|Year : 2022 | Volume
| Issue : 2 | Page : 70-81
Newer indications of tranexamic acid in dermatology beyond melasma: a review
Astha Arora, Mala Bhalla
Department of Dermatology and Venereology, Government Medical College and Hospital, Chandigarh, India
|Date of Submission||16-Dec-2021|
|Date of Decision||04-Mar-2022|
|Date of Acceptance||06-Mar-2022|
|Date of Web Publication||12-Aug-2022|
Dr. Mala Bhalla
Department of Dermatology and Venereology, Government Medical College and Hospital, Chandigarh 160030
Source of Support: None, Conflict of Interest: None
Tranexamic acid (TXA) is an antifibrinolytic agent approved for use to control bleeding during surgery and after trauma. It has been used in dermatology as a therapeutic and prophylactic agent in angioedema since 1970s but its recently discovered role in melasma has made it the current molecule of interest. At present TXA is being widely researched for multiple indications in view of its role in reducing melanogenesis and angiogenesis in skin. Various case reports and clinical trials have been published over the last few years describing its role in postinflammatory hyperpigmentation, dermal melanosis, rosacea, telangiectasia, and even as an antiaging agent. We present this review here summarizing the various publications for the aforementioned indications.
Keywords: Antiaging, dermatosurgery, postinflammatory hyperpigmentation, rosacea, tranexamic acid
|How to cite this article:|
Arora A, Bhalla M. Newer indications of tranexamic acid in dermatology beyond melasma: a review. Pigment Int 2022;9:70-81
| Introduction|| |
Drugs often find their application and use in clinical practice after undergoing various trials and studies. More often than not a drug finds its use for conditions beyond indications for which it was developed either by serendipitous discovery or expansion in understanding of its pharmacodynamics. Tranexamic acid (TXA) is a derivative of lysine and acts primarily by inhibiting plasminogen activator. It was initially used to control bleeding in surgeries and trauma due to its antifibrinolytic activity., Its use was expanded to hereditary angioedema where it is given in acute episodes and for long-term maintenance by reducing levels of bradykinin.
The serendipitous discovery of lightening effect of TXA on melasma in a patient of chronic urticaria has led to expansion of its use in various pigmentation disorders. In recent years, TXA has been increasingly used in patients of dyschromias especially melasma through various routes of administration like topical, intradermal, and systemic. The proposed mechanism of action is through preventing melanocyte activation due to hormones, ultraviolet light (UV) B, and keratinocyte injury by inhibiting plasminogen activator. Additionally, the contributing effect of reduction in melanocyte tyrosinase activity and inhibition of vascular endothelial growth factor (VEGF) leading to decreased angiogenesis has also been studied.,
Multiple experimental studies have been performed in cell cultures, skin samples, and animal models elucidating various actions of TXA. Hiramoto et al. in 2014 used mice to study role of TXA in reducing levels of prohormone convertase 2 (PC-2) and α-melanocyte-stimulating hormone (α-MSH). PC-2 present in the pituitary gland is a prohormone which cleaves α-MSH from proopiomelanocortin. UVB irradiation of eyes and ears was carried out and skin and pituitary were studied. Mice pretreated with 750 mg/kg TXA showed suppression in expression of PC-2 and α-MSH thereby decreasing melanocyte activation. Zhu et al. studied effect of UVB irradiation on cultured melanocytes and concluded that cells pretreated with TXA (1 mg/mL) showed reduced expression of VEGF165 and abolition of VEGF receptors 1 and 2 phosphorylation after UVB exposure. Expression of melanocyte-induced transcription factor, tyrosinase- and tyrosinase-related protein 1 and 2 was also reduced. Another study in mice evaluated the effect of 750 mg/kg/day TXA orally for 20 days on wrinkles induced by skin dryness. The proliferation of mast cells was found to be decreased, whereas the fibroblasts increased resulting in an improvement in wrinkles.
Considering the evolving use of TXA in various indications, this review has been written to explore and evaluate the currently available evidence in literature of its use for indications other than angioedema and melasma.
| Materials and methods|| |
A literature search of PubMed electronic database was performed using key words “tranexamic acid” AND “dermatology” NOT “melasma.” A total of 65 search results appeared. All review articles, meta-analyses, in vitro cell studies, animal studies, and articles not in English were excluded. Studies of TXA used in patients of angioedema (hereditary and nonhereditary) and urticaria were also excluded as efficacy and treatment guidelines have been well studied. A total of 17 relevant studies were found and abstracts of these were studied and reviewed by the two authors. The relevant references of the included articles were also traced and included making a total of 27 case reports, clinical trials, and therapeutic pearls which have been reviewed here.
The available literature has been presented under various indications of use and level of evidence provided for each study in accordance with Levels of Evidence for Therapeutic Studies by Centre for Evidence-Based Medicine which defines five levels of evidence based on the types of study available for the therapy for indication being studied.
| Postinflammatory hyperpigmentation|| |
Pigment of skin has a great impact on a person’s personality and both loss and gain of pigment are a cause of worry for the patients. Remnant pigmentation postinflammation in patients at site of dermatoses and also following aesthetic procedures like chemical peel, microdermabrasion, and laser is an unavoidable and difficult to manage complication especially in darker skin types (Fitzpatrick skin types III–V). Postinflammatory hyperpigmentation (PIH) is usually managed with various lightening agents postdevelopment but prevention of this troublesome effect would be ideal. Various authors have studied the role of TXA in prevention as well as treatment of these patients.
Role of TXA in reducing skin pigmentation and maintaining skin lipids and hydration was studied by Batory et al. who applied 5% topical TXA in acidic medium (pH 2.38) with and without microdermabrasion on dorsal surface of hands and back every week for 6 weeks in 12 patients. It was observed that TXA causes reduction in melanogenesis, improves skin hydration and lipids, and reduces redness.
Kato et al. studied role of oral TXA in prevention of PIH, a known and distressing complication in Asian skin (Fitzpatrick skin type − III), after Q-switched (QS) ruby laser treatment in patients of senile lentigines. The authors concluded that TXA may be ineffective in preventing PIH but they had started TXA at the time of laser sitting for a duration of 4 weeks. The timing and duration of treatment may not have been adequate and further time taken for clearance of pigment was also not studied [Table 1].
Rutnin et al. studied the role of oral TXA in prevention of PIH after removal of solar lentigo with QS Nd:YAG laser (532 nm) in a randomized controlled trial. This study provides an adequate dermascopic evidence of role of TXA in reduction of pigmentation developing after inflammation although clinically evident difference was not observed between the groups.
Lindgren et al. described two cases in which they used oral TXA 650 mg/day to prevent PIH after contact dermatitis to topical anesthetic cream and patient of acne excoriée with PIH. In the first case, topical clobetasol 0.05% was also prescribed for the first 1 week and TXA was continued for 8 weeks with good results. In the second case, they used TXA both for treatment of PIH as well as its prevention following exfoliative medium depth chemical peel (vitalize peels; Allergan, Irvine, CA, USA). The authors state that they have been using oral TXA for prevention of PIH in multiple indications and these two cases highlight the same but larger studies with statistically significant results are awaited.
Lee et al. reported a case of PIH postallergic contact dermatitis to henna hair dye treated with oral TXA and QS Nd:YAG laser weekly sittings for 10 weeks. There was a significant improvement which was maintained at follow-up. Oral TXA in combination with laser may have a promising role in management of PIH but more studies are required for TXA as a standalone therapy.
A study was conducted by Sirithanabadeekul and Srieakpanit to study the effect of single-dose intradermal TXA in preventing PIH after QS Nd:YAG laser for solar lentigo removal and showed overall PIH at 16% in TXA group versus 28% in control group at 4 weeks [Table 2].
Sayed et al. compared intradermal TXA to QS-KTP (532 nm) laser in treatment of facial ephelides in a split face study. Though a more significant improvement was found on laser side compared to TXA, four patients (13%) developed PIH following laser.
PIH is a difficult condition to treat once it develops and may take months to years to resolve depending on individual tendency. Case reports document a beneficial role of oral TXA in combination with other therapies in resolution of PIH but it may be due to a positive reporting bias. In addition, the additive, synergistic, or standalone effect of TXA still needs to be established in resolution of PIH by well-planned studies.
The prevention of PIH would be the ideal solution as it is a bane for cosmetic procedures especially in darker skin types (Fitzpatrick skin types III–V). Current literature and studies described here show a great variation in role of TXA in PIH. It seems that it has greater role in reducing or clearing of pigment than preventing the incidence of PIH itself. TXA has been used topically, orally, and intradermally for this indication for a variable duration but the ideal regime and timing still remains elusive. The literature reflects that PIH developing postdermatoses responds more favorably when compared with that after laser treatment and intradermal route may have better efficacy with lesser risk of systemic adverse effects. Further studies on larger number of patients comparing various routes of TXA administration for different indications are needed to help establish its efficacy.
| Riehl melanosis and lichen planus pigmentosus|| |
Riehl melanosis (RM) is an acquired dermal macular pigmentation with several irritants, allergens, and photo exposure playing a role in development of brown-gray pigmentation chiefly over face and photoexposed areas and is refractory to treatment. A few initial studies have been performed to study efficacy of TXA in recalcitrant RM [Table 3].
Kwon et al. used triple combination of low fluence QS Nd:YAG laser, topical hydroquinone and oral TXA in 8 patients of recalcitrant RM, and Xu et al. performed a pilot study using a combination of oral TXA and glycyrrhizin compound for treatment of RM in 10 patients. Both these studies show marked improvement in most patients but a cocktail of treatment was used and efficacy of TXA as mono treatment still needs to be evaluated.
Lichen planus pigmentosus (LPP) is a variant of lichen planus resulting in bluish gray pigmented macules starting over face and predominantly over flexures causing significant cosmetic concerns. A study in French was found during literature search and thereby not included in this review. The abstract was submitted in English and is summarized here. It was a prospective study of 20 patients who were given oral TXA 250 mg/day for 4 to 6 months with photoprotection. Partial improvement was noted in 10 patients, no improvement in 3 patients, and 7 were lost to follow-up with pruritus resolution in all. Thereby concluding TXA could be effective in LPP.
RM and LPP are deeper dermal pigmentation with a bluish hue when compared with melasma which is usually epidermal or mixed type. Theoretically oral or intradermal TXA may be more effective than topical. Though the present two open studies have shown encouraging results but the number of patients included are too few to establish its efficacy. More studies with larger number of patients are required for both these difficult to treat and recalcitrant conditions to ascertain the place of TXA in their management as there is a lack of effective therapies.
| Rosacea|| |
Rosacea is characterized by immune system abnormalities and hyperactive vasculature leading to chronic inflammation. The inhibition of VEGF by TXA resulting in decreased angiogenesis was observed on dermal blood vessels in melasma and same has been extrapolated to its use in rosacea. Li et al. studied the mechanism of action of TXA in rosacea in LL37-induced mouse and HaCa T-cell model. They observed a reduction in skin erythema, levels of proinflammatory cytokines, and reduction in expression of innate immunity genes. There also was reduction in angiogenesis with downregulation of VEGF levels [Table 4].
Kwon et al. reported a 37-year-old female patient of rosacea treated with combination of oral propanolol 40 mg, TXA 250 mg, and minocycline 50 mg daily for 4 weeks. A significant reduction in erythema and improvement of subjective symptoms were reported. Although this report provides favorable evidence, further role needs to be evaluated.
Kim et al. treated six patients of rosacea with response assessed after five treatments for reduction in erythema, itching, burning, and flushing which showed a significant improvement.
Bageorgou et al. studied 20 patients of erythematotelangiectatic rosasea and a significant reduction in Investigator Global Assessment of Rosacea Severity Score in both groups was present. This study helps to establish the role of TXA in rosacea with microneedling improving the penetration of TXA into the dermis resulting in better clinical results.
Jakhar et al. published a therapeutic pearl utilizing topical TXA for the management of erythematotelangiectatic steroid-induced rosacea. There was improvement in erythema and burning sensation thereby providing a cheaper alternative than topical calcineurin inhibitors for management of erythema in rosacea.
Daadaa et al. showed the efficacy of monthly intradermal TXA microinjections in erythematotelangiectatic rosasea. This is the only study using TXA intradermally in rosacea but inclusion of only six patients and retrospective nature of study limit its validity and larger study sample with prospective design is needed.
Facial erythema and burning are most common, persistent, and difficult to treat complaints in patients of rosacea and TXA in topical and intradermal forms seems to have promising results in these patients. These studies and case reports help to establish initial efficacy of TXA in this condition which has limited treatment options but large sample size clinical trials are still awaited. Although TXA injection applied topically or in soaks is cheap and easily available, cream and ointment formulations would be less messy, easy to dispense, and have dosing accuracy.
| Postacne complications|| |
Acne vulgaris heals with varied sequelae of complications such as PIH, persistent inflammatory erythema. TXA has been tried for both these indications with favorable results [Table 5].
Jakhar et al. presented a therapeutic pearl utilizing topical TXA for management of postacne inflammatory erythema leading to reduction in erythema and burning sensation.
Intradermal microinjections of TXA were compared with fractional carbon dioxide (CO2) laser in postacne hyperpigmentation by Tawfic et al. The study showed that both the options improve pigmentation but CO2 laser results were superior to TXA.
The TXA may be helpful in reducing the acne-associated erythema but probably split face studies are required to establish its true value as erythema in acne is usually transient and individual variation is there in the extent of associated erythema as well as postacne pigmentation.
| Other indications|| |
Literature search showed only singular studies or case reports for multiple indications and they are discussed here but the efficacy of TXA for these indications still needs to be established by well-planned studies [Table 6].
Infraorbital pigmentation is a multifactorial difficult to treat condition with no single therapy completely effective. Ghandehari et al. compared efficacy and safety of TXA applied topically postmicroneedling and fractional CO2 laser in patients of infraorbital hyperpigmentation. Both reduced pigmentation but CO2 laser had better results.
Topical steroid-dependent face
Jakhar et al. reported effectiveness of topical TXA in a 21-year-old female patient of topical steroid-dependent face. The patient reported decrease in erythema and burning sensation after 4 weeks of treatment.
Ayhan treated two patients of telangiectasia with intralesional TXA weekly for 3 weeks. An initial response in the form of loss of vessel and fading was observed with subsequent reappearance of vessels thereby concluding that telangiectasias might be resistant to intralesional TXA therapy. There are only case reports available for the use of topical or intradermal TXA in various conditions resulting in erythema and telangiectasias which have shown equivocal results. Well-planned studies with an adequate number of patients are required to elucidate the role of TXA in these conditions.
Macular amyloidosis (MA) is characterized by pigmentation in rippled manner with intense pruritus mostly over photoexposed areas. Topical corticosteroids are mainstay of treatment but remnant pigmentation is a cause for concern for patients as it is recalcitrant. Ghassemi et al. demonstrated a similar efficacy of intradermal TXA and Kligman triple combination ointment in 43 patients of MA. This study gives initial evidence of role of TXA in MA and it may be further investigated. The pigmentation in MA is usually of great cosmetic concern to the patients and is resistant to most topical treatments, TXA may offer a viable alternative therapy but more studies are required to establish the same.
| Dermatosurgery and hemostasis|| |
The TXA has a long standing use as an effective agent to both prevent and control bleeding. It is continually finding newer uses during surgical procedures in different specialties via various routes for the same [Table 7].
Powell et al. presented two cases of infants having congenital hemangioma (10 weeks and 3 weeks old) who presented with bleeding from crusted areas with fall in hemoglobin. In both the cases, TXA soaked gauze compression was used to control bleeding and prevent need of interventions.
Zilinsky et al. assessed the bleeding from wound in 131 patients of Moh micrographic surgery. After stage 1 of surgery, wound was dressed and ratio of bloodstain size to wound size along long axis was assessed prior to stage 2 or closure and hemostasis was evaluated subjectively. This randomized controlled trial proves the efficacy of TXA mixed with anesthetic in reducing bleeding during and after procedure and seems beneficial by eliminating the need to stop anticoagulants prior to surgery.
The TXA solution (5%) with gauze can be applied to buccal lesions of SJS/TEN to prevent hemorrhage. The solution as advised in therapeutic pearl by Adams and Creamer can be prepared by diluting intravenous preparation.
Effect of oral TXA in the prevention of ecchymosis postlipoma excision was studied in 40 patients retrospectively by Choi et al., who concluded that TXA given postoperatively may reduce ecchymosis in patients of lipoma excision.
Although these studies show a favorable effect of TXA in reducing bleeding in dermatosurgical procedures but Eikebrokk et al. studied keratinocyte and fibroblast cell cultures and ex vivo skin wound model for the effect of topical TXA. Chronic exposure to small doses or short exposure to high doses to TXA led to cytotoxicity and disruption of wound re-epithelization, due to disruption of integrin adhesion mediated by plasminogen. This experimental study raises concern that long-term and very high-dose exposure to TXA topically during surgeries may be detrimental to healing but well-planned clinical studies demonstrating this effect in the real-life scenario are required before recommendations for or against the use of TXA can be made .
| Antiaging and skin brightening therapies|| |
The role of TXA role in reducing pigmentation by influencing vascularity and inflammatory mediators has been exploited in the development of various cocktails used for antiaging effect as well as for facial dyschromias.
Byun et al. used skin resurfacing instrument Jet M to introduce preparation containing copper-GHK, oligohyaluronic acid, rhodiolar extract, TXA, and β-glucan into the skin in a 59-year-old male patient of crow’s feet once a week for 12 weeks. There was improvement in wrinkles around the eyes with increased collagen deposition on biopsy.
Jung et al. assessed a new complex cream comprising of niacinamide, TXA, oxyresveratrol, glutathione disulfide, and linoleic acid for skin lightening in 26 healthy Asian women (Fitzpatrick skin type III). Patients applied the cream twice daily for 12 weeks and outcomes were assessed in form of melanin index, erythema index, and chromatic aberration value all of which showed significant improvement at 12 weeks.
Desai et al. used a novel facial serum comprising of 3% TXA, 5% niacinamide, and 1% kojic acid in 55 patients of facial hyperpigmentation and melasma used twice daily for 12 weeks. The patients showed clinically significant improvement in pigmentation, skin texture, and tone in addition to decrease in modified melasma area severity index (MASI) and melanin index (MI) establishing its effectiveness for facial dyschromias.
Shin et al. used a cocktail solution comprising of copper-glycyl-L-histidyl-L-lysyl, oligohyaluronic acid, rhodiola extract, TXA, and β-glucan delivered via hydroporation technique in six female patients as antiaging treatment. Skin biopsy sample analysis showed intrafollicular epidermal stem cell increased due to regain of stem-cell potential of basal cells and reduction in aryl hydrocarbon receptor expression and increase aryl hydrocarbon receptor repressor which has a role in correction of dermal microenvironment.
Antiaging topical preparations as well as treatments usually use a multitude of active ingredients rather than a single agent so it is difficult to attribute the improvement to one molecule. TXA seems to have a beneficial effect though the exact percentage of expected benefit cannot be quantified, as in cosmetic indications, the subjective satisfaction may exceed the objective improvement.
| Newer modalities to increase topical uptake of txa|| |
Hsiao et al. studied role of conventional nonfractional ablative lasers (Er:YAG) when compared with CO2 laser in increasing transdermal delivery of 12% TXA solution on porcine skin and concluded that laser pretreatment increases drug permeability. This can be applied similarly in patients to increase TXA transdermal delivery with laser pretreatment of affected skin.
Liu et al. used human A375 melanoma cells and hyperpigmented guinea pig models to study the efficacy of delivery of TXA liposome nanogels in hylauronic acid and concluded that this delivery system resulted in targeted delivery of TXA to melanosomes and resulted in reduced tyrosinase activity. In addition, it also reduced the epidermal diffusion of TXA. Liposome-based topical TXA preparations may prove to be ideal vehicles for TXA in future clinical studies.
| Conclusion|| |
The TXA is finding newer uses in dermatology beyond hereditary angioedema and melasma. The current review summarizes its application in various indications. Although currently available literature shows great promise of utilization of TXA in various indications, there still is a deficiency of well-planned randomized control trials with an adequate sample size to help establish efficacy, route of administration, and safety of TXA for these indications.
concept and design of review and compilation of data, drafting the article.
concept and design of review,
revising it critically for important intellectual content, and final approval of the version to be published.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]