Semin Thromb Hemost 2024; 50(01): 119-129
DOI: 10.1055/s-0043-1768937
Letter to the Editor

Hematohidrosis in 15th Century Renaissance Art and a Review of Modern Literature

Shyer Wern Goh
1   Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
,
Wen Hon Darren Wee
1   Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
,
Wen Xin Rachel Chua
1   Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
,
Bingwen Eugene Fan
1   Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2   Department of Haematology, Tan Tock Seng Hospital, Singapore, Singapore
3   Department of Laboratory Medicine, Khoo Teck Puat Hospital, Singapore, Singapore
4   Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
› Author Affiliations

Hematohidrosis, or hematidrosis, is a rare medical condition characterized by blood oozing from the intact skin in the absence of a bleeding problem.[1] Prior to modern-day medical literature, these phenomena had been captured in Renaissance and also present-day artwork. While the purpose of medical literature is to aid healthcare professionals and patients in the better understanding and treatment of disease, a significant proportion of Renaissance art commissioned by the church depicted scenes from the Bible, for the purposes of a visual depiction of key events to promote teachings of the faith, and to encourage devotion to God.

We explored the theme of hematohidrosis in historic art and performed a rapid review of modern medical literature, noting that the earliest works featuring hematohidrosis were depictions in Renaissance art as early as the 15th century. The German painter known as Meister Der Freisinger Passion (Master of the Freising Passion) depicts Jesus Christ in the Garden of Gethsemane at the foot of the Mount of Olives, sweating drops of blood ([Fig. 1]). Around him, his disciples sit, fast asleep. Another piece given the same name, the Christus am Ölberg, is featured in one of the frescoes of the Tabernakelbildstock in Welsberg-Taisten (Wayside Shrine of Tesido; [Fig. 2]). Believed to have been painted by Wolfgang Sauber in the 1460s, it depicts Christ with his hands clasped together in prayer as bloody sweat dots his forehead. These two artworks provide visual testimony to Luke's account of the Gospel of Jesus Christ praying in the Garden of Gethsemane before crucifixion. The motif of the cup is featured in the two artworks, echoing Christ's words in Luke 22:42, “Father, if you are willing, remove this cup from me. Nevertheless, not My will, but Yours, be done.” The cup is a symbol of the cup of God's wrath that Jesus takes upon Himself, as He takes on the sins of the nations. In the words of preacher Charles Spurgeon, “at one tremendous draught of love, He drank damnation dry.” Luke tells us that “being in agony, He prayed more earnestly; and His sweat became like great drops of blood falling down to the ground” (Luke 22:45). This was likely the first documented case report of hematohidrosis in the existing literature. Given Luke's background as a physician, this could possibly explain his attention to medical detail that is otherwise not reported in the other Gospels. In an era where the lay people were largely illiterate and printed Bibles were not largely available till the advent of Johannes Gutenberg's printing press in 1440, religious art was crucial in passing on teachings of the faith, and in encouraging reflection on Biblical events and devotion to God.

Zoom Image
Fig. 1 Christus am Ölberg, Christ on the Mount of Olives; Meister der Freisinger Passion. (© Bayerische Staatsgemäldesammlungen [Creative Commons; CC BY-SA 4.0); http://www.sammlung.pinakothek.de/en/artwork/02LAvw3Gyk)
Zoom Image
Fig. 2 Tabernakelbildstock in Taisten. Christus am Ölberg, Wolfgang Sauber. (© Bayerische Staatsgemäldesammlungen [Creative Commons; CC BY-SA 4.0); https://commons.wikimedia.org/wiki/File%3ATaisten-Tabernakelbildstock_04.jpg)

Despite its rarity, several cases of hematohidrosis have been reported globally and reviewed in the literature in recent years. We performed a search for “hematohidrosis,” “haematohidrosis,” “hematidrosis,” or “haematidrosis” in PubMed for articles published up to January 2023. We excluded cases with chromhidrosis, a rare condition with a presentation of the secretion of colored sweat secondary to dyes, drugs, chromogenic bacteria, fungi, and chemical contactants. Cases of hemolacria (presence of blood in tears), as well as mucosal bleeding (i.e., bleeding from the nose, tongue, or intestinal bleeding), as a single, exclusive site of bleeding were excluded, as these surfaces do not contain sweat glands. Cases presenting only with otorrhagia (bleeding from the ear) were also excluded.

Our preliminary search results comprised 64 articles, of which 42 were included; these yielded 4 case series and 38 case reports with the earliest report from 1918, with most of the cases published in 2008 to 2023 ([Table 1]). A total of 22 articles were excluded, of which 11 articles were in non-English languages, 7 were literature reviews without new case reports, 1 report was on a dog, 1 was a patient with Henoch Schonlein purpura presenting with bloody sweats, 1 was a sole presentation of hemolacria, and 1 article presented four cases of otorrhagia. In total, 48 cases of hematohidrosis were identified from the 42 articles; these comprised predominantly of females (38; 79.2%), with a median age of 12 years, with a trend toward younger patients, with the youngest patient being 2 months, with the majority of patients (41; 81.4%) being younger than 21 years ([Table 2]). A significant proportion of cases originated in India and more specifically in Asia, with few cases from Europe and North America, which was a trend also observed by Kluger.[2] There seems to be increasing literature on hematohidrosis (given the tempo of case reports published) as noted by Duffin,[3] when comparing articles published between 1880 and 1935, and 1952 and 2016. As compared with 76 cases analyzed by Holoubek and Holoubek in 1996 (many of which were from before the 20th century)[4] and 25 cases by Kluger[2] in 2017 and 28 peer-reviewed cases by Duffin[3] in 2017, Carrion-Alvarez et al[5] identified 60 cases; however, this review included cases of trichorrhage (bleeding from hair follicles) and hemolacria. This could be attributed to a true increase in incidence of the condition, or an increase in the recognition or reporting of such cases. As hematohidrosis can be considered a somatization disorder, social and cultural background can also play a part in its occurrence or reporting. In addition, skepticism around its very existence may hinder publication in Western literature.[6] A total of 32 (66.7%) cases were able to identify a triggering event—including a stressful or emotionally stimulating event, or head trauma. Three cases experienced head trauma prior to the bleeding event (cases 24, 33, and 34). Two cases experienced hematohidrosis during exertion (cases 35 and 48). Case 32 identified pressure to the palm by a metal bar as a precipitating factor for hematohidrosis on the palm. Emotional stress seems to be a common precipitating factor among the majority of the cases. A large proportion of cases were precipitated by acute emotional events (e.g., witnessed beheading of a woman, acute emotional distress, or by longer-term emotional stress such as separation from loved ones, bullying, and unemployment). This is consistent with Luke's account where Christ's sweat became like great drops of blood as He prepared Himself for his crucifixion. Jesus Christ also bore similar baseline characteristics to cases of hematohidrosis assessed by modern literature—presenting at the age of 33 years, and with no documented medical history or family history of bleeding disorders. Of interest, 8 (16.7%) cases originate from the Middle East, as did Christ (cases 10, 17, 20, 23, 25, 26, 27, and 42).

Table 1

Patients with hematohidrosis (listed by chronological age of publication)

Case

Country of origin

Sex

Age

Triggering event

Past medical history

Presentation

Treatment

Outcome

Mechanism

Biopsy

Publish date

Author

1

England

F

11

Frightened by gas explosion in neighboring house a week before bleeding began

Premature born child

Bleeding from forehead. Frothy sweats, often secreted rapidly that it seemed to issue in a fine jet and could be heard upon the bedclothes.Prodrome of “sick feeling” in epigastrium

May 1918

Scott[14]

2

Brazil

F

9

Post strenuous exercise and prolonged exposure to heat

3 episodes witnessed by medical staff of erythematous secretions noted on upper lip 30 min after ambient temperature was raised

No treatment

Spontaneous improvement after ambient temperature reduced

Minor fistula between small blood vessels and sweat glands

Small, congested periglandular capillaries with no obvious red blood cell extravasation

January 2008

Carvalho et al[7]

3

Thailand

F

14

None

No

Episodes of prodromal body soreness followed by bloody secretions on the palms, soles, scalp, arms, legs, and trunk for 1.5 y

Lorazepam

Cessation of bleeding

Stress-induced vasoconstriction leading to vascular rupture and blood extravasation

Focal collection of red blood cells in follicular lumens near the orifices

Inconspicuous loosening areas caused by separation of collagen fibers, containing fibrin and red blood cells scattered in dermis, especially near hair follicles

April 2008

Manonukul et al[13]

4

India

F

12

Witnessed beheading of woman in village

No

Prodromal sensation of a tingling sensationBright red secretions from the forehead and umbilical region

Tricyclic antidepressants

Reduced frequency and severity of episodes

May 2009

Bhagwat et al[8]

5

India

M

72

Emotional stress due to family

Depressive disorder

Bloodstains on undergarmentsNo eyewitness accounts of bleeding

No treatment

Spontaneous cessation of bleeding

Sympathetic mediated constriction followed by dilation causing periglandular vessel rupture and extravasation of blood into sweat glands

Normal skin biopsy

July 2009

Jerajani et al[9]

6

India

F

13

None

PF3 dysfunction

Bleeding from gums, hematuria, gastrointestinal bleeding

Sympathetic mediated constriction followed by dilation causing periglandular vessel rupture and extravasation of blood into sweat glands

September 2009

Mishra[15]

7

India

M

13

None

Self-resolving 1-min episodes of daily blood sweats (arms, trunk, ear)

Alprazolam, 20% aluminum hexahydrate in alcohol.Alternate therapy including breathing exercises

Alprazolam and aluminum hexahydrate were ineffective. Patient reported reduction in episodes with the alternate therapy

Dermal stromal weakness

July 2010

Patel and Mahajan[16]

8

China

F

13

Emotional excitement or spontaneously

Bleeding from tongue, subungual area, palms, feet, thighs, trunk, forehead skin

Vitamin CCarbazochrome sodium sulfonateDiazepamPropranolol

Cessation of bleeding with propranolol

Sympathetic nervous system related

Normal sweat glands containing no blood, unobstructed blood capillaries, some minor blood extravasation from capillaries, areas of loosening of tissue in dermis

December 2010

Wang et al[17]

9

India

F

10

Stress from examinations

3-mo history of recurrent hemolacria, hematohidrosis, and epistaxis, there was a prodrome of soreness at areas that would sweat blood (forehead, ear, neck umbilicus)

Propranolol, lorazepam

Lorazepam was stopped due to side effects, reduced episodes with propranolol

Sympathetic mediated constriction followed by dilation causing periglandular vessel rupture and extravasation of blood into sweat glands

January 2012

Praveen and Vincent[18]

10

Saudi Arabia

F

18

High stress

6-mo history of intense headache with abdominal pain followed by mucocutaneous bleeding from the nose, lacrimal ducts, forehead, hands, nails, navel

Beta-blockers

Reduction in frequency

Defects in the dermis create blood-filled spaces that exude onto skin surface

Normal skin biopsy

February 2013

Mora and Lucas[19]

11

Pakistan

F

35

Crying during emotional outburst, voluntarily

5 y of bleeding from eyes and ears

Propranolol

Psychotherapy

Improvement without cure

April 2013

Khalid et al[20]

12

India

F

12

None

No

1-mo episode of skin bleeding from face, limb, palm, sole

Diazepam

Propranolol

No response to diazepam.

Episodes stopped following 6-d treatment with propranolol with no further recurrence

Irregular acanthosis of epidermis with broadening of rete pegs along with hypergranulosis and marked hyperkeratosis with edema or superficial dermis.No abnormality in sweat or sebaceous gland

July 15, 2013

Bhattacharya et al[21]

13

India

F

12

None

2 y of bleeding from intact skin over forehead, scalp, cheek, nose, and trunk

Atropine transdermal patch

Cessation of bleeding

Sympathetic mediated constriction followed by dilation causing periglandular vessel rupture and extravasation of blood into sweat glands

Normal skin biopsy

November 2013

Biswas et al[22]

14

India

M

10

None

Oppositional defiant disorder

Bleeding from navel, eyes, ears, and nose

Lorazepam

Propranolol

Cessation of bleeding

Sympathetic mediated constriction followed by dilation causing periglandular vessel rupture and extravasation of blood into sweat glands

July 2014

Deshpande et al[23]

15

China

F

9

Recurred during incident following physical fight with another girl

Epilepsy

6-mo history of diffuse bloody sweat sometimes preceded by white frothing from tongue and umbilicus. Episodes were followed immediately by headaches and abdominal pain. Some episodes were also followed by epileptic tonic seizures

Diazepam and propranolol followed by oxcarbazepine

Diazepam and propranolol were ineffective. Oxcarbazepine prevented relapse

Sympathetic mediated pathology

Normal skin biopsy

April 2015

Shen et al[24]

16

Brazil

F

18

None

Conversion, dissociative, and generalized anxiety disorders

6-y history of spontaneous bleeding from dorsum and palms of hands, forehead, and tear ducts.

Coincided with high blood pressure peaks (180–90)

Atenolol

Cessation of episodes, with sporadic return on irregular consumption of meds

Sympathetic mediated pathology

Normal skin biopsy

December 2015

Uber et al[25]

17

Kuwait

F

12

None

Menarche at 10 y old, regular for 4 mo, stopped for 2 y then returned spontaneously

2 wk of bleeding from left side of face, left eye, and tear duct

Stress-induced constriction, dilation, and rupture of blood vessels around sweat glands

March 2016

Jafar and Ahmad[26]

18

Thailand

M

9

None

Multiple episodes of short self-resolving bloody sweats across the scalp, palms, cheeks, arms, and legs

No treatment

Spontaneous resolution

Sympathetic mediated pathology

Normal skin biopsy

August 2016

Techasatian et al[27]

19

India

F

10

Fought with classmate and was punished

Mixed anxiety and depressive disorder

Bloody secretion from scalp for 1 wk

Imipramine and clonazepam for mixed anxiety and depressive disorder.

Taught relaxation exercises

Reduction in frequency and stopped completely

Normal skin biopsy

January 2017

Jayaraman et al[28]

20

Turkey

F

11

Head trauma the day prior

Bleeding on right side of forehead

Topical adrenaline

Cessation of bleeding

Trauma causing ruptured periglandular vessels to leak blood into eccrine gland

February 2017

Yeşilova et al[29]

21

Italy

F

21

None

Major depressive disorder, panic disorder

3-y history of self-limited blood sweats from palms and face. Associated with symptoms in line with depressive disorder and panic disorder

Paroxetine

Clozapine

Propranolol

Propranolol led to reduction in episodes

Abnormal periglandular sympathetic constriction followed by dilation leading to exudation of blood into eccrine glands

October 2017

Maglie and Caproni[30]

22

Italy

F

15

None

Major stressful experience of Abruzzo earthquake 9 y earlier

3-mo history of mucocutaneous bleeding.

Sometimes preceded by headaches and asthenia

Propranolol

Cessation of bleeding

February 2018

Ricci et al[31]

23

Saudi Arabia

F

9

Bullied in school

Bloody secretions from skin, scalp, ear, mouth, eyes twice weekly

Propranolol

Cessation of bleeding

Constriction, dilation, and rupture of blood vessels mediated by sympathetic nervous system.

Defects in dermis causing stromal weakness, communicating with vascular spaces in dermis

April 2018

Alsermani et al[1]

24

Iran

F

11

Extreme emotional stress

Prodromal abdominal pain, vomiting and headache.

Frothy, bloody secretions from forehead, eyes, ears, nails, arm, umbilicus, back, vagina, GIT

Psychotherapy

Propranolol

Reduced frequency and severity of episodes

Intensified sympathetic activation leading to constriction and dilation of blood vessels, and subsequent rupture.

Dermal vasculitis and defects in the dermis, due to stromal weakness

November 2018

Shahgholi[32]

25

Iran

M

8

Upcoming exam, playing computer games, watching fiction TV movies, parents not satisfying demands

Painless spontaneous bloody secretions from nail beds of hands and feet

No treatment

Spontaneously resolved without intervention

26

Iran

F

9

None

Bloody nonviscous secretions from ear lobes, nose, and eyes

Propranolol

Resolution of episodes

Constriction and rupture of blood vessels under stress

27

India

F

10

None

5 d of bleeding from forehead and chest

No treatment

No further bleeding

May 2019

Pari[33]

28

Sweden

M

9

None

Bloody sweat from head and neck with headache.

Headache was reported to shift locations and was hypersensitive to light and sound.

There was a reported prodrome of paresthesia at areas that would bleed

Propranolol

Reduction in episodes

Sympathetic stimulation of vessels causing constriction leads to blood extravasation

June 2019

Hansson et al[34]

29

Germany

F

10

Emotional and general distress.

Recent head trauma

Prodrome of headache followed by spontaneous bloody secretion from right forehead

Psychiatric support

Ineffective

November 2019

Meyer et al[35]

30

India

F

15

Head trauma

2-wk history of bleeding from ears and nose with hemolacria

Anxiolytics

Propranolol

Reduction in episodes

Sympathetic mediated constriction followed by dilation causing periglandular vessel rupture and extravasation of blood into sweat glands

Normal skin biopsy

January 2020

Das et al[36]

31

India

F

13

Anxiety

Bleeding from face, forearms and shoulders with hemolacria

Anxiolytics

Propranolol

Cessation of bleeding

Sympathetic mediated constriction followed by dilation causing periglandular vessel rupture and extravasation of blood into sweat glands

Normal skin biopsy

32

Japan

F

6

Pressure to palm while playing with horizontal bar or spontaneously with no identifiable trigger

Bloody aqueous secretions from palm

Tap water iontophoresis

Cessation of bleeding

Atrophy and low number of gross cystic disease fluid protein-15-positive eccrine sweat glands. Increased CD-43-positive cells around eccrine sweat glands

February 2020

Murota et al[37]

33

Japan

F

11

None

Dissociative disorder and self-harm

Bloody secretion from forehead, hands, feet, scalp associated with pain

Propranolol

Cessation of bleeding

Blood vessel rupture around sweat glands

No obvious abnormalities apart from microvessels adjacent to sweat glands

August 2020

Matsuoka and Tanaka[38]

34

India

F

15

Stress, anxiety, exercise

AD optical atrophy

5-y history of average 5 episodes daily of bloody secretion from mouth.

4 concomitant episodes of hemolacria reported

Propranolol and psychological counseling

Reduction in daily episodes from 5 to 0–2

Adrenaline-induced constriction of periglandular vessels, followed by an exacerbated dilatation which allows blood to fill the eccrine ducts

November 2020

Corrà et al[39]

35

French

F

22

During intense physical exertion.

Reported considerable stress during COVID-19 pandemic containment period

Bleeding from forehead.

A vascular pathway appeared to remain apparent for 24 h

No treatment

No further bleeding

November 2020

Récher[40]

36

Mexico

M

22

Acute emotional distress

Episodes of bloody secretion from the head associated with pain and hemolacria since 6 y of age

Anxiolytics

Propranolol

Ineffective

Genetic mutations related to ECM function and development that affects vessel integrity and formation, and in coagulation events

Histological examination showed capillary dilation, associated with vascular congestion and slight extravasation of blood

March 2021

Salas-Alanis et al[41]

37

Africa

M

9

None

Malaria, HIV, hepatitis B

Bleeding from eyes, gums, axillae, umbilicus, intermittent hematochezia, hematemesis, hematuria.

Began when developed malaria but continued despite completing treatment for malaria

Propranolol

Vitamin C supplementation

Oxymetazoline

Natural tears

Reduction in frequency

Blood vessels around sweat gland constrict under pressure induced by exogenous stressor, then dilate to point of rupture and extravasation of blood

Intradermal bleeding and obstructed capillaries.No abnormalities in sweat glands, hair follicles, and sebaceous glands.Multiple blood-filled spaces in dermis opening directly into follicular canals or skin surface

March 2021

Hoover et al[42]

38

Africa

F

2 mo

None

Sister to above boy.

Mother's sibling passed away due to unidentified bleeding complication

Spontaneous bleeding from eyelids, ears, hairline

Propranolol

Improvement with reduced frequency and duration of bleeding

39

India

F

13

None

Recurrent panic attacks with tachycardia

Bloody secretions from her nose and palmar creases for the past 3 mo

Anxiety disorder already being treated with propranolol, valproic acid, and sertraline.

Oxybutynin

Cessation of condition

Possible defects in dermis causing stromal weakness that communicated with vascular spaces. Blood exuded via follicular channels or directly onto skin surface

July 2021

Tirthani et al[43]

40

USA

F

10

Psychosocial stress due to recent separation of parents

3-mo history of episodic blood-like discharge from all over the body

Propranolol

Cognitive behavioral therapy

Resolution of episodes with no recurrence

Constriction of blood vessels around sweat glands, followed by a rapid dilation and rupture, causing extravasation of blood into the sweat glands

Defects in dermis that intermittently fill with blood and exude contents to skin surface

September 2021

Shafique et al[44]

41

India

M

12

Adjustment disorder due to separation from aunt

Adjustment disorder due to separation from aunt

Blood-stained tears, epistaxis and bleeding from ear and mouth.

Burning sensation, irritation, redness of eyes before bleeding.

One episode of hematuria and hematochezia

Psychiatric therapy.

Propranolol

Complete recovery

Blood vessels around sweat glands constrict in response to stress, then dilate to the point of rupture.

Dermal defects causing stromal weakness, communicating with vascular spaces that exude blood onto skin surface

November 2021

Talwar et al[45]

42

Saudi Arabia

F

20

None

Menorrhagia few months, fibroadenoma 6 mo, neurological symptoms, sinus tachycardia

Gum bleeding, mild ear bleeding, epistaxis for 4 mo

Propranolol

Reduction in frequency of episodes

High vascular pressure causing blood to pass into ducts of sweat glands.

Dermal vessel vasculitis

Slightly prominent blood vessel adjacent to sweat gland

January 2022

Alasfoor et al[46]

43

China

F

8

Induced by slight trauma, external stimulus, emotional excitement, or during class

Epistaxis without pain, bleeding from corner of eyes, forehead, oral, arms, legs, and intestine

Vitamin C

Carbazochrome tables

Carbazochrome sodium sulfonate

Vitamin K1

Propranolol

Oryzanol

Compound rutin tablets.

Pharmacotherapy discontinued. Patient was removed from school and encouraged leisure activities and strengthening of mentality

Medical therapy showed no improvement.

Cessation of bleeding episodes with conservative management

Sympathetic induced capillary relaxation and rupture causing bleeding

Skin histopathology showed subcutaneous bleeding and capillary clogging, suggesting vasculitis

June 2022

Zheng et al[47]

44

India

F

18

Sometimes during eating and sleeping. Coincided with school examinations.

Episodes of hemoptysis 2 y prior, undiagnosed etiology

Bleeding from eyes, ear, nose, and mouth.

Tingling sensation before episodes

Fluoxetine

Clonazepam

Propranolol

Olanzapine

Reduction of episodes but still persistent.

Cessation of bleeding with addition of Olanzapine

July 2022

Biswas et al[48]

45

India

F

21

Untimely demise of father, feeling low.

Episodes followed stressors at home

Bleeding from eyes and facial skin

Fluoxetine

Clonazepam

Olanzapine

Cessation of bleeding

46

India

F

20

Friend of case 45, developed similar symptoms upon knowing of case 45's symptoms

Bleeding from ear and axial skin

Benzodiazepines

Cessation of bleeding

47

India

M

14

Coincided with school examinations

Mixed anxiety and depressive disorder

1 y of bleeding from nose, forehead, scalp, eyes (nonconjunctival), ear, cheeks, limbs, trunk.

Reported prodrome of generalized itching

Adenoidectomy

Sertraline

Behavioral therapy

Cessation of bleeding

Sympathetic activation of capillary network around sweat glands, causing dilating and rupture leading to localized hemorrhage

Normal skin biopsy.Enlarged adenoids

September 2022

Mitra et al[49]

48

USA

F

19

During times of exertion, exercising

Epilepsy, juvenile absence seizures

1 y of bloody sweat from bilateral axillary regions, forearms

Declined treatment

Continues to experience same symptoms

March 2023

Ogbuneke and Allen[50]

Table 2

Demographics, precipitating factors, and management of patients with hematohidrosis

N (%)

Female

38 (79.2)

Male

10 (20.8)

Age

 Adults ≥ 21 y old

9 (18.8)

 Youth < 21 y old

41 (85.4)

 Infants ≤ 1 y old

1 (2.1)

Geographical location

 Asia

26(54.2)

  India

19

 Africa

2 (4.2)

 Americas

5 (10.4)

 Middle East

8 (16.7)

 Europe

7 (14.6)

Precipitating factors

 Emotional stress

32 (66.7)

 Head trauma

3 (6.3)

 Psychiatric illness

9 (18.8)

 Exercise

2 (4.2)

Treatment

 Spontaneous resolution without treatment

6 (12.5)

 Received pharmacotherapy

37 (77.1)

  Treated with β-blockers

26 (33.7)

   Good response with β-blockers

23 (68.2)

   Concomitant psychotherapy with good response

4 (11.9)

   No response

3 (8.9)

  Treated with benzodiazepines

12 (15.6)

   Good response with benzodiazepines

6 (38.5)

  Treated with unspecified anxiolytic

3 (3.9)

   Good response with unspecified anxiolytics

2 (51.4)

Nine cases had been diagnosed with some form of psychiatric illness, including mixed anxiety and depression disorder (case 47), adjustment disorder (case 41), dissociative disorder (case 16), and oppositional defiant disorder (case 14). The caveat here is that many of the cases did not receive a formal psychiatric assessment; thus, it is difficult to build a strong association with psychiatric illnesses and hematohidrosis.

Of the 48 cases reviewed, 21 (43.8%) had skin biopsies performed, of which 10 showed various abnormalities such as congested capillaries (cases 2, 37, 38, 43). Areas of loosening of tissue in the dermis were also seen in some studies (cases 3, 8). Notably, blood-filled spaces in the dermis opening directly into follicular canals or skin surface were seen in cases studied by Hoover et al (Case 37, 38). This is consistent with the well-agreed mechanism of hematohidrosis caused by dermal defects that become filled with blood, which is supported by smear of blood secretion[7] [8] and benzidine testing[9] that showed normal components of sweat with some red blood cells. A total of 37 (77.1%) cases were treated using pharmacotherapy. Beta-blockers were commonly used to treat hematohidrosis, with 26 (33.7%) cases treated with β-blockers (most commonly propranolol) of which 23 observed a good response with resolution of hematohidrosis. Of these 23, four cases employed simultaneous psychotherapy of some form, and observed good response. Benzodiazepines were also commonly used, with 12 (15.6%) patients receiving benzodiazepines such as lorazepam, clonazepam, or alprazolam. Six cases observed a good response; 4 of these cases were treated in conjunction with other medical therapy. Four cases saw no response to benzodiazepines. One case stopped lorazepam due to side effects. Unspecified anxiolytics with propranolol were used in three (3.9%) cases, with two having a good response. Seven cases had spontaneous resolution without treatment, including one case that did not respond to medical therapy but seemed to improve when all medical therapy was withdrawn, and the patient was withdrawn from school and encouraged “strengthening leisure activities and adjusting mentality” (case 43).

The proposed pathophysiology of hematohidrosis can be broadly divided into adrenergic, structural, and genetic causes. The most common postulated adrenergic-related mechanism is related to the constriction of the vessels in the dermal plexus around the eccrine glands. According to previous studies on the vasculature of eccrine glands,[10] it is likely that the arterioles constrict during stressful periods due to sympathetic nervous activation, followed by dilation to the point of rupture.[9] For Jesus Christ, Zugibe[11] postulated that this dilation was caused by a counterreaction by the parasympathetic nervous system in response to Jesus' acceptance of His fate. When blood rushes back into the delicate capillaries, this causes them to rupture into the sweat gland tubules, mixing blood with the increased amount of sweat that extrudes to the surface of the skin. The good response to β-blockers with resolution of hematohidrosis also supports the role that the sympathetic nervous system plays. Another sympathetic-mediated mechanism that we would like to propose is the role of adrenaline-associated endothelial damage. Certain metabolites have been found to exhibit a dose–response relationship with the adrenaline–noradrenaline equimolar treatment.[12] These 46 metabolites align with the glutathione–ascorbate cycle and nitric oxide biosynthesis pathway. Upon catecholamine stimulation, an increase in glucose consumption and aerobic respiration was observed in endothelial cells, which supports how catecholamine stimulation of endothelial cells can cause increased oxidative stress and nitric oxide metabolism, and is associated with increased vascular permeability. The use of β-blockers also supports this as they antagonize the action of adrenaline and noradrenaline, particularly in blood vessels. A structural mechanism that was postulated is that defects in the dermis result in structural stromal weaknesses that can communicate with vascular spaces in the dermis. When these vascular spaces are filled with blood, pressure on the dermis causes blood to exude onto the skin surface.[13]

Lastly, we would like to also raise the possibility of genetic predispositions to hematohidrosis. Geographically, as noted previously by Kluger,[2] the condition seems to be more prevalent in Asiatic regions compared with Western regions. Genetic testing performed in case number 36, a young 22-year-old male patient with previous episodes of bloody secretion from the head associated with pain and hemolacria since 6 years of age, showed pathogenic variants related to the extracellular matrix (ECM), such as different types of collagen chains, a disintegrin and metalloproteinase (ADAM), metallopeptidases, laminins, integrins, matrix metallopeptidases, mucins, and von Willebrand factor. Genetic mutations related to ECM function and development can affect vessel integrity and formation and can lead to a bleeding phenotype.[5] Cases 37 and 38 are siblings, suggesting potential familial association in patients who experience hematohidrosis. The mother of cases 37 and 38 is reported to have a sibling who passed away due to some unknown bleeding complication, potentially additionally suggestive of familial association in cases of hematohidrosis.

The limitations of our review include the heterogenous reporting of cases, with some cases lacking histopathological proof or laboratory evaluation to exclude coagulopathy by performing standard coagulation tests. As such, the pathophysiology of hematohidrosis cannot be convincingly elucidated. Furthermore, skin biopsies and adrenaline sampling were not done during the time of bleeding but performed after the cessation of bleeding. As such, pathological changes to the dermis, eccrine glands, and blood capillaries might have resolved, leading to inconclusive skin biopsy findings.[9] Similarly, we are unable to corroborate the hypothesized mechanism of adrenaline-associated endothelial damage with biochemical evidence. Lastly, most cases did not have genetic testing performed.

In summary, cases of hematohidrosis have been documented throughout history and art, as well as in modern medical literature. Hematohidrosis has previously been perceived with religious mystery and can plausibly be explained for a multitude of reasons.[6] Given our review and the histopathological findings from skin biopsies, we postulate that hematohidrosis is precipitated by periods of extreme stress, resulting in a combination of dilatation and rupture of fine blood vessels supplying eccrine glands, and possibly endothelial damage from adrenaline causing increased vascular permeability. Hematohidrosis in Jesus Christ, as illustrated in 15th century Renaissance art, is a prime example of a young Middle Eastern patient experiencing blood-like sweat, amidst immense mental suffering in the grounds of Gethsemane. Perhaps this is where medicine and biblical scripture can find a common ground, where what was previously regarded as a supernatural phenomenon can now be explained with plausible clinical reality.

Data Availability Statement

All data are presented within the manuscript.


Authors' Contribution

All authors contributed extensively to the creation of this manuscript. B.E.F. conceptualized the review and provided critical revision of the manuscript for important intellectual content.




Publication History

Article published online:
16 May 2023

© 2023. Thieme. All rights reserved.

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