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

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.

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)

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

• References

• 1 Alsermani M, Alzahrani H, El Fakih R. Hematidrosis: a fascinating phenomenon-case study and overview of the literature. Semin Thromb Hemost 2018; 44 (03) 293-295
• 2 Kluger N. Hematidrosis (bloody sweat): a review of the recent literature (1996-2016). Acta Dermatovenerol Alp Panonica Adriat 2018; 27 (02) 85-90
• 3 Duffin J. Sweating blood: history and review. CMAJ 2017; 189 (42) E1315-E1317
• 4 Holoubek JE, Holoubek AB. Blood, sweat and fear. “A classification of hematidrosis”. J Med 1996; 27 (3-4): 115-133
• 5 Carrion-Alvarez D, Trejo-Castro AI, Salas-Garza M, Fajardo-Ramirez OR, Salas-Alanis JC. Hematohidrosis, hemolacria, and “trichorrhage”: a systematic review. Skin Appendage Disord 2022; 8 (03) 179-185
• 6 Favaloro EJ, Lippi G. Commentary: controversies in thrombosis and hemostasis Part 1 - Hematidrosis: “Blood, sweat and fears” or a “pigment of fertile imaginations?”. Semin Thromb Hemost 2018; 44 (03) 296-297
• 7 Carvalho AC, Machado-Pinto J, Nogueira GC, Almeida LM, Nunes MB. Hematidrosis: a case report and review of the literature. Int J Dermatol 2008; 47 (10) 1058-1059
• 8 Bhagwat PV, Tophakhane RS, Rathod RM, Shashikumar BM, Naidu V. Hematohidrosis. Indian J Dermatol Venereol Leprol 2009; 75 (03) 317-318
• 9 Jerajani HR, Jaju B, Phiske MM, Lade N. Hematohidrosis - a rare clinical phenomenon. Indian J Dermatol 2009; 54 (03) 290-292
• 10 Kennedy WR, Wendelschafer-Crabb G, Brelje TC. Innervation and vasculature of human sweat glands: an immunohistochemistry-laser scanning confocal fluorescence microscopy study. J Neurosci 1994; 14 (11, Pt 2): 6825-6833
• 11 Zugibe FT. The Crucifixion of Jesus, Completely Revised and Expanded: A Forensic Inquiry. 2nd ed. M. Evans& Co Inc; 2005: 11-15
• 12 López García de Lomana A, Vilhjálmsson AI, McGarrity S. et al. Metabolic response in endothelial cells to catecholamine stimulation associated with increased vascular permeability. Int J Mol Sci 2022; 23 (06) 3162
• 13 Manonukul J, Wisuthsarewong W, Chantorn R, Vongirad A, Omeapinyan P. Hematidrosis: a pathologic process or stigmata. A case report with comprehensive histopathologic and immunoperoxidase studies. Am J Dermatopathol 2008; 30 (02) 135-139
• 14 Scott CT. A case of haematidrosis. BMJ 1918; 1 (2993): 532-533
• 15 Mishra KL. Bloody tears and hematohidrosis in a patient of PF3 dysfunction: a case report. Cases J 2009; 2: 9029
• 16 Patel RM, Mahajan S. Hematohidrosis: a rare clinical entity. Indian Dermatol Online J 2010; 1 (01) 30-32
• 17 Wang Z, Yu Z, Su J. et al. A case of hematidrosis successfully treated with propranolol. Am J Clin Dermatol 2010; 11 (06) 440-443
• 18 Praveen BK, Vincent J. Hematidrosis and hemolacria: a case report. Indian J Pediatr 2012; 79 (01) 109-111
• 19 Mora E, Lucas J. Hematidrosis: blood sweat. Blood 2013; 121 (09) 1493
• 20 Khalid SR, Maqbool S, Raza N, Mukhtar T, Ikram A, Qureshi S. Ghost spell or hematohidrosis. J Coll Physicians Surg Pak 2013; 23 (04) 293-294
• 21 Bhattacharya S, Das MK, Sarkar S, De A. Hematidrosis. Indian Pediatr 2013; 50 (07) 703-704
• 22 Biswas S, Surana T, De A, Nag F. A curious case of sweating blood. Indian J Dermatol 2013; 58 (06) 478-480
• 23 Deshpande M, Indla V, Kumar V, Reddy IR. Child who presented with hematohidrosis (sweating blood) with oppositional defiant disorder. Indian J Psychiatry 2014; 56 (03) 289-291
• 24 Shen H, Wang Z, Wu T. et al. Haematidrosis associated with epilepsy in a girl successfully treated with oxcarbazepine: case report. J Int Med Res 2015; 43 (02) 263-269
• 25 Uber M, Robl R, Abagge KT. et al. Hematohidrosis: insights in the pathophysiology. Int J Dermatol 2015; 54 (12) e542-e543
• 26 Jafar A, Ahmad A. Child who presented with facial hematohidrosis compared with published cases. Case Rep Dermatol Med 2016; 2016: 5095781
• 27 Techasatian L, Waraasawapati S, Jetsrisuparb C, Jetsrisuparb A. Hematidrosis: a report with histological and biochemical documents. Int J Dermatol 2016; 55 (08) 916-918
• 28 Jayaraman AR, Kannan P, Jayanthini V. An interesting case report of hematohidrosis. Indian J Psychol Med 2017; 39 (01) 83-85
• 29 Yeşilova Y, Turan E, Aksoy M. Hematidrosis on the forehead following trauma: a case report. Int J Dermatol 2017; 56 (02) 212-214
• 30 Maglie R, Caproni M. A case of blood sweating: hematohidrosis syndrome. CMAJ 2017; 189 (42) E1314
• 31 Ricci F, Oranges T, Novembre E. et al. Haematohidrosis treated with propranolol: a case report. Arch Dis Child 2019; 104 (02) 171
• 32 Shahgholi E. A case series of hematohidrosis: a puzzling medical phenomenon. Turk J Pediatr 2018; 60 (06) 757-761
• 33 Pari T. Hematohidrosis - a rare case. Indian Dermatol Online J 2019; 10 (03) 334-335
• 34 Hansson K, Johansson EK, Albåge M, Ballardini N. Paediatric haematohidrosis: an overview of a rare but clinically distinct condition. Acta Paediatr 2019; 108 (06) 1023-1027
• 35 Meyer J, Spacil K, Stehr M, Hinrichs W, Haller S, Schäfer FM. Hematidrosis after head injury - a case report. Klin Padiatr 2019; 231 (06) 326-327
• 36 Das D, Kumari P, Poddar A, Laha T. Bleeding to life: a case series of hematohidrosis and hemolacria. Indian J Pediatr 2020; 87 (01) 84
• 37 Murota H, Kotobuki Y, Yamaga K, Yoshioka Y. Female child with hematidrosis of the palm: case report and published work review. J Dermatol 2020; 47 (02) 166-168
• 38 Matsuoka R, Tanaka M. Hematidrosis in a Japanese girl: treatment with propranolol and psychotherapy. Pediatr Int 2020; 62 (08) 1001-1002
• 39 Corrà A, Quintarelli L, Caproni M. Bleeding from the oral cavity: a new case of hematohidrosis. Int J Dermatol 2020; 59 (11) e421-e422
• 40 Récher C. Hematidrosis as a manifestation of COVID-19 containment-induced stress. eJHaem 2020; 2 (01) 25
• 41 Salas-Alanis JC, Salas-Garza M, Goldust MM, Fajardo-Ramirez OR. Haematidrosis and haemolacria in a young adult. Clin Exp Dermatol 2021; 46 (02) 394-396
• 42 Hoover A, Fustino N, Sparks AO, Rokes C. Sweating blood: a case series of 2 siblings with hematohidrosis. J Pediatr Hematol Oncol 2021; 43 (02) 70-72
• 43 Tirthani K, Sardana K, Mathachan SR. Hematohidrosis of the mid-face and hands treated with oral oxybutynin. Pediatr Dermatol 2021; 38 (04) 962-963
• 44 Shafique DA, Hickman AW, Thorne A, Elwood HR, Zlotoff BJ. Pediatric hematidrosis - a case report and review of the literature and pathogenesis. Pediatr Dermatol 2021; 38 (05) 994-1003
• 45 Talwar M, Chidambaram AC, Mekala S, Parameswaran N, Delhikumar CG. Haematohidrosis in a 12-year-old boy: blood, sweat and tears. Paediatr Int Child Health 2021; 41 (04) 300-302
• 46 Alasfoor S, Albashari M, Alsermani A, Bakir M, Alsermani M, Almustanyir S. A strange occurrence of hematohidrosis: a case report from Saudi Arabia. Cureus 2022; 14 (01) e21682
• 47 Zheng J, Bian MR, Wu XQ. et al. Hematidrosis: a case report. Dermatol Ther 2022; 35 (06) e15462
• 48 Biswas D, Mondal DK, Biswas R, Halder A. Hematidrosis: a rare entity - case series and review of literature. Indian J Psychiatry 2022; 64 (04) 423-425
• 49 Mitra S, Chatterjee SS, Roy S, Kumar M. Stress-induced haematohidrosis: a case report. East Asian Arch Psychiatry 2022; 32 (03) 62-63
• 50 Ogbuneke JU, Allen JC. Case report and review of the pathophysiology and therapeutics of adult hematohidrosis. Cureus 2023; 15 (03) e36187