Systematic Reviews Open Access
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Dermatol. Feb 6, 2023; 11(2): 7-29
Published online Feb 6, 2023. doi: 10.5314/wjd.v11.i2.7
Systematic review of hematidrosis: Time for clinicians to recognize this entity
Gilbert Sterling Octavius, Fellisa Meliani, Rivaldo Steven Heriyanto, Theo Audi Yanto, Department of Medicine, Universitas Pelita Harapan, Tangerang 15811, Indonesia
ORCID number: Gilbert Sterling Octavius (0000-0002-6439-6265).
Author contributions: Octavius GS and Yanto TA did the conception of this research; Data collections and selections are done by Octavius GS, Heriyanto RS, and Meliani F; Octavius GS, Heriyanto RS, and Meliani F drafted the article while Yanto TA did critical revision of the article; Final approval of the version to be published was granted by all authors.
Conflict-of-interest statement: All the authors declare that they have no conflict of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gilbert Sterling Octavius, MD, MM, Doctor, Researcher, Department of Medicine, Universitas Pelita Harapan, MH Thamrin Boulevard 1100, Klp. Dua, Kec. Klp. Dua, Kota Tangerang, Banten, Tangerang 15811, Indonesia. sterlinggilbert613@hotmail.com
Received: August 22, 2022
Peer-review started: August 22, 2022
First decision: September 27, 2022
Revised: October 12, 2022
Accepted: November 29, 2022
Article in press: November 29, 2022
Published online: February 6, 2023

Abstract
BACKGROUND

Hematidrosis is a sporadic disease, to a point where its existence is still denied up to date. It is also linked to stigmata, psychological roots, and religious beliefs, whih has strengthened clinicians' disbelief in hematidrosis.

AIM

To conduct a thorough review to classify the likelihood of hematidrosis cases.

METHODS

We searched PubMed, Science Direct, Medline, and Google Scholar, as well as four different preprint databases, including Medrxiv, Research Square, SSRN, and Biorxiv. We included studies from 1996 onwards, with no limitation on language. Hematidrosis was classified as "unlikely", "likely", and "highly likely".

RESULTS

There are 74 articles with 106 hematidrosis cases. India (n = 40) and China (n = 11) report the most cases. Patients are mostly female (76.5%) with a median age of 13 years. The head region is the most common bleeding site (n = 168/254). Headaches (26.9%) and abdominal pain (16.4%) are the most common prodromes. Beta-blockers (43%) and anxiolytic (23.2%) are the most commonly prescribed pharmacotherapy. Psychotherapy (37.5%) and counseling (32.5%) are the most utilized non-pharmacotherapy measures. Only 41.1% and 19.8% of all cases reach complete resolution and are highly likely to be hematidrosis, respectively.

CONCLUSION

Although hematidrosis is rare and the pathophysiology is still largely unknown, that does not mean hematidrosis does not exist. It is important to note that the most frequent trigger factors are either anxiety, fear, or excessive stress. Clinicians need to exclude other diagnoses and search for stressors to alleviate the bleeding.

Key Words: Hematidrosis, Bloody sweat, Stigmata, Blood

Core Tip: This is a systematic review on hematidrosis, an entity that is still mostly unknown, even to the experts. While this is not a guide to diagnose hematidrosis, this systematic review will help clinicians understand hematidrosis, the clinical pictures, the current available treatment, as well as the next steps in hematidrosis research.



INTRODUCTION

The first case of hematidrosis dates back to the 3rd century B.C., where the first two treatizes by Aristotle contained sweat mixed with blood[1]. In the Bible, it is mentioned that these symptoms were written during Jesus Christ's sufferings in the garden of Gethsemane (Luke 22:44)[2,3]. Hematidrosis is an eccrine sweat disorder where sweat mixed with blood appear spontaneously without any visible trauma to the skin appendages. It is a diagnosis of exclusion[3]. Under International Classification of Disease 10 (ICD 10) in 2016, hematidrosis is given a diagnosis code of L74.8 under "other eccrine sweat disorders". However, this disease entity is still not widely accepted as a "true pathological disease" for various reasons[2,3].

Initially, the very existence of hematidrosis is questioned up to date. The mythical perception about hematidrosis creates a stigma where the bleeding is more related to pious beliefs than a genuine medical condition[4]. Another contributing factor is that a previous review on hematidrosis was done by Holoubek and Holoubek in 1996, encompassing 76 hematidrosis cases[5]. However, this review has been criticized for reporting the cases without laboratory confirmation[3,5]. Lastly, Favaloro & Lippi[6] mention some factors contributing to the plausible deniability of hematidrosis. Those explanations include the rarity of the disease, the possibility of Munchausen's syndrome (or Munchausen's by proxy), stress and its consequence on self-inflicted injuries, little scientific evidence that hematidrosis is an entity, and most reports are from older literature, in a foreign language, published in non-haematology journals, and there is a lack of publications in high-quality journals[6].

Several authors have attempted to conduct a literature review or systematic review on this topic[2,3,7]. However, the reviews do not present a comprehensive search, do not specify in which journals the articles were published, and more importantly, do not define what constitutes a hematidrosis. Therefore, we conduct a more thorough systematic review about hematidrosis, with a classification of the likelihood of hematidrosis cases in each journal. This review shall guide clinicians in identifying what hematidrosis is, how it presents, the necessary laboratory or radiology tests needed, as well as the treatments.

MATERIALS AND METHODS
Eligibility criteria

The Preferred Reporting Items for Systematic Review (PRISMA) 2020 guidance was used[8]. The protocol of this review was registered on the International Prospective Register of Systematic Reviews (PROSPERO) database with a registration number CRD42021289372.

The subjects studied were all patients diagnosed with hematidrosis without any age limitations. The diagnosis of hematidrosis is determined by the respective authors, and we classified the diagnosis as "unlikely", "likely", or "highly likely". A patient was considered to have “highly likely” hematidrosis if: (1) The bleeding episode was witnessed directly by medical professionals, (2) attempts were made to exclude other possible diagnoses, (3) skin biopsies and bleeding analysis were done and found to be normal or inconclusive, and (4) bleeding photos were included in the article; while a patient was determined to have “unlikely” hematidrosis if: (1) The bleeding episode was not witnessed by medical professionals or from family members, (2) minimal or no tests were done to exclude hematidrosis (only routine blood work was done), (3) other disorders possibly explain the bleeding, and (4) no bleeding photos were provided. Lastly, a hematidrosis case was classified as “likely” if it did not satisfy all the highly likely or unlikely criteria.

This review's inclusion criteria are any original articles published after 1996 without any restrictions in language. We restricted the year for literature search to ensure that studies that had been reviewed by Holoubek & Holoubek were not included[5]. We also included grey literature such as conference abstracts, thesis, or dissertations. The exclusion criteria of this study are reviews, opinion-based articles (letter to the editors or commentary), bleeding caused by other disorders, pure hemolacria, and animal studies. Citations from review studies were combed to ensure literature saturation. In order to guarantee that all available studies were included, we conducted citation and hand searches manually and via Research Gate.

Search strategy and study selection

The literature search started on December 6, 2021 and ended on the same day. We searched four different academic databases, including PubMed, Science Direct, Medline, and Google Scholar, and four different preprint databases, including Medrxiv, Research Square, SSRN, and Biorxiv. The keywords used were "hematidrosis", "hematohidrosis", and "bloody sweat". The Medical Subject Heading (MeSH) terms for each database are listed in Table 1. All records were imported into the Rayyan software, where duplicates were detected automatically and screened manually[9]. This software also allowed authors to collaborate in selecting the relevant studies. Two independent authors conducted the initial search (GSO and RSH), importing all the findings into Rayyan software. Another author (FM) cross-checked the initial searches. These three authors independently screened all available studies. Conflicts were resolved by discussion with the expert (TAY). In the case of studies with overlapping publications (abstracts later published into a full paper), we chose studies that provided more data.

Table 1 Medical subject heading terms used in each database.
Database
Medical subject heading
Number of studies found
PubMed“hematidrosis”[All Fields] OR (“haematohidrosis”[All Fields] OR “hematohidrosis”[All Fields]) OR (“bloody”[All Fields] AND (“tearings”[All Fields] OR “tears”[MeSH Terms] OR “tears”[All Fields] OR “tearing”[All Fields] OR “lacrimal apparatus diseases”[MeSH Terms] OR (“lacrimal”[All Fields] AND “apparatus”[All Fields] AND “diseases”[All Fields]) OR “lacrimal apparatus diseases”[All Fields] OR “lacerations”[MeSH Terms] OR “lacerations”[All Fields])) OR (“bloody”[All Fields] AND (“sweat”[MeSH Terms] OR “sweat”[All Fields] OR “sweating”[MeSH Terms] OR “sweating”[All Fields] OR “sweats”[All Fields] OR “sweatings”[All Fields])) OR “hemolacria”[All Fields]203
Medline((hemathidrosis) OR haematohidrosis) OR bloody sweat1057
Google Scholarallintitle: hematidrosis OR haematohidrosis OR bloody sweat55
Science Direct(Hematidrosis) OR (haematohidrosis) OR (bloody sweat)200
MedRxiv(Hematidrosis) OR (haematohidrosis) OR (bloody sweat)367
BioRxiv(Hematidrosis) OR (haematohidrosis) OR (bloody sweat)839
SSRN(Hematidrosis) OR (haematohidrosis) OR (bloody sweat)0
Research Square(Hematidrosis) OR (haematohidrosis) OR (bloody sweat)134
Data extraction and quality assessment

Data extraction was carried out independently by two authors (FM and RSH), then reviewed by another author (GSO) to ensure accuracy. We extracted relevant information such as study identification (author and year of publication), study characteristics (location and article type), and patients' characteristics (number of patients, age, sex, underlying conditions, characteristics of bleeding, laboratory and radiological examinations, therapies, and outcome).

The Joanna Briggs Institute (JBI) checklist for case reports and case series were used to assess their quality, respectively[10]. Three reviewers (GSO, FM, and RSH) independently assessed the scale, and any discrepancies were sorted with the expert (TAY) until a consensus was attained. If any missing data or further data were needed, corresponding authors were contacted via an inquiry email.

Data synthesis

To incorporate all of the data in this review, pooled descriptive tests were employed. The mean and standard deviation of data reported in median and range (or interquartile range) were calculated[11-13]. The means and standard deviations were then combined into a single value using the Cochrane method[14].

RESULTS

The initial search yielded 2955 articles, where 188 articles were immediately excluded as duplicates. After title and abstract screening, 2692 articles were excluded. Out of the 75 articles assessed for eligibility, three articles did not have full texts[15-17], three articles were review articles[18], one article mentioned other causes of the bleeding[19], and four articles were purely hemolacria[20-22]. These articles were then excluded, resulting in 68 articles[7,23-28]. We found another six articles through hand-searching and citation searching[29-34]. In total, there are 74 articles included in this review, with a total of 106 patients (Figure 1 and Table 1).

Figure 1
Figure 1 PRISMA flowchart for selection of included studies.

Most of the cases are heavily concentrated in Asia, particularly India (n = 40/106) and China (n = 11/106). Australia only reports one case of hematidrosis, the least among other continents (Figure 2). Patients presented with the disease as early as an hour or as late as seven years before consulting to doctors. Anxiety, stress, and fear are the most common trigger for bleeding, while psychiatric disorders are the most common comorbidities in most patients. Notably, 36 cases (34%) do not have any obvious bleeding triggers. Besides bleeding from the skin, patients may also present with hematuria, gastrointestinal (GI) bleed (hematemesis, melena, hematochezia or rectal bleed), or epistaxis. Patients may bleed as frequently as more than 35 times a day or as rare as two times in two years. Most bleeding episodes subside in a few seconds to a few minutes, although in one case, the bleeding stops after 30 min (Table 2).

Figure 2
Figure 2 Worldwide distribution of 106 hematidrosis cases from 74 articles.
Table 2 Characteristics of hematidrosis patients.
Ref.
Patient No.
Time from onset to consultation
Triggers of bleeding
Other kinds of bleeding
Comorbidities
Bleeding frequency
Bleeding duration
Other Bleeding characteristics
Octavius et al[70], 2021 #1One monthNot mentionedNot mentionedNot mentionedThree times per dayStopped immediatelyNot mentioned
#2One monthNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned Not mentioned
Bhattacharya et al[42], 2013 #1One monthNot mentionedNot mentionedNot mentioned> 10 times per dayNot mentionedNot mentioned
Manonukul et al[43], 2008 #11.5 yr agoNot mentionedNot mentionedNot mentionedRecurrent episodesNot mentionedNot mentioned
Murota et al[45], 2020#1A few monthsExcess pressure exerted while playing on the metal barNot mentionedNot mentionedNot mentionedNot mentionedIt did not occur during sleeping
Das et al[89], 2020 #1Two weeksHead traumaNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned
#2One hourAnxiety symptomsAnxiety
Matsuoka et al[36], 2020#1Two yearsNot mentionedNot mentionedDissociative disorder and self-harmingFew times per weekNot mentionedBloody sweat-like fluid secretion
Chabchoub et al[49], 2013 #16 mauNot mentionedNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned
Shafique et al[38], 2021#13 moNot mentionedRectal bleedSignificant psychosocial stress due to parental separation3-35 times per dayNot mentionedOccurred during sleep and wakefulness
Carvalho et al[35], 2008#1November 2004Physical exertion, increase in room temperatureNot mentionedNot mentionedNot mentionedNot mentioned Ceased spontaneously
Rossio et al[32], 2014#1Not mentionedHis family was experiencing an extremely stressful time, and his mother had just passed awayNot mentionedNot mentionedNot mentioned1-2 minNo predetermined time for recurrence
Gayal et al[90], 2020#1Six monthsHearing voices and anxietyNot mentionedSchizophrenia1-2 or 10-15 times per dayNot mentionedDepending on the intensity of psychotic symptoms
Dragan et al[91], 2017 #1Not mentionedNot mentionedEpistaxis, hemoptysisTonsillectomy, benign hypertensionNot mentionedNot mentionedNot mentioned
Alsermani et al[23], 2018#1Five monthsBullying in schoolsNot mentionedCeliac diseaseTwice weekly1-2 minSelf-limited, usually in the evening
Jayaraman et al[92], 2017#1Seven daysScolding from parents due to academic performanceNot mentionedMixed anxiety & depressive disorders, nocturnal enuresis1-2 a day3-5 minAppears when punished or stressed
Jibbawi et al[33], 2021#1Not mentionedEmotional stressNot mentionedNot mentionedNot mentionedNot mentionedAppears during stress and self-limited
Arakkal et al[24], 2016#15 mauExtreme physical exertionNot mentionedNot mentionedNot mentioned2-3 minBleeding when waking up, extreme physical activities, self-limited
Corrà et al[93], 2020#1Five yearsStress, anxious situation, exerciseNot mentionedThe peripheral visual deficit, non-hemorrhagic chronic gastritis, severe intestinal subocclusionFive times dailyFew minutesSelf-limited
Mishra[72], 2009#1Not mentionedMinor traumaHematuria, gastrointestinal bleed, epistaxisPlatelet function (PF3) dysfunctionNot mentionedNot mentionedNot mentioned
Mutanabbi et al[29], 2021 #14 mauStressHematemesis, hematuria, epistaxisNot mentioned1-2 a week3-5 minCeased spontaneously, precipitated by upcoming stress & family issues
Soliman et al[61], 2019#1Six monthsNot mentionedNot mentionedHypotension, tachycardia, syncopeNot mentioned30 secondsNever at sleep and self-remitting
Tshifularo[94], 2013 #1Not mentionedSevere mental stresses at work, study, and homeNot mentionedNot mentioned2-3 a week every 3-4 mo15-20 min2-5 ml blood-stained non-clotting discharge
#2Two yearsSevere stressFour times in 2 years (2009-2010)Not mentionedBlood-stained sweaty discharge, not clotting and watery
#3Not mentionedStressTwo times in 2 years (2010-2011)Not mentionedPainless blood-stained sweat-like discharge
#4Not mentionedSevere stress at school and home1st episode at July 2013Not mentionedNot mentioned
Meyer et al[95], 2019#1Two daysStumbled and fell on an iron toy train (trauma)Not mentionedNot mentionedAlmost dailyN/ASelf-limiting, episodic. Bleeding occurred from apparently healthy and undamaged skin; no superficial injuries
Techasatian et al[81], 2016#1April 2014Not mentionedNot mentionedNot mentioned> 10 times10-30 secondsThe time of the bleeding episode was unpredictable, not related to exertion or triggers
Yeşilova et al[96], 2016#12 dMove from cold to a warm environment, fallen out of bed (trauma) one day beforeNot mentionedNot mentioned20 times in 2 dNot mentionedNot mentioned
Quentric et al[97], 2019#1Not mentionedGeneral anxiety related to schoolEpistaxis, nipple bleedNot mentioned3-4 times a dayNot mentionedSpontaneously, mostly at night
Mora et al[98], 2013#16 moStressNot mentionedNot mentionedSeveral times a dayNot mentionedSpontaneous, self-limited, >30 episodes during hospitalization
Praveen et al[99], 2012#13 moStress (She had witnessed her elder sister being kidnapped nine months ago)EpistaxisNot mentioned2-3 times every week and had two episodes on the same day on four occasionsNot mentionedNot mentioned
Hansson et al[7], 2019#1Four weeksNot mentionedNot mentionedNot mentioned20 episodes in 4 weeksNot mentionedNot mentioned
Wang et al[44], 2014#1One monthNot mentionedNot mentionedNot mentioned2-3 times a dayNot mentionedThe bleed is described as a fresh, small amount of blood
Jerajani et al[41], 2009#1Two monthsContinuous mental stressNot mentionedDepressive disorderNot mentionedNot mentionedNot mentioned
Lipsitt et al[100], 2018#19 moExtreme emotional stress, excitement, or physical exertionNot mentionedDepression, anxiety, PTSD, non-epileptiform seizureSeven times a dayNot mentionedProgressive, episodic
Bhagwat et al[101], 2009#1Two yearsTrauma (witnessing a woman beheaded), Feeling anxiousNoneSevere depression1-2 a day15-20 minEpisodic
Sue Tin et al[40], 2015 #1Three weeksNo obvious triggerNot mentionedNot mentioned20 times a dayNot mentionedSpontaneous, worse during warmer months
Pari[102], 2018#1Five daysWithout any provoking factorNot mentionedNot mentioned2-3 a day30 minNot mentioned
Patel et al[79], 2010#1Sincmaury 2007Not mentionedNot mentionedNot mentionedOnce-daily1 minuteSpontaenous, during school hours 9-11 am
Biswas et al[76], 2013 #1Two yearsNot mentionedNot mentionedAn intelligent quotient (IQ) of 60-70 with a loss of insight1-2x daily10-15 minEpisodic, more frequent when waking up in the morning
Jafar et al[69], 2016 #1Two weeksNot mentionedEpistaxisRepeated faint attacks two years agoNot mentioned10-20 minIt was spontaneous, unpredictable, and intermittent, with no specific patterns, and it stopped spontaneously.
Wang et al[103], 2010 #13 yrEmotional excitementNot mentionedNot mentioned> 20 times during hospitalizationNot mentionedIt always occurred during the middle of the day, never when sleeping at night
Thigarajan[83], 2019#1Three daysStress fr’m father's demand on academicsNot mentionedPrimary enuresis, head tonsure, and trivial head trauma in a different location to the bleedNot mentionedFew seconds to a few minutesSelf-limited
Khalid et al[82], 2013 #1Five yearsEmotional stressNoneNoneNot mentionedNot mentionedNot mentioned
Maglie et al[104], 2017 #1Three yearsNot mentionedNot mentionedMajor depressive disorder and panic disorderNot mentioned1-5 minCould occur in sleep or during physical activity & more intense bleeding occurs during emotional stress
Uber et al[71], 2015#16 yrNot mentionedNot mentionedConversion, dissociative, and generalized anxiety disorder, high peak blood pressureNot mentionedFew minutesSpontaneous, sometimes occur during sleep, coincidental with high blood pressure peak
Salas-Alanis et al[37], 2021#1Not mentionedAcute emotional distressNot mentionedNot mentionedNumerous3-25 minFrom 6 years old, all following emotional distress
Talwar et al[80], 2021#1One yearSeparation from his auntEpistaxis, hematuria, hematocheziaAdjustment disorderOnce per weekA few minutesIt can occur during sleep
Chowdhury et al[105], 2019#1Two yearsMigraineEpistaxis, previous cesarean scar, menorrhagiaMigraineNot mentionedNot mentionedAssociated with headache, her son also had hematidrosis
Das et al[89], 2016#15 moNot mentionedNoneOtitis externaNot mentionedNot mentionedMore frequent on 06:00 A.M.
Hossain et al[77], 2018 #1One and a half yearsNot mentionedNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned
#2Last two monthsNot mentionedNot mentionedRepeated episodes of stiffening of limbs with associated self-mutteringNot mentionedNot mentionedNot mentioned
#3Six monthsNot mentionedNot mentionedAcute anxiety state, repeated episodes of unresponsiveness and conduct disorderNot mentionedNot mentionedNot mentioned
Thao et al[39], 2019 #1One monthMarriageNot mentionedContinuous mental stressNot mentionedNot mentionedNot mentioned
Récher[31], 2021#1Not mentionedCOVID-19 containment induced stressNot mentionedNot mentionedNot mentionedNot mentionedA vascular pathway remains after 24 hours of bleeding
Omar[30], 2018 #1Not mentionedStressNot mentionedNot mentionedOccured in boutsNot mentionedNot mentioned
Tirthani et al[86], 2021 #1Three monthsLoss of parentsNot mentionedRecurrent panic attacks with tachycardiaNot mentioned2-3 minNot mentioned
Ricci et al[106], 2018 #1Three monthsMajor stressful event from an earthquakeNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned
Bezner et al[25], 2013#1Two yearsNot mentionedHematuriaHeavy and irregular menstrual bleedUp to 20 dailyNot mentionedThe bleeding episodesreportedly decreased during her menstrual period, which typically lasted for approximately ten days
Mahamat Abderraman et al[50], 2019 #1Five years agoNot mentionedHistory of hematuria, epistaxis,Moderate anxiety-depressive disorder, acute urine retention, seizure, genu flexumNot mentioned10 minNot mentioned
Rharrabti et al[51], 2016#1Not mentionedFamily abuse, parental conflictsVulvar bleedingConversion disorder. primary enuresisNot mentionedNot mentionedMostly at day, worsening during parental conflicts
Morillo et al[52], 2019 #1Seven monthsNot mentionedNot mentionedBronchial asthma, previous history of abortionNot mentionedNot mentionedNot mentioned
Kumar et al[78], 2021#1Not mentionedAfraid, stress (during exams), anxietyNot mentionedHigh-grade anxietyNot mentionedNot mentionedSpontaneous and recurrent (4-5 times in three days)
Camargo et al[53], 2020 #1Four yearsStress and anxietyHematuriaNot mentioned2-3 times a weekNot mentionedSporadic occurrence
Shen et al[107], 2015 #1Six monthsNot mentionedNot mentionedTonic seizures1x every few days1-2 minSpontaneous, transient, self-limited
Shahriari et al[108], 2020 #1Six monthsGoing to the toilet or feeling lonelyNot mentionedNot mentionedEvery two weeksNot mentionedNot mentioned
#2Not mentionedNot mentioned EpistaxisNot mentionedEvery three weeksNot mentionedNot mentioned
#3Not mentionedFighting with her younger sister without any skin damageNot mentionedA history of aggressionNot mentionedNot mentionedNot mentioned
Badry et al[27], 2020 #1One monthStressHematemesisDepression3-5 per weekA few minutesNot mentioned
Hoover et al[54], 2019#1Almost more than seven years Illness (malaria) or distressHematemesis, hematochezia, hematuriaPrevious history of treated malaria, human immunodeficiency virus(HIV) and hepatitis B due to blood transfusionsNot mentionedNot mentionedNot mentioned
#2Not mentionedIrritability and cryingNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned
Latorre Martinez et al[109], 2012#1One yearStressNot mentionedNot mentionedNot mentionedA few minutesNot mentioned
Kleymenova et al[47], 20201#1Not mentionedWeather, stressEpistaxisMenstruation problemsNot mentionedNot mentionedNot mentioned
Rani et al[84], 2018 #1Not mentionedAutonomic dysfunctionHematuriaAutonomic dysfunctionNot mentionedNot mentionedNot mentioned
#2Autonomic dysfunctionNot mentionedSpontaneous skin breaches resembling incision
#3Emotional & Psychological stressorsNot mentionedNot mentioned
#4Emotional & Psychological stressorsNot mentionedNot mentioned
#5Emotional & Psychological stressorsNot mentionedNot mentioned
#6Emotional & Psychological stressorsNot mentionedNot mentioned
Wang et al[110], 2021#1One yearNot mentionedNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned
#2Four monthsNot mentionedHematemesisNot mentionedOnce every few days to dozens of times a daySeveral minutesNot mentioned
#3Five monthsCarsicknessHematuriaCanker soresUp to 60 times a daySeveral minutesNot mentioned
#4Nine monthsAnxiety or nervousness, hemolacria induced by intense lightHematemesis, hematuriaTonic-clonic seizuresOnce every few days to dozens of times a daySeveral minutesNot mentioned
#5Two monthsNot mentionedNot mentionedNot mentionedOnce every few days to dozens of times a daySeveral minutesNot mentioned
#6Four yearsMilitary training, minor emotional stress, or even during studyingNot mentionedNot mentionedOnce every few days to dozens of times a daySeveral minutesNot mentioned
#7Six monthsNot mentionedNot mentionedNot mentionedOnce every few days to dozens of times a daySeveral minutesNot mentioned
Malik et al[34], 2019 #16-8 yrEmotional stressHistory of hemolacriaGestational hypertension (after lost to follow up)Not mentionedNot mentionedBleeding started 6-8 years ago
#2Not mentionedPeriods of rage and stressEpistaxisNot mentionedNot mentionedNot mentionedUnprovoked, self-limited, and not triggered
Shahgholi[75], 2018 #1Several monthsExtreme physical or emotional stressHematemesisNot mentionedOnce or twice a day10-15 minSometimes occurred spontaneously during sleep, subsided as soon as it is wiped
#2Not mentionedUpcoming exam, playing a computer game, watching fiction TV movies or when parents not satisfying his demandsNot mentionedNot mentionedNot mentionedNot mentionedNot mentioned
#3Not mentionedNot mentionedNot mentionedNot mentionedNot mentioned5 minSpontaneous, unpredictable, and intermittent
Jagannathan et al[111], 2016 #1Not mentionedMental stressEpistaxisNot mentionedNot mentionedNot mentionedNot mentioned
#2Not mentioned
#3Not mentioned
#4Not mentioned
#5Not mentioned
#6Not mentioned
#7Not mentioned
#8Hematemesis
Agarwal et al[28], 2017 #1One monthNot mentionedNot mentionedNot mentionedNot mentioned10 secondsSelf-limited, during the day
Deshpande et al[112], 2014#1Since February 2013 (around more than one year ago)Upcoming exams, fight with parents, and parents not satisfying his demandsHemoptysis, hematuria, epistaxis, hematochezia, hematemesisOppositional defiant disorderNot mentionedNot mentionedNot mentioned
Zhang et al[16], 2004#1Four monthsNot mentionedHematemesisA previous diagnosis of Henoch-schonlein purpuraSeveral times a day or once every 3-5 dLasts secondsThe bleeding can occur during sleep
Kumar et al[78], 2019#1One year agoSuspected fear and anxiety of his lecturer Not mentionedNot mentionedThree episodes per day to 20 episodes per monthNot mentionedNot mentioned
#2Three months agoFearful dreamsNot mentionedNot mentioned> 5 episodes per dayNot mentionedEpisodes are not coinciding with dreams but occur after the event at night without any triggering factor in the day times as observed by parents at home and the hospital
Karpukhina et al[48], 2020#1One month agoNot mentionedEpistaxisHigh anxiety, neurotic behaviour, and depressionNot mentionedA few minutesNot mentioned

The majority of the patients are females (76.5%), with a median age of 13 (0.17-72) years old (Table 3). When patients experience prodrome(s) before the bleed, they mostly report headache (26.9%) or abdominal pain (16.4%). Most articles were published in 2019 (n = 15/74), followed by 2021 (n = 10/74) (Figure 3). When analyzed by the category of the journals, most hematidrosis cases are published in dermatology journals (25.7%), followed by internal medicine journals (23.0%) and pediatric journals (20.3%).

Figure 3
Figure 3 The number of cases is based on the year of publication. Note that no studies were found to be published between 2005-2007 and 2011. There is one study published in 2004 and two studies in 2010.
Table 3 Demographics of patients with hematidrosis.
Variables
N (%)
Sex (n = 102)
Male 24 (23.5)
Female78 (76.5)
Age in years (n = 94) (Median - range)13 (0.17-72)
Prodromes1
Headache18 (26.9)
Dizziness3 (4.5)
Abdominal pain11 (16.4)
Nausea4 (6.0)
Vomiting4 (6.0)
Tingling5 (7.5)
Photophobia2 (3.0)
Phonophobia2 (3.0)
Pain3 (4.5)
Soreness4 (6.0)
Asthenia3 (4.5)
Easily irritable2 (3.0)
Others6 (8.7)
Presence of hemolacria34 (32.1)
Types of journals
Case report4 (5.4)
Dermatology19 (25.7)
Otorhinolaryngology4 (5.4)
General or internal medicine17 (23.0)
Hematology and oncology9 (12.2)
Pediatric (including pediatric hematology and oncology)15 (20.3)
Pharmacy1 (1.3)
Preprint (Research Square)1 (1.3)
Psychiatry3 (4.1)
Reproductive health1 (1.3)
Healthcare professionals witness the bleeding episodes
Yes 69 (65.1)
No25 (23.6)
Not explicitly mentioned12 (11.3)
Family members witness the bleeding episodes
Yes 50 (47.2)
No6 (5.6)
Not explicitly mentioned50 (47.2)
Provided bleeding pictures85 (80.2)
Laboratory tests done100 (94.3)
Radiologic and/or other tests done41 (38.7)
Normal results from all the diagnostic tests done92 (86.8)
Skin biopsies done30 (28.3)
Normal or non-specific19 (63.3)
Analyzed the blood from the bleeding site71 (67.0)
Doctors involved in the case1
Otolaryngologist25 (16.6)
Ophthalmologist6 (4)
Obstetrics and gynaecologist3 (2)
Psychiatrist29 (19.3)
Primary care4 (2.7)
Pediatrics31 (20.5)
Internal medicine19 (12.8)
Dermatologist25 (16.6)
Vascular surgeon1 (0.7)
Neurologist7 (4.8)
Tried to exclude other diagnoses90 (84.9)
Pharmacotherapy2
Beta-blockers65 (43.0)
Anxiolytic35 (23.2)
Antidepressants10 (6.6)
Atropine patches2 (1.3)
Drops of adrenaline with gauze1 (0.7)
Ascorbic acids6 (4.0)
Antifibrinolytic agents2 (1.3)
Antihistamine receptor blockers6 (4.0)
Hemostatics2 (1.3)
Others22 (14.6)
Psychosocial therapy2
Psychotherapy15 (37.5)
Behavioural therapy6 (15)
Relaxation technique6 (15)
Counseling13 (32.5)
Outcome (n = 90)
Complete resolution37 (41.1)
Time taken for complete resolution in days (median) (n = 26)60 (2-730)
Improvement of symptoms37 (41.1)
Time taken for improvement of symptoms in days (median) (n = 19)28 (10-720)
Relapse8 (8.9)
Time taken for relapse in days (mean) (n = 6)60 (53.4)
Spontaneous resolution4 (4.4)
The patient is still under follow up1 (1.1)
Loss to follow up3 (3.3)
Possibilities of hematidrosis
Highly likely21 (19.8)
Likely58 (54.7)
Unlikely27 (25.5)

Out of all the body regions, the head region is the most commonly affected (n = 168/254), especially around the ears or earlobes (n = 46), forehead (n = 24), and nose (n = 23). The next most common site is in the upper limbs (n = 31/254), with the arms being the most common site of bleeding in this region (n = 14). Although most cases do not state the laterality of bleeding (n = 81), more cases are bilateral (n = 15), as compared to being unilateral bleeding (n = 10) (Figure 4).

Figure 4
Figure 4 Characteristics of bleeding sites. The head region is the most commonly affected (n = 168/254), especially around the ears or earlobes (n = 46), forehead (n = 24), and nose (n = 23). The next most common site is in the upper limbs (n = 31/254), with the arms being the most common site of bleeding in this region (n = 14). Although most cases do not state the laterality of bleeding (n = 81), more cases are bilateral (n = 15), as compared to being unilateral bleeding (n = 10).

The bleeding episodes are mostly witnessed by healthcare professionals (65.1%). In the case of family members witnessing the bleeding episode, 50 cases (47.2%) are witnessed directly, and another 50 cases (47.2%) are not explicitly mentioned. The majority of the cases provide bleeding pictures (80.2%). Laboratory tests and radiologic or other tests are done in 94.3% and 38.7% cases, respectively, resulting in a normal result in 86.8% of the cases. An analysis of the bleed is done in 67.0% of cases, generally resulting in the discovery of peripheral blood components. There are many doctors from different specialities involved in the care of hematidrosis patients, with paediatricians (20.5%), psychiatrists (19.3%), dermatologists, and otolaryngologists (both at 16.6%) being the most common specialities consulted.

Skin biopsies, the "best reference standard", is only done in 28.3% of cases, with 63.3% of them being normal or non-specific. Among skin biopsies that have been done, abnormal findings include dilation of blood vessels with extravasation of blood[35-39], possible mild squamous hyperplasia and mild dermal fibrosis[40], papillary dermal edema[41,42] with dermal melanophages[41], bloody exudate from areas that do not contain sweat glands[43,44], a low number of gross cystic disease fluid protein 15-positive eccrine sweat glands[45], loosening areas caused by the separation of collagen fibres[43], and acanthosis of the epidermis with broadening of rete pegs along with hypergranulosis and marked hyperkeratosis[42].

The most common pharmacologic therapy used is beta-blockers (43.0%), with anxiolytic the second (23.2%). Among the non-pharmacologic modality, psychotherapy (37.5%) and counseling (32.5%) are the most common therapies prescribed. Most patients experienced complete resolution (41.1%) in 60 d (2-730 d), as well as an improvement of bleeding symptoms (41.1%) in 28 d (10-720 d).

Among all the 106 cases, the majority of cases belong to the "likely" group with 58 cases (54.7%), followed by "unlikely" with 27 cases (25.5%). Only 21 cases (19.8%) are considered "highly likely" to be hematidrosis.

DISCUSSION

This systematic review contains 74 articles with 106 hematidrosis cases. We included more articles and cases compared to the other reviews and adjusting to their search timeline[2,3,7]. Hand-searching, citation searching, and including grey literature in our reviews certainly add more cases to our study. Although there has been some scepticism in including grey literature into a review, a proper systematic review shall be thorough during article searching, including finding grey literature[46]. Including the 76 cases from Holoubek and Holoubek's review[5] and our cases, there are currently 182 hematidrosis cases in the world.

Favaloro & Lippi's[6] arguments that most cases are outdated and presented in a foreign language are not valid anymore. Although some articles are written in Chinese[16,44] Russian[47,48], French[49-51], Spanish[52], and Portuguese[53], the majority of the articles are written in English language. Since the publications are mostly less than ten years old, we argue that the cases presented here are quite recent. Almost half of the articles were published in the years of 2019-2021. There is one study where the article was published in 2019, but on the website, the article is presented as if it was published in 2021. Therefore, we classify the study as published in 2019[54]. However, we believe that there is still a significant number of cases not published in a "high-quality journal" and thus may affect clinicians' perspectives on the eligibility of these cases[55]. Reflecting on the types of journal specialities, most cases are published in dermatology, pediatric, or internal medicine journals. Only 12.2% of the cases are published in a hematology journal. This point supports Favalaro & Lippi's argument about lacking publication in a high-profile hematology journal[6].

Most of the cases originate from China and India, the top two most populous countries globally. Although it seems convenient to link the connection between the majority of the cases belonging to the top two countries with the most population, the United States of America (USA) only reports three cases. Therefore, genetic, socio-cultural, race or environmental factors might play a role[56]. Lastly, publication bias may play a role in determining which cases get published[57]. Due to the rarity of the cases, many clinicians, even the most senior ones, may not encounter a hematidrosis case. Therefore, there is a lack of quality peer-reviewers who understand this case. This problem is confounded because many clinicians still doubt this disease entity[6].

The median age of patients with hematidrosis is 13 years, which is consistent with previous review findings of 9-15 years[3]. In this systematic review, 76.5% of the patients are females, while the most common trigger for hematidrosis is anxiety, fear, or mental illness. The connection between mental illnesses being more common in females[58-60] has been established and might explain the higher prevalence among these populations. In this study, the bleeding characteristics vary significantly. Some patients experienced bleeding episodes during sleep[38], while others never experienced bleeding during sleeping[45,61]. In some cases, patients usually bleed during the day or evening[23,28]. These patterns may reflect the physiological state of sympathetic nervous systems and hormonal fluctuations and their impacts on blood vessels and the pathophysiology of hematidrosis[62-64].

The head is the most common bleeding site, while headaches are the most common prodrome symptom. Spontaneous extracranial hemorrhagic phenomena may be caused by trigemino-autonomic reflex and sterile neurogenic inflammation[65]. Neural activation may also explain the prodromes of dizziness, nausea and vomiting, tingling, pain, photophobia, and phonophobia. Epistaxis is a frequent accompanying bleeding manifestation and may result from activating the trigeminovascular system and subsequent vasodilation of Kiesselbach's plexus[66]. Abdominal pain is the second most common prodrome. While certainly, the cause of abdominal pain is a multitude of etiologies, a case was reported in which bleeding from distant sites preceded by abdominal migraine[67]. Activation of selected nerves and release of neuropeptide and neurotransmitters may facilitate haemorrhage remote from the site of pain[68].

The pathophysiology of bleeding in other areas is still unknown. The blood seeps into the sweat ducts due to vasculopathies in the dermal vasculature and enhanced sympathetic activation due to acute stress and anxiety, resulting in periglandular vascular constriction and subsequent expansion[69,70]. Multiple blood veins arranged in a net-like structure surrounding the sweat glands. These vessels are thought to contract and then widen to the point of rupture when they are under much stress. The blood now travels to the sweat glands, which are pushed to the surface and manifested as blood droplets mixed with sweat[70,71]. These pathways explain why patients who suffer from anxiety, high blood pressure, or elevated sympathetic nervous system tone suffer from hematidrosis more frequently[71]. However, none of the biopsy results mention any vasculitis and this pathophysiology needs to be confirmed. The pathophysiology mentioned also does not explain the common co-occurrence of hemolacria, GI bleed, and hematuria. While there is a case of PF3 dysfunction[72], other patients do not have any hematological abnormalities after extensive workups. In the past, hematidrosis was thought to be caused by infections such as Chromobacterium prodigiosum and Micrococcus castellani[73]. One author also tested for the presence of these bacteria in their case report, although they did not find any chromogenic bacteria[38]. Figure 5 presents a complete postulated pathophysiological pathway of hematidrosis.

Figure 5
Figure 5 Postulated pathophysiology of hematidrosis. There are several hypotheses in hematidrosis pathophysiology. The vasculitis in the dermal vessels, exacerbated by sympathetic activation related to extreme stress and anxiety, leads to periglandular vessel constriction, and subsequent expansion, allowing the blood content to seep into the sweat ducts. Another theory states that multiple blood vessels around the sweat glands are arranged in a net-like form. It is believed that under tremendous stress, the vessels contract. Once anxiety passes, the blood vessels dilate to the point of rupture. The blood, at this point, goes into the sweat glands, which push the blood to the surface and manifests as droplets of blood mixed with sweat. RBCs: Red blood cells.

Cutaneous manifestation of Munchausen syndrome or other factitious bleeding related to stigmata usually presents in areas within reach of the arms of the patients (legs, arms, anterior part of the body, and face). These episodes always occur alone and is never witnessed by family members or general practitioners[74]. Therefore, when 34.9% and 52.8% of cases are not witnessed or explicitly mentioned to be witnessed by healthcare professionals and family members, respectively, the diagnosis of hematidrosis becomes weaker. It is important to note that family members as a witness have a lower strength of proof compared to being directly witnessed by healthcare professionals such as doctors, nurses, or residents. Munchausen syndrome cases by proxy where the parents smear their blood to their children to mimic hematidrosis[18].

Analysis of the exudate is done to ensure that the reddish or pinkish liquid contains blood components[75]. Some authors add benzidine test[32,41,53,76-82], hemochromogen test[39], chloride test[83], or blood group matching[84] in order to ensure that the blood is likely from the patient. However, as stated above, even though the presence of blood is confirmed via observation of red blood cells and other peripheral blood components under the microscope, the blood does not necessarily belong to the patient, even when matched by their blood group. Therefore, we propose that a skin biopsy needs further studies to be the "gold standard" to exclude other skin pathologies before safely confirming that a patient has hematidrosis[43]. However, a biopsy needs to be taken immediately during or after bleeding episodes. When the biopsy is taken any later, the results may be insignificant or even normal[43]. This means that patients need to be admitted just for the biopsy procedures. Clinicians need to weigh the unnecessary risks of hospitalization and added fear and stress against the need for a confirmatory procedure that may add little value to the diagnosis.

The wide involvement of specialists indicates that clinicians are initially perplexed by this condition. Multicollaboration among specialists is needed to exclude other causes of bleeding before diagnosing a patient with hematidrosis. The majority of the cases presented in this review tried to exclude other diagnoses before jumping into diagnosing hematidrosis. The full differential diagnosis of hematidrosis is presented in Table 4.

Table 4 Differential diagnosis of hematidrosis.
Hematologic disorders (Bezner et al[25], 2013; Peretz et al[68], 2016)
Acquired disorder of hemostatic mechanism
A hereditary disorder of hemostatic mechanism
Infection (Jirka, 1968; Peretz et al[68], 2016)
Chromobacterium prodigiosum
Micrococcus castellani
Disorders of vascular integrity (Bezner et al[25], 2013; Peretz et al[68], 2016)
Vasculitis
Amyloidosis
Connective tissue disorders
Gynecologic disorders (Bezner et al[25], 2013)
Ectopic endometriosis
Pathologic processes causing an acute increase in intracranial pressure
Cerebral venous thrombosis
Subarachnoid hemorrhage
Valsalva maneuver
Drugs (Girolami et al[74], 2014; Peretz et al[68], 2016)
Antiplatelets such as non-steroidal anti-inflammatory drugs
Anticoagulants
Glucocorticoids
Antidepressants (e.g. selective serotonin reuptake inhibitors)
Antiepiletics (e.g. topiramate)
Antibiotics
Chemotherapeutic agents
Intoxication with lysergic acid diethylamide (LSD)
Herbal supplement (e.g. Gingko Biloba)
Trauma (Meyer et al[95], 2019; Peretz et al[68], 2016; Rani et al[84], 2018; Yeşilova et al[96], 2017; Zhang et al[16], 2004)
Sleep disorders (parasomnia) (Peretz et al[68], 2016)
Psychiatric disorders (Bezner et al[25], 2013; Karpukhina et al[48], 2020; Peretz et al[68], 2016)
Factitious disorder/factitious disorder by proxy
Psychogenic purpura
"Artistic bleeding"
Religious stigmata or culture-bound phenomenon (Bezner et al[25], 2013; Girolami et al[74], 2014)
Sweat gland disorders (e.g. chromhidrosis) (Jerajani et al[41], 2009)

The most effective treatment seems to be a combination of pharmacologic and non-pharmacologic therapies. Beta-blockers and anxiolytics are the most commonly used pharmacotherapies in concordance with the postulated pathophysiology. However, other therapeutic modalities such as tap-water iontophoresis[45], inosine[44], aluminium chloride hexahydrate[85], and oxybutynin[86] are also used with mixed results. The wide range of therapies indicates that the optimal route, timing, and dosage of therapy is still largely unknown. For example, while atropine transdermal patches may be an effective treatment, certain bleeding locations such as the eyes or vaginal bleeding will exclude this treatment modality[40,76]. When a patient has underlying anxiety or fear, a psychiatrist should be consulted to give appropriate psychosocial therapy[87]. Only 41.1% of patients are fully resolved from bleeding episodes. This emphasizes that the current treatment is still not effective in managing hematidrosis. Clinicians are encouraged to educate and communicate about the aetiology and nature of the disease, emphasizing that this is not a stigma or a "shame" to suffer from hematidrosis. Underlying psychiatric disorders need to be addressed as well.

Shahgholi et al[75] also attempt at establishing hematidrosis diagnostic criteria. We agree on health professionals witnessing the bleeding episode to exclude psychiatric causes. However, Shahgholi et al[75] mentioned blood analysis as one of their criteria. We opt for skin biopsies as they are the "gold standard" for diagnosis, however more confirmatory studies need to be done before skin biopsies can be considered the “gold standard” for hematidrosis. Blood analysis can be plagued by some issues mentioned above. The last criteria by Shahgholi et al[75] are summarised in our criteria as the authors tried to exclude other possible diagnoses. This is imperative as hematidrosis is currently a diagnosis of exclusion. However, to be categorized as "highly likely" as hematidrosis, we also encouraged authors to include the bleeding pictures in the publication. This criterion is usually unable to be met by abstract or poster publications[84]. Our criteria serve only as guidance to consider hematidrosis as a plausible diagnosis and not as a confirmatory guideline.

Our review has some limitations. We could not confirm the true nature of hematidrosis in each case due to limited presentations in some of the articles. Therefore, we judged each case with the best available information. None of the contacted authors replied. Secondly, we could only postulate some associations, theories, and hypotheses between each finding without any causal confirmation. A cohort study with a standardized protocol will help determine the nature, progression, and treatment of hematidrosis. The exclusion of three articles without access to the full article is another limitation. However, those three articles are from China screened from their abstracts, they are unlikely to alter our review's findings significantly. Lastly, we do not include pure hemolacria cases in our review because pure hemolacria has its own sets of causes[88]. Therefore, including pure hemolacria in this review will cause heterogeneity.

Despite the limitations, our review is the most up-to-date with the most comprehensive literature search compared to other reviews[7,16,23-25,27-39,40-45,47,48,49-54,61,69-72,75-78,79-84,86,89-112]. Including articles in any language, combined with grey literature, citation searching, and hand searching, ensured that all available articles were included. We present clinical, diagnostic, and other socio-demographic findings that will help clinicians identify hematidrosis.

The future direction in diagnosing hematidrosis is currently evolving. Manonukul et al[43] performed electron microscopy and immunoperoxidase studies with normal results on both. Salas-Alanis et al[37] performed a genetic analysis and found that 91.5% of the variants are missense variants. The pathogenic variants were found in genes related to the extracellular matrix. These examinations will help us better understand the pathophysiology of hematidrosis.

CONCLUSION

Hematidrosis is a rare disorder with an increasing number of cases. This disease is more common in Asia and young females with underlying anxiety, fear, stress, or depression. The head region is the most common bleeding site, and some patients may experience prodromal symptoms such as headache and abdominal pain. An important note to take is that hematidrosis might be accompanied by other kinds of bleeding episodes such as hemolacria, GI bleeding, and epistaxis. The diagnosis is primarily on exclusion after ensuring that all the other diagnostic tests are normal. The most common treatment modality is a combination of pharmacologic (beta-blockers and anxiolytics) and non-pharmacologic (psychotherapy and counselling).

Although hematidrosis is rare and the pathophysiology is still largely unknown, that does not mean hematidrosis does not exist. It can bring severe panic towards parents or family members who care for these patients. Communication about the disease entity is imperative. A statement by Chambers perfectly surmmarized the rarity of hematidrosis "And as a rule, too, the more common the ailment, the more useful it is for you to hear about it"[113].

ARTICLE HIGHLIGHTS
Research background

Hematidrosis is a largely unknown entity, even to professional doctors.

Research motivation

In order to bridge the underlying knowledge deficit about hematidrosis, an updated systematic review is conducted.

Research objectives

We aim to conduct a systematic review of hematidrosis and identify the clinical characteristics, laboratory findings, as well as treatments given so far.

Research methods

We conducted a systematic search on eight different databases with no restrictions on the timeline using the English language.

Research results

There are 74 articles with 106 hematidrosis cases with India and China contributing the most cases. Patients are mostly females aged around 13 years. Bleeding occur most in the head region while beta-blockers and anxiolytics are the most frequent treatment given.

Research conclusions

Hematidrosis exists, and it is up to clinical researchers to further dissect this entity so that physicians can give better treatment in the future.

Research perspectives

More controlled skin biopsies and genetic studies with prospective follow-up or case-control studies may be needed to elucidate further and deepen our understanding of the pathophysiology and treatment of this disease.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Dermatology

Country/Territory of origin: Indonesia

Peer-review report’s scientific quality classification

Grade A (Excellent): A

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Shalaby MN, Egypt; Sofou EI, Greece S-Editor: Liu JH L-Editor: Ma JY P-Editor: Liu JH

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