The diagnosis of hematidrosis could be made by recurrent, spontaneous and self-limited bleeding which is witnessed by medical personnel, and by identifying all blood components in the bleeding samples leaking from intact skin and mucous membrane without any lesion observed[4]. Hematidrosis affects more females than males, usually with an onset in adolescence[1,3]. Our series case was consistent with this depiction. The bleeding could occur on various parts of the body with occasional digestive or urinary bleeding[7,8], which was also observed in our case 2 and case 4. The episodes occur rather frequently. In case 3, the highest frequency even reached up to 60 times a day. In general, episodes last for 2 to 20 minutes with amount of each bleeding being several milliliters. Patients had no prior medical or psychological illness, and their family histories were normal, except for a boy and his half-sister who were born to a same mother, suggesting their possible genetic predisposition. However, whole genome sequencing was not performed to search its doubtful gene mutation[8].
It is of note that the spontaneous bleeding phenomena are distinctive, but not definitive criteria for hematidrosis. Other conditions such as vascular disorders, hematologic dyscrasias, infections, influence of drugs, vicarious menstruation, and self-inflicted lesion should be excluded in the differential diagnosis[2,3,9,10].
In the literature many triggering factors have been identified in most patients such as substantial physical or emotional stress and fear, and the bleeding episodes are often accompanied by many symptoms including headache, abdominal pain, nausea and vomiting[3,6], which were also presented in our case series. We found that the bleeding could be stirred up by minor events such as carsickness (case 3) and intense light (case 4). On the other hand, it might occur in association with psychotic symptoms (cases 2 and 4). All these phenomena strongly indicate a functional disturbance of the central nervous system-autonomic nervous system. Autonomic nerveous system is controlled by the central nervous system mainly via the hypothalamus, and is involved in homeostasis, emotional processing, and all bodily functions. It has been found that seizure discharges commonly spread into autonomic pathways which are mediated through the cortical, limbic, and hypothalamic systems[11]. Therefore, it would be possible that activation of nerves and the release of neuropeptides as well as neurotransmitters would facilitate the appearance of hematidrosis under some unknown conditions. On the other hand, histamine, although mainly released by mast cells, is also localized in many tissues including brain, sympathetic ganglion and nerve fibers where it functions as a neurotransmitter involving in the regulation of peripheral sympathetic activity[12,13]. Moreover, histamine receptors H1R and H2R are coexpressed in most cell types, such as neurons and some ganglions, endothelial and epithelial cells, and they may function in a crossregulation manner[14]. H1R and H2R inhibitors are mainly used for the treatment of allergic and gastric acid–related conditions. It is well known that histamine can also dilate vasculature and increase blood flow via activation of H1R and H2R located in blood vessel[15], and disrupt endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin localization at endothelial cell junction, and then increase vascular permeability, which could be abolished by histamine H1 receptor antagonists[16,17].
The pathophysiology of hematohidrosis remains unclear. Several hypotheses have been proposed including abnormal constriction and then dilation of capillary vessels to the point of rupture, dermal vasculitis, and stromal weakness due to defects in the dermis[4,6]. From our investigation, we could postulate that the basic pathogenesis of hematohidrosis might be perplexing regulation disturbance of central nervous system-hypothalamus-autonomic nervous system pathway in association with histaminergic activation. This disorder could be considered as an exceptive kind of mental and nervous illness rather than an organic disease.
It is generally believed that hematidrosis is due to blood leakage from ruptured skin capillaries to neighboring sweat glands[3,18]. However, the skin biopsy studies, including ours, never revealed any abnormalities apparent in sweat glands. On the other hand, blood oozing is not accompanied by sweating, and it could appear on the tongue and mucous membrane, and from subungual area where there are no sweat glands. Therefore, we believed that the term hematidrosis or “bloody sweat” is not accurately correct[19]. However, it is still an enigma how blood could spontaneously exude from intact skin and mucous membrane without leaving any trace of petechia, ecchymosis, or lesion. The mostly puzzling enigma is that we previously found a girl with hemotidrosis whose bloody exudate was shown to contain all the components of peripheral blood, while she occasionally discharged white frothy fluid from the tongue and the umbilicus, containing only white cells but no red cells[20]. Such oddity was described only in an Indian girl with hemotidrosis[21].
Up to date, there is no specific treatment regimen available for hematidrosis. Management with vitamin C, hemostatic drugs, corticosteroids or plasma products have been proven to be valueless. Some extensive therapeutic intervention treatments could cause dangerous risk. A patient had been reported to be infected with human immunodeficiency virus and hepatitis B virus, presumably acquired via blood transfusions[8].
Anxiolytics and atropine have respectively been reported effective in single case[21,22]. We first successfully treated a patient with b-receptor blocker propranolol, as we speculated that sympathetic nerve activation might play a role in her episodes[18]. This treatment method has been used by many other researchers, but its efficiency could be limited, and relapses occured in some cases after the drug withdrawal[1,3,8,23]. Again our seven patients did not completely response to propranolol. According to the possible pathogenesis described above, we tried to form a mixture of multi-drug "cocktail therapy" consisting of anxiolytics, propranolol, and histamine H1/2 receptor antagonists in order to manage the related tricky problems. Following this therapeutic regimen, both frequency and severity of bleeding episodes gradually disappeared during 2-6 months period. According to our experience, the drug withdrawal should be gradually tapered, and most of our patients finally discontinued treatment. We previously reported a girl with hematidrosis whose bleeding onset was trigged by epilepsy, who was not responsive to propranolol or general therapy, but made a complete recovery after being treated with an anti-epileptic drug, oxcarbazepine[20]. Case 2 got a temporary remission following a therapy of “cocktail of drugs”, but then repeatedly relapsed. Because she sometimes had transient disturbance of consciousness before bleeding onset, addition of another antiepileptic drug levetiracetam was given, and she finally got a complete remission. According to our experience, each patient needs to be treated individually in light of different situations. It was noted that the relapse occured in most patients. The treatment sould be continued for 6 to 12 months after the inicial episode was disappeared. Meanwhile ensuring a compassionate approach by physicians was important, as the patients always felt down and discriminated.
Hematidrosis is an extremely rare disorder with only about 100 cases reported worldwide from ancient time to nowadays[2,3]. It is amazing that we have found 9 patients (including two published elsewhere[19,20]) in our single institute during the past 10 years. That is perhaps because of the largest population in China, and our department of hematology is among the list of the most influential services in our country. On the other hand, this fact could indicate that hematidrosis is certainly not as scarce as originally thought.