take care of both epidermal and dermal components in
melasma.
Kanechorn Na Ayuthaya et al.[34] conducted a double‑blind
RCT among Asians and used 5% TXA in a liposome gel
formulation for epidermal melasma for a duration of
12 weeks. This was compared with the vehicle in a split‑face
trial. Even though 78.2% of patients showed a decrease
in the melanin index, the results were not significant as
compared with the vehicle. Moreover, in the study, topical
TXA induced erythema in many subjects. The newer topical
preparation of TXA cetyl ester HCl is available in recent
cosmetic formulations. This might prove helpful in reducing
erythema and stinging sensation experienced by a few.
TXA is temperature‑stable, not UV sensitive, and does not
get oxidized easily. Thus, it makes a good component in
fairness creams in contrast to hydroquinone which gets
oxidized fast.[35]
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INTRADERMAL TRANEXAMIC ACID
The dermal and mixed variants of melasma are highly treatment
resistant. In this case, TXA may be administered intradermally.
The microneedling method proves to be efficacious in the
intradermal delivery of the drug. In this method, multiple
microinjuries are made in the dermis, using a derma roller
and this facilitates transport of substances through various
transport channels, leaving the epidermis intact. The derma
roller is a handheld instrument consisting of a handle with a
cylinder studded in eight rows with fine stainless steel needles
of 0.5–3 mm in length, which is rolled in multiple directions.
TXA is available as 5 mL ampoule containing 500 mg of the
drug. In an open‑label RCT in South India, 4 mg/mL of TXA
was used with microneedling on melasma lesions. This was
done three times at monthly intervals (0, 4, and 8 weeks) and
followed up for further 3 months at monthly intervals. Exactly
41.38% patients experienced more than 50% improvement
without any major adverse events.[36]
In another study conducted in Korea on melasma patients,
TXA was directly administered intradermally (4 mg/mL)
weekly for a period of 12 weeks. More than 75% patients
experienced a statistically significant improvement.[15] The
time period between consecutive microneedling sessions is
left to the prerogative of the operating personnel and hence
a proper quantification is lacking. Moreover, pertinent is the
scheduling of the maintenance sessions which are necessary
as melasma is prone for recurrence.
Another notable application is the intravenous administration
of TXA for the purpose of skin lightening. Here, a dose of
500 mg/week is administered for a period of 1–2 months and
500 mg every month for maintenance[6] [Table 1].
ADVERSE EFFECTS
TXA is a well‑tolerated drug and it is mostly considered
safe at the usual dosage. Nausea and diarrhea are the most
common side effects.[9] Other systemic side effects observed
Contd...
Table1: Summary of tranexamic acid studies: As a depigmenting agent
Year Author Type of study Objective Number of
patients
Study group Results Comments
2012 Karn et al.[13] Prospective, RCT Oral TXA in melasma 260 Group A: Capsule TXA 250
mg BD for 3 months and
cases were followed for
3 months; Group B: Other
topical measures
Statistically significant
decrease in the mean MASI
from baseline to 8 and
12 weeks was observed
among Group A patients
Oral TXA provides
rapid and sustained
improvement in the
treatment of melasma
2012 Wu et al.[14] Descriptive Oral TXA in melasma 74 All patients treated with
capsule TXA 250 mg BD
for 6 months and followed
up for more than 6 months
after the treatment
Excellent results in
10.8%, good in 54%,
fair response ‑ 31.1%,
poor ‑ 4.1%. Recurrence of
melasma was observed in
9.5%
Oral TXA is an effective
and safe therapy for the
treatment of melasma
2014 Aamir and
Naseem[27]
Descriptive
cross‑sectional
Oral TXA in melasma 65 Capsule TXA 250 mg BD
for 6 months along with
topical sunscreen alone
and cases were followed
up for 6 months
15 patients had
>90% (excellent)
improvement and
41 patients had >60%
(good) improvement without
any serious systemic side
effects
Encouraging results
with very few adverse
effects
2013 Shin et al.[29] Randomized
prospective trial
Oral TXA combined
with low‑fluence
1064‑nm Qs Nd‑YAG
laser
48 2 patient groups:
combination group and
a laser treatment group.
All patients were treated
with two sessions of
low‑fluence Qs Nd‑YAG
laser, and patients in the
combination group took
8 weeks of oral TXA
Mean mMASI score 4 weeks
after the second treatment
decreased significantly in
both groups from baseline
Oral TXA may prove
a safe and efficient
treatment option
for melasma in
combination with
low‑fluence Qs Nd‑YAG
laser therapy
2013 Cho et al.[28] RCT Oral TXA in melasma
patients treated with
IPL and low‑fluence
Qs Nd‑YAG laser
51 Group A: Patients on oral
TXA for 8 months during
IPL and laser treatments
and Group B: Patients on
only IPL and laser
Reduction in mMASI
score from 11.33±7.07
to 6.21±5.04 in Group A
and from 11.70±6.72 to
8.93±5.89 in Group B.
Modified MASI score right
before and after IPL were
more reduced in Group A
Oral TXA may improve
clinical efficacy in
light‑ or laser‑based
melasma treatment,
especially during the
period of relative high
sun exposure without
serious adverse effects
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70 Pigment International / Jul-Dec 2016 / Volume 3 / Issue 2
George: Tranexamic acid as a depigmenting agent
with low‑dose administration include oligomenorrhea,
gastric upset, and palpitations.[27] Venous thromboembolism,
myocardial infarction, cerebrovascular accidents, and
pulmonary embolism have been reported when given in
hemostatic doses (up to 1000 mg daily). The contraindications
of the drug include acquired defective color vision, active
intravascular clotting conditions, and drug hypersensitivity.[13]
Though it is used in low doses for a short duration as a
systemic depigmenting agent, it is always vital to rule out
underlying coagulation defects to prevent untoward adverse
events. Hence, a thorough history along with essential
investigations pertaining to coagulation defects will ensure
better safety with the drug usage. Mild discomfort, burning
sensation, and erythema were observed when it was used
intradermally, which subsided without the need for other
interventions.[36]
CONCLUSION
The literature review reveals that TXA is a safe and promising
drug not only in the treatment of melasma but also in
other pigmentary conditions. However, larger RCTs with
Table1: Contd...
Year Author Type of study Objective Number of
patients
Study group Results Comments
2015 Padhi and
Pradhan[30]
Open‑labeled
RCT
Oral T XA with
fluocinolone‑based
triple combination
cream versus
fluocinolone‑based
triple combination
cream alone in
melasma
40 Group A: Patients on only
fluocinolone‑based triple
combination cream and
Group B: Patients on oral
TXA 250 mg BD along
with the same cream
once daily for 8 weeks;
follow‑up for 6 months
Intergroup comparison
showed a faster reduction
in pigmentation in Group
B as compared to Group
A and the results were
statistically significant
at 4 weeks (P=0.014)
and 8 weeks (P=0.000).
There was no recurrence
throughout the follow‑up
period
Addition of oral TXA
to fluocinolone‑based
triple combination
cream results in a
faster and sustained
improvement in the
treatment of melasma
2012 Kanechorn Na
Ayuthaya et al.[34]
Double blind RCT Topical 5% TXA in
melasma treatment
23 Patients blindly applied
topical 5% TXA and its
vehicle, to the designated
sides of the face twice
daily in addition to the
assigned sunscreen each
morning
78.2% showed decrease in
the melanin index on either
or both sides of the face
by the end of 12 weeks
compared to baseline. The
MASI scores were also
significantly reduced on both
tested sides
Although lightening
of pigmentation was
obtained, the results
were not significant
between the two
regimens. Moreover,
topical TXA produced
erythema
2014 Ebrahimi and
Naeini[3]
Double‑blind
split‑face trial
Topical 3% TXA in
melasma
50 Topical 3% TXA was given
on one side of the face,
and topical solution of 3%
hydroquinone +0.01%
dexamethasone on the
other side two times a
day (trial for 12 weeks)
A significant decrease
in MASI score of both
groups with no significant
difference between them
during the study (P<0.05).
However, the side effects
of hydroquinone +
dexamethasone were
significantly prominent
compared with TXA
(P=0.01)
TXA is effective and
safe in the treatment of
melasma
2006 Lee et al.[15] Prospective open
pilot study
Localized intradermal
microinjections in
the treatment of
melasma
100 4 mg/mL of TXA was
injected intradermally
into the melasma lesion;
repeated weekly for
12 weeks
Significant decrease in
MASI from baseline to
8 and 12 weeks was
observed (13.22±3.02 vs.
9.02±2.62 at week 8 and
vs. 7.57±2.54 at week 12;
P<0.05 for both)
Intralesional
microinjection of TXA
acid: A potentially new,
effective, and safe
therapeutic modality
for the treatment of
melasma
2013 Budamakuntla
et al.[36]
Prospective
randomized
open label
study
Comparative
study of TX A
microinjections
and TXA with
microneedling
in patients with
melasma
60 Thir ty patients were
administered with
localized microinjections
of TX A in one ar m,
and other 30 with TXA
microneedling; done at
monthly intervals (0,
4, and 8 weeks) and
followed up for three
consecutive months
In the microinjection
group, there was 35.72%
improvement in the MASI
score compared to 44.41%
in the microneedling
group, at the end of the
third follow‑up visit
An office‑ based
procedure wit h
relatively quick
resul ts, no significant
side ef fects, and
almost no downtime
TXA‑Tranexamic acid, MASI‑Melasma assessment severity index, RCT‑Randomized controlled trial, Qs Nd‑YAG‑Q‑switched neodymium: yttrium‑aluminum‑garnet, IPL‑Intense‑pulsed light
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George: Tranexamic acid as a depigmenting agent
long‑term follow‑up are needed to fully elucidate the exact
mechanism of action, ideal route, frequency, and duration of
administration. None of the existing depigmenting drugs can
provide fast and sustained results. Although the gold standard
in the management of melasma involves the use of triple
combination regimens, these have umpteen adverse effects.
The thirst for a fair and clear skin can never be fully quenched.
Hence, the quest for newer and safer depigmenting agents
continues with TXA evolving to be a safe and effective one
in the armamentarium of a dermatologist.
Financial support and sponsorship
Nil.
Conicts of interest
There are no conflicts of interest.
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