Oral tranexamic acid in the treatment of hyperpigmentation disorder beyond melasma: A review

Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic, procoagulant agent approved by the Food and Drug Administration for the treatment of cyclic heavy menstrual bleeding and prevention of bleeding in patients with hemophilia undergoing tooth extraction. Oral tranexamic acid has been used off‐label in dermatology in the treatment of melasma and other hyperpigmentation disorders. In a recent study, oral tranexamic acid was reviewed thoroughly in treating melasma, and its effectiveness was demonstrated. Their role in treating other hyperpigmentation disorders has also been tried in several studies.


| INTRODUC TI ON
Tranexamic acid (TA), a synthetic derivative of the amino acid lysine, is an antifibrinolytic, procoagulant agent that the Food and Drug Administration approves for the treatment of cyclic heavy menstrual bleeding and prevention of bleeding in patients with hemophilia undergoing tooth extractions. 1 Oral TA has been used off-label in dermatology in the treatment of melasma and other hyperpigmentation disorders. 2 In a recent study, oral TA has been reviewed thoroughly in treating melasma, and its effectiveness has been demonstrated. 2 Their role in treating other hyperpigmentation disorders has also been tried in several studies. The present review discusses the emerging role of oral TA in the treatment of hyperpigmentation disorders other than melasma.

| MECHANIS M OF AC TION
Tranexamic acid is known to decrease bleeding by its antifibrinolytic effect by inhibiting the conversion of plasminogen to plasmin involved in fibrin degradation. In addition to its antifibrinolytic effect, TA is thought to have anti-inflammatory, antimelanogenic, and antiangiogenic effects by its potent inhibitory effect on plasmin. 3,4 TA inhibits UV light induces plasmin activation, and decreases plasminogen binding to keratinocyte. 5 Plasmin activation stimulates keratinocytes to release alpha mesh and inflammatory mediators such as alpha-archiedonic acid prostaglandin E2, which in turn result in melanocytes tyrosinase activation, which plays an essential role in skin hyperpigmentation. The antiangiogenic effect of TA is thought to be due to a decrease in plasmin mediate expression of vascular endothelial growth factor and endothelin-1, a significant skin angiogenic factor, which is involved in the vascular theory of the pathogenesis of melasma. 6,7

| S ID E EFFEC TS
The most common adverse effect include abdominal pain, bloating, nausea and vomiting, numbness or facial pruritus, tinnitus, transient amnesia, tremor, dysmenorrhoea, hair shedding, facial hypertrichosis, lip or periorbital swelling, and palpitations. In the largest retrospective review of patients taking oral TA for melasma, one patient did develop a deep vein thrombosis, but this patient found to have protein S deficiency. 8

| CONTR AINDIC ATIONS
Tranexamic acid is contraindicated in patients allergic to TA, with intracranial bleeding, known defective color vision, history of venous or arterial thromboembolism, or active thromboembolic disease. It is also contraindicated in the patient who is currently taking or have previously taken anticoagulant medications; and in a patient taking oral contraceptive pills, the patient who are pregnant or breastfeeding or are smokers; and those with renal, cardiac, and pulmonary disease. 4,9 Patients must be screened carefully through careful history for contraindications and risks and given thorough instructions to monitor for side effects before initiating therapy with TA.

| ME THODOLOGY
A comprehensive literature review was searched using the electronic online database "PubMed" and "Google Scholar" using key words "Postinflammatory hyperpigmentation," "lichen planus pigmentosus," "ashy dermatosis," "riehl melanosis". After that, a full-text review of the studies was performed.

| LITER ATURE RE VIE W
Postinflammatory hyperpigmentation (PIH) is a common cosmetic skin condition that occurs after dermatologic procedures, exogenous stimuli like burns or as a sequela of different dermatoses such as acne and eczema. Management of PIH lesions could be challenging as it takes a long time to fully resolve, with or without treatment. 10 Kim et al. 11 used oral TA to treat PIH and found it effective.
They report a case of PIH lesions on both malar areas due to intense Therefore, she received oral TA 650 mg daily for 8 weeks and topical clobetasol 0.05% cream twice daily for 1 week. Then after a 16- week follow-up visit, she presented with normal appearing skin. The second case, a case of acne excoriate with PIH, planned to have a series of light chemical peels for her acne-related PIH lesions. As prophylaxis, she was prescribed oral TA 650 mg daily. Over a 2.5year period, she completed nine exfoliative chemical peels without complications or new PIH lesions despite continued excoriation. 10 Moreover, the prophylactic role of oral TA post-Q-switched ruby laser treatment was evaluated by Kato et al. 13 , who included 32 Japanese women who underwent Q-switched ruby laser treatment for senile lentigines on the face. One group was given 750 mg/day of oral TA for 4 weeks after Q-switched ruby laser treatment, and the other group did not receive TA after Q-switched ruby laser. As a result, there was no significant difference in the incidence of PIH between participants who received oral TA and those who did not.
Similarly, in a trial conducted on 40 patients with solar lentigines treated with Q-switched 532 nm Nd: YAG laser, who were randomly assigned to receive oral TA 1500 mg daily or placebo for 6 weeks. Oral TA appears to be ineffective in preventing PIH postlaser in the treatment group compared with the control group.
There were no serious adverse events in either group during the study period. On the other hand, the incidence of dermatoscopic pigmented granules in the TA group was significantly lower than

TA B L E 1 (Continued)
in the placebo group at the 6th and 12th weeks. This finding might indicate the efficacy of TA in enhancing PIH clearance rather than protection. 14 Tranexamic acid has also been reported in the treatment of Lichen planus pigmentosus (LPP), a variant of lichen planus manifested as ill-defined oval grayish to brown macules on the sunexposed area, which represents a real therapeutic challenge with several proposed therapies have limited efficacy. TA has been studied in a case series conducted in North Africa, including 17 patients diagnosed with LPP; 11 were given oral TA 500 mg twice daily for 3 or 6 months. Lesions were mainly in the perioral area, followed by the neck. At follow-up, only three had an excellent result with a complete disappearance of the lesions. The remaining patients have slight or no improvement. 15 Zenjari et al. 16  With that being said, we suggest that combination therapy by oral TA in addition to adjuvant multiple therapeutic modalities for a compelling long-term period could provide several advantages, as shown in melasma treatment. 20 The literature is summarized in Table 1.

| CON CLUS ION
Oral tranexamic acid is a promising treatment option in a different type of hyperpigmentation disorder refractory to topical treatment.
However, more evidence from blinded randomized controlled trials and case-control studies is needed to determine their efficacy in the treatment of the different types of hyperpigmentation disorders.

AUTH O R CO NTR I B UTI O N S
Taghreed Mahjoub, contributed to the study conception and design, writing, and reviewing manuscript. Heba Milibary, contributed to writing and reviewing manuscript. All author commented in previous version of the manuscript. All authors read and approved the final manuscript.

ACK N OWLED G M ENTS
The study has no funding support.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.