Platelet Rich Plasma as a Potential Treatment for Melasma: A Review

Silvia Valentina, M.D.1, Dewa Ayu Agus Sri Laksemi, M.D., Ph.D.2,*

1Biomedical Science, Anti-Aging Medicine, Faculty of Medicine, Universitas Udayana, Denpasar, Indonesia, 2Department of Parasitology, Faculty of Medicine, Universitas Udayana, Denpasar, Indonesia.

*Corresponding author: Silvia Valentina E-mail: silvia14valentina@gmail.com

Received 31 October 2024 Revised 4 December 2024 Accepted 5 December 2024 ORCID ID:https://orcid.org/0009-0007-6729-4954 https://doi.org/10.33192/smj.v77i3.271926

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

INTRODUCTION

Melasma is a formidable cosmetic issue and ranks among the three most prevalent skin issues in medical aesthetic practice, alongside acne and wrinkles. While melasma is not a dangerous condition, it can considerably affect an individual’s physical appearance, resulting in emotional and psychosocial distress associated with embarrassment, frustration, low self-esteem, and interpersonal interactions, ultimately diminishing quality of life.1–7Melasma is characterized by irregular brown macules symmetrically distributed on sun-exposed areas of the body, particularly on the face. It is a common reason for seeking dermatological care, primarily affecting women (especially during the menacme). Managing melasma is notably challenging in dermatology, as many treatment approaches frequently yield variable outcomes that fall short of patient expectations.8 Melasma treatments vary in efficacy and often present issues such as irritation, post-inflammatory hyperpigmentation, and rebound hyperpigmentation9, highlighting the need for adjunctive or novel alternative therapies.

Platelet-rich plasma (PRP) is a procedure that uses centrifuged blood with a high concentration of platelets in a small plasma volume.2,10 PRP is a regenerative treatment that remains under investigation. This therapy has garnered significant attention in the medical field due to its favorable benefit-risk profile. The application of PRP has shown promising results for individuals unresponsive to conventional therapies. Numerous skin conditions progress over time and necessitate extended treatment; however, managing these conditions can be challenging due to significant adverse effects, suboptimal therapeutic responses, and high recurrence rates. PRP

may serve as a promising treatment option for such complex skin disorders.

Asanovel therapeutic approach, PRPhas demonstrated potential in treating various skin and cosmetic conditions, including alopecia, wound healing, skin rejuvenation, and acne scarring.11 Recent studies have indicated positive outcomes for PRP therapy in managing skin hyperpigmentation, especially in individuals with melasma. However, the understanding of PRP’s therapeutic efficacy in melasma treatment remains limited. This review aims to examine the efficacy and mechanism of PRP as an alternative and adjunctive therapy for treating melasma.

Melasma

Melasma is a prevalent chronic skin hyperpigmentation that impacts a significant proportion of the global population.11–13 Melasma presents as brownish macules with uneven borders, symmetrically located on sun-exposed areas of the body, predominantly on the centrofacial areas of the forehead, cheeks, nose, philtrum, and chin.1–3,6,9,11,12,14–19 Melasma predominantly occurs in women with dark hair, brown eyes, and dark skin. Its prevalence reaches 75% in pregnant women and typically manifests throughout their reproductive years.20 A population-based study in 2010 reported pigmentation issues as a leading cause of skin treatment requests, affecting 23.6% of men and 29.9% of women.1 In Southeast Asia, 40% of women seek dermatological care for melasma, with a female-to- male ratio of 9:1 and onset occurring between the ages of 20 and 30. Individuals at a higher risk include those of reproductive age, pregnant individuals, and those with Fitzpatrick skin types III-IV.6,15,17

The pathogenesis of melasma is intricate, multifaceted, and not completely elucidated. Melasma results from dysregulation in melanogenesis, with contributing factors such as sun exposure, hormonal fluctuations during pregnancy, use of oral contraceptives and other steroids, hormone replacement therapy, photosensitizing cosmetics and medications, antiseizure therapy, and genetic predisposition.1,3,4,6,9,11,12,14,16,17,20–22 Melasma is also associated with vascular factors, inflammation, and skin barrier dysfunction.19 Histopathological studies have shown increased dermal vascularity, basement membrane disruption, higher melanocyte count, increased melanosome, solar elastosis, mild inflammatory cell infiltration, and greater melanin deposition in the dermis and/or epidermis of melasma-affected skin.3,9,20 Sun exposure is the primary catalyst for melasma, as it stimulates melanogenic activity, upregulating melanin synthesis and its transfer to keratinocytes, leading to increased eumelanin deposition in the epidermis.1,15,23

Melasma is diagnosed clinically. Wood's lamp examination can ascertain the distribution of melanin pigment in the dermis or epidermis to assess the type of melasma (epidermal, dermal, or mixed).20 Dermoscopic evaluation can assess the intensity of melanin pigmentation and the regularity of pigment network, which may suggest the location and density of melanin pigment deposition. It can also be utilized to evaluate the severity of melasma.1,20 The Melasma Area and Severity Index (MASI) and modified MASI (mMASI) score are standard scales for evaluating the extent and severity of facial melasma.1 In contrast, the Melasma Quality of Life scale (MELASQOL) assesses the impact of melasma on patients' quality of life.7

The management of melasma poses challenges for clinicians and patients. Supportive treatment often begins with avoiding sun exposure or applying sunscreen to mitigate disease progression.14,23 However, effective treatment necessitates active intervention. Numerous melanogenesis inhibitors have been developed, although many raise significant toxicity concerns and common skin adverse effects, including erythema, dry skin, irritation, desquamation, and hypopigmentation.8,15,24 Available treatment options for melasma include topical depigmenting agents, such as hydroquinone, kojic acid, glycolic acid, azelaic acid, retinoids, corticosteroids, arbutin, and niacinamide; oral therapies such as tranexamic acid, melatonin, cysteamine, and glutathione; chemical peels; and laser and light therapies.8,9,11,14,15,25 Current therapeutic approaches exhibit varying degrees of efficacy, leading to inconsistent and predominantly poor outcomes, varying side effects, and a significant recurrence rate post-therapy cessation.8,11,13,22,23,26

Platelet-Rich Plasma (PRP)

PRP is a biological product characterized by a small volume of autologous plasma with a platelet concentration three to seven times higher than that of whole blood2,16, achieved through centrifugation and platelet suspension.9,11,14,27 Typically, blood comprises approximately 94% red blood cells (RBCs), 6% platelets, and 1% white blood cells. PRP preparation alters the ratio of RBCs to platelets, resulting in a composition of 95% platelets and 5% RBCs.28 The optimal platelet concentration for effective PRP therapy in skin treatments is 1-1.5 million platelets/μL.10

Platelets are small cellular fragments derived from megakaryocytes and contain two types of storage granules: alpha granules and dense granules.10 Alpha granules are crucial for PRP therapy due to their high concentration of growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and fibroblast growth factor (FGF)10,15 which are instrumental in mediating various mechanisms such as cell differentiation, proliferation, and regeneration. Meanwhile, dense granules contain ADP, ATP, calcium, serotonin, and glutamate, which contribute significantly to the therapeutic benefits of this treatment.10 Within 10 minutes following PRP injection, 70% of the growth factors in alpha granules are secreted, with at least 95% released within one hour. For up to seven days, platelets continue producing and releasing supplementary growth factors.10,29

The clinical applications of PRP have expanded across multiple medical fields. PRP is frequently used in plastic surgery, particularly for treating chronic wounds, ulcers, and burns.30 PRP has emerged as a promising therapeutic method in aesthetic and dermatological medicine in recent years, demonstrating effective outcomes in wound healing, alopecia with or without scarring, skin rejuvenation, acne scars, and pigmentation disorders.3,10,15,16,27,28,30 Research indicates that PRP enhances skin quality and increases collagen and elastic fiber production, as it stimulates the proliferation of human dermal fibroblasts and boosts type I collagen synthesis.28 The ability to stimulate collagen synthesis, reduce recovery time, and yield lasting results renders PRP a compelling therapeutic alternative in cosmetic dermatology.31

PRP therapy exhibits an enhanced safety profile due to its autologous nature.10,14 Adverse effects of PRP are infrequent and minor, including localized pain, infection, skin discoloration, allergic reactions, and thrombus formation.25 Absolute contraindications include severe thrombocytopenia, platelet dysfunction, unstable

hemodynamics, sepsis, and localized infection at the injection site. Relative contraindications include NSAID administration within 48 hours preceding treatment, glucocorticoid injections within two weeks prior, recent illness or fever, cancer, anemia with hemoglobin below 10 g/dL, moderate thrombocytopenia, and tobacco use.10 Currently, there is no global consensus or standardized protocol for optimal PRP preparation.16,32 PRP preparation typically commences with the collection of 10 to 60 cc of venous blood, which is subsequently transferred into a tube containing dextrose citrate acid or sodium citrate to inhibit platelet activation, degranulation, and premature release of effector molecules. A first centrifugation separates the RBCs from the plasma, after which the yellow-colored plasma supernatant is extracted and subjected to a second centrifugation to isolate plasma rich in platelets and leukocytes from platelet-poor plasma. Following centrifugation, two-thirds of the supernatant plasma is discarded, and the remaining plasma containing a platelet pellet is classified as PRP. The final product typically has a platelet concentration of approximately 1 million/mL, two to eight times higher than whole

blood.15,27,29,32

PRP as a treatment option for melasma

PRP is an innovative treatment approach for melasma, with numerous case reports and studies have demonstrated its efficacy. Research indicates that PRP, whether used in combination with other treatments or as an independent therapy, is associated with notable clinical improvement in patients with melasma, leading to high patient satisfaction.15 Patients undergoing PRP treatment achieve a more balanced complexion and improved skin quality, including reduced wrinkles, enhanced elasticity, and increased moisture.9 Moreover, compared to other melasma therapies, PRP treatment results in fewer adverse effects and reduced pigmentation rebound.3,16,21,33

In 2014, Cayrili et al.30 reported the advantageous application of PRP as an alternative treatment for melasma, with over 80% reduction in epidermal hyperpigmentation in a patient with centrofacial melasma following three biweekly PRP sessions, with the initial objective of skin rejuvenation. Furthermore, no melasma recurrence was observed up to six months post-treatment. Yew et al.12 found that intralesional PRP as an adjunctive therapy reduced pigmentation in two cases of melasma unresponsive to conventional treatments. Administered over two sessions at four-week intervals, alongside monthly Q-switched Nd:YAG 1064 nm laser treatments and daily topical alpha arbutin, PRP was associated with a

reduction in mMASI scores. Garg et al.35 documented improvement in a case of recalcitrant melasma unresponsive to multiple treatments, including topical depigmentation agents (e.g., topical steroids, tretinoin, hydroquinone, kojic acid, and arbutin), oral tranexamic acid, and chemical peels. Six intradermal PRP sessions achieved clinical improvement and a lowered MASI score, with no recurrence over a three-month follow-up. Recent reports by Wulandari et al.18 and Shahraki et al.31 further indicated positive responses in melasma patients treated with microneedling-PRP characterized by brighter skin and significant reductions in brown patches. In other words, PRP can reduce pigmentation and revitalize the skin, enhancing the patient's overall appearance.

Sirithanabadeekul et al.9 conducted a randomized, split-face, placebo-controlled trial using PRP as an alternative treatment for melasma. Four sessions of intradermal PRP with two-weeks interval significantly improved melasma within six weeks, as evidenced by significantly lower mMASI score, decreased melanin levels, increased patient satisfaction, and reduced wrinkles. These findings are consistent with those of Tuknayat et al.21 and Rout et al.6, who observed significant melasma improvements following three intradermal PRP sessions at four-week intervals, with minimal side effects and no recurrence over a three-month follow-up. Rout et al.6 reported a 77% reduction in mMASI in mild melasma, a 52% reduction in moderate melasma, and a 50% reduction in severe melasma. The improvement of pigmentation depended on skin type, gender, and the type and pattern of melasma. In addition, patients experienced significant improvement in skin quality and reduced wrinkles.21 Similarly, González-Ojeda et al.3 reported that three intradermal PRP sessions at 15-day intervals resulted in a significant reduction in the intensity and extent of hyperpigmentation, as assessed by the MASI score, along with improvements in patients' self-perception and quality of life as measured by MELASQOL.

Hofny et al.11 documented the prospective therapeutic efficacy of PRP as an alternative treatment for melasma, employing two different techniques: microneedling with a dermapen and intradermal microinjection with microneedles. Both techniques resulted in notable improvements in melasma patients, as evidenced by a significant decrease in MASI and mMASI scores following three PRP sessions at four-week intervals. The findings are consistent with a randomized clinical trial by Boparai et al.26, which demonstrated improvements in melasma following three microneedling sessions with PRP administered every three weeks. No significant adverse effects or recurrence were observed up to 18 weeks post-treatment. A study

TABLE 1. Studies on the use of PRP for melasma treatment.

TABLE 1. Studies on the use of PRP for melasma treatment. (Continue)

TABLE 1. Studies on the use of PRP for melasma treatment. (Continue)

TABLE 1. Studies on the use of PRP for melasma treatment. (Continue)

by Panda et al.13 yielded comparable results, concluding that microneedling followed by topical application of PRP effectively treated melasma, leading to decreased MASI scores, higher patient satisfaction, and sustained MASI score reductions three months post-treatment.

Nada et al.36 conducted a case-control study comparing two melasma treatment approaches: topical hydroquinone (HQ) 2% administered for nine weeks and intradermal PRP administered in four sessions at three-week intervals. At week 13, the PRP group exhibited a mean MASI score reduction of 54.79%, whereas the HQ group demonstrated a reduction of 24.52%. This indicated that PRP may serve as a more alternative to standard melasma therapies. A split-face study by Rout et al.17 compared the efficacy of intradermal PRP administered biweekly over seven sessions with weekly 1064 nm Nd:YAG Qs laser treatment for 12 weeks in patients with mixed resistant melasma. The results showed significant pigmentation improvement and a lower relapse rate on the PRP-treated side three months post-treatment compared to the Nd-YAG Qs laser side. These findings suggested PRP may serve as a

primary and maintenance therapy for mixed-resistant melasma.

Recent studies indicate that PRP significantly outperforms tranexamic acid (TXA) in treating melasma, particularly in the long-term.4,14,23,33,37 This indicates PRP’s potential to surpass conventional therapies. According to Mumtaz et al.23, PRP demonstrated statistically significant outcomes by week 12. In split-face studies4,14, TXA 4 mg/ ml was administered intradermally on the right side of the face, while PRP was injected intradermally on the left side. After 12 weeks, a statistically significant reduction in mMASI scores was observed on both sides, but the percentage reduction was greater on the PRP side than the TXA side without notable side effects. Research comparing the benefits of microneedling combined with PRP and microneedling combined with TXA33 indicated that melasma patients receiving microneedling- PRP had superior improvement compared to those treated with microneedling-TXA. Consequently, without contraindications to PRP administration, PRP may be a practical option for treating melasma.

Bikash et al.38 and Tekam et al.39 evaluated the efficacy of PRP combined with HQ comparing it to the gold standard of HQ alone. It was concluded that the combination of microinjection/microneedling PRP with topical HQ 4% enhanced melasma treatment efficacy. Gamea et al.22 evaluated the effectiveness of topical TXA 5% versus its combination with intradermal PRP administered every three weeks for 12 weeks. Both groups exhibited a notable decrease in mMASI scores following therapy, leading to a recommendation of PRP as a safe adjunctive therapy to enhance the effectiveness of TXA in treating melasma. Tawanwongsri et al.5 evaluated the efficacy and safety of combined PRP and oral TXA against standalone PRP, finding that after 12 weeks, the improvement in mMASI scores was more significant in the group receiving three intradermal PRP sessions at four-week intervals alongside oral TXA at a dosage of 500mg/day for 12 weeks. No significant adverse effects were observed, except for mild and tolerable gastrointestinal symptoms. Zhang et al.40 confirmed that combining intradermal PRP and oral TXA can enhance therapy efficacy and reduce the risk of melasma recurrence for up to six months post-treatment. Adel et al.34 investigated the effectiveness of PRP injection alone administered over four sessions at two-week intervals and its combination with intense pulsed light (IPL) in patients with refractory melasma. A notable reduction in melasma scores was observed after six weeks of PRP treatment, although no statistically significant difference was identified between the two groups concerning mMASI scores and patient satisfaction.

Mechanisms of PRP action on melasma

PRP has shown notable potential as a treatment for melasma. However, the exact mechanism responsible for its therapeutic effects remains inadequately comprehended and is only tentatively hypothesized.6 The therapeutic efficacy of PRP relies on the premise that the degranulation of alpha granules following platelet activation results in the release of multiple growth factors, including EGF, TGF-β, and PDGF. These factors bind to specific receptors on various cells, initiating signal transduction pathways that lead to gene expression and the release of proteins involved in melanogenesis and tissue repair.2,11,16,21 Two primary processes underlying the effects of PRP on melasma include suppressing melanin synthesis facilitated by TGF-β1 and EGF and enhancing skin volume facilitated by PDGF.10,11,13,14

Transcriptional examination of skin samples from melasma patients revealed the upregulation of numerous genes associated with melanin formation, including

microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase related protein (TYRP).16 A randomized clinical trial by Hofny et al.2 reported a significant reduction in TGF-β protein expression in the skin lesions of melasma patients compared to healthy skin, potentially attributable to UV exposure, which is linked to the suppression or cessation of TGF-β production at transcriptional and translational levels. Conversely, PRP treatment can elevate TGF-β protein expression to levels nearly equivalent to those of healthy skin, correlating with significant clinical improvement. These findings indicate that alterations in TGF-β protein expression in the skin lesions of melasma patients corroborate its involvement in the pathogenesis of the disorder and possess therapeutic implications.

The TGF-β family regulates various cellular activities in the skin, including cell proliferation, differentiation, and melanogenesis.2,12 TGF-β is a critical growth factor for melasma treatment as it modulates melanocyte pigment synthesis.6,17 Prior research has demonstrated that TGF-β1 can limit melanin production by directly suppressing the expression of paired-box homeotic gene 3 (PAX3), which encodes a transcription factor crucial for melanocyte proliferation and/or survival, and by downregulating MITF, which is crucial for the transcriptional regulation of tyrosinase, TYRP1, and TYRP2.2,5,10,21,25 Conversely, another study revealed that TGF-β1 can reduce melanogenesis through delayed extracellular signal-regulated kinase (ERK) activation.5 TGF-β1 strongly inhibits the MITF promoter's transcriptional activity, thus decreasing MITF expression and consequently inhibiting tyrosinase gene transcription.2,10,15,17,30 The formation of eumelanin and reduction of pigmentation can be diminished by lowering the expression of tyrosinase and other enzymes involved in melanin biosynthesis.

Prior research has demonstrated that melasma is a melanocytic disorder and a photoaging skin disease. Ultraviolet exposure elevates the levels of MMP-2 and MMP-9, leading to the degradation of collagen types IV and VI in the skin and resulting in basement membrane damage, thereby facilitating the infiltration of melanocytes and melanin into the dermis.16 Consequently, conventional therapy targeting melanosome or melanocyte activity may prove inadequate for treating this condition. On the other hand, PRP induces a pigmentary lightening effect by promoting basement membrane repair facilitated by laminin, collagen IV, and tenascin, which are stimulated by TGF-β1 produced upon PRP activation, thereby inhibiting the migration of melanocytes and melanin into the dermis.5,10,11,13,16,22

EGF is widely used in cosmetic formulations for skin

lightening, wound healing, and reducing post-inflammatory hyperpigmentation from lasers or UV exposure.25 EGF can influence the activity of pro-inflammatory mediators released by damaged keratinocytes, such as prostaglandin-E2 (PGE2), which stimulates melanogenic activity in the skin by regulating melanocyte dendrite formation, proliferation, and tyrosinase expression. EGF can limit melanogenesis by suppressing PGE2 expression and activating the ERK pathway, thereby reducing tyrosinase enzyme activity and ultimately decreasing melanin synthesis.5,10,21,23 The improvement in pigmentation following PRP treatment is also attributed to increased skin volume induced by PDGF stimulation. PDGF plays a critical role in angiogenesis, collagen production, and the formation of extracellular matrix component, particularly hyaluronic acid, which enhances skin tone and volume, leading to a radiant complexion.5,10,11,16,21,25,30

The synergy of bioactive compounds present in PRP improves pigmentation in patients with melasma. PRP possesses bacteriostatic, anti-inflammatory, and reparative properties that rectify the aberrant hyperpigmentation metabolism associated with melasma.40 Growth factors, fibrin, and leukocytes present in PRP can modulate and restore the overall architecture of the skin layer, enhance skin barrier function, re-establish microcirculation, reduce hyperpigmentation, and stimulate collagen synthesis and epidermal regeneration to enhance skin quality and texture. They can also minimize the risk of re-pigmentation in the area.6,17,31,40 Thus, the therapeutic efficacy of PRP is thought to be associated with the restoration of aberrant pigment metabolism and numerous reparative actions that address compromised skin-barrier integrity, inflammation, and vascular alterations contributing to the etiology of melasma.

CONCLUSION

Platelet-rich plasma (PRP) is emerging as a promising and safe treatment option for melasma, potentially serving as either an adjunctive or alternative therapy. When used as a first-line treatment, PRP has shown the ability to significantly improve clinical outcomes and enhance skin quality, with minimal adverse effects and sustained results. Combining PRP with other melasma therapies may further reduce hyperpigmentation and increase patient satisfaction. However, individual responses to PRP can vary, and multiple sessions may be required to achieve optimal results. PRP’s mechanism of action is believed to involve the growth factors in alpha granules, which may suppress melanin production while promoting skin volume. Nevertheless, further research is needed to fully understand the efficacy of PRP in treating melasma.

Specifically, biomolecular studies and clinical trials are essential to determine optimal treatment protocols and assess the long-term safety and efficacy of PRP therapy.

Data Availability Statement

The data supporting the findings of this review are available within the article.

DECLARATION

Grants and Funding Information

No grants and funding were received for this review article.

Conflict of Interest

The authors have declared that there are no conflicts of interest.

Registration Number of Clinical Trial

None

Author Contributions

Conceptualized the study and wrote the main manuscript text, S.V.; Reviewed, revised, and approved the final manuscript, D.A.A.S.L. All authors have read and agreed to the final version of the manuscript.

Use of Artificial Intelligence

None

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