Mitochondrial Vacuolization and Basement Membrane Disruption in Dermal Micro‐Vessels: A Novel Pathogenesis in Hematidrosis

A 14-year-old girl presented with spontaneous, recurrent, self-limiting blood sweating on her forehead and face (Figure 1), beginning in late 2018. Her episodes, initially associated with blood-tinged saliva, were later complicated by hematemesis, melena, and hematuria. By 2024, the low mood had lasted for a year. Physical examination was unremarkable. No family history of bleeding disorders existed and her parents had normal laboratory results. Her blood group was O Rh-positive. Laboratory findings showed mild reduction in von Willebrand factor (antigen 60%; activity 46%; reference range 50%–200%) and impaired platelet aggregation (adenosine diphosphate [ADP] 10.2%; collagen 19.4%; reference range 30%–70%). Urinalysis revealed 800,000 RBC/mL with 3% dysmorphic erythrocytes, and vomitus was positive for occult blood. Other laboratory results were unremarkable. Imaging and endoscopy revealed no structural lesions. Genetic analysis identified heterozygous variants in ENG, ITGB3, and VWF, but these were not diagnostic of a hemorrhagic disorder. A 2019 salivary smear showed intact red blood cells (RBCs), while skin biopsy (quiescent phase) was unremarkable (Figure 2A). During a 2023 active phase, sweat smear and skin biopsy confirmed intact erythrocytes in sweat gland ducts (Figure 2B). Electron microscopy revealed capillary endothelial cell mitochondrial vacuolization, arteriolar endothelial damage with basal lamina dissolution, and elastic fiber fragmentation (Figure 2C,D); platelet morphology appeared normal. After excluding other conditions, hematidrosis was diagnosed. She received propranolol from 2018 to 2020 and 2023 to 2024, with symptom recurrence upon discontinuation. Hematidrosis, characterized by spontaneous blood sweating through intact skin, can also manifest as hematemesis or hematuria. Its higher prevalence in Asia suggests a possible genetic predisposition, though conclusive evidence is lacking. The heterozygous CD36 variant has been reported to impair platelet function, and familial cases in half-siblings have also been noted [1, 2]. However, a definitive pathogenic mechanism is lacking. In our case, whole-exome sequencing revealed heterozygous ENG, ITGB3, and VWF variants inherited from asymptomatic parents. Reduced VWF activity was attributed to blood group O. No imaging or clinical findings supported pathologies related to the ENG or ITGB3 variant. Consequently, the systemic bleeding in our case was not explained by these heterozygous variants. Thus, the genetic basis of hematidrosis remains elusive, necessitating larger multi-omics studies. The pathophysiology of hematidrosis remains elusive. The prevailing neurovascular theory attributes it to stress-induced sympathetic activity, causing capillary rupture around the sweat glands. However, many cases lack identifiable triggers, challenging this view. Alternative theories propose structural dermal abnormalities or sweat gland dysregulation. However, light microscopy showed no significant pathology in our case or others [3], indicating the involvement of unknown mechanisms. However, electron microscopy revealed mitochondrial vacuolization in capillary endothelial cells, arteriolar endothelial damage, dissolved basal lamina, and fragmented elastic fibers. This suggests hematidrosis may originate from a systemic microvascular abnormality rather than being confined to sweat glands, as evidenced by gastrointestinal bleeding and hematuria. We propose that a congenital or acquired microvascular vulnerability allows minor physiologic triggers to cause vessel rupture, even without significant psychological stress. This hypothesis is supported by two cases: one triggered by minor mechanical pressure, revealing structurally immature and leaky CD34+ vessels [4], and another, induced by elevated temperature, showing only dilated dermal micro-vessels alongside normal sweat glands [5]. Thus, this microvascular hypothesis can refine the traditional pathophysiological understanding, offering a novel perspective on hematidrosis pathogenesis. We express our gratitude to all individuals who provided valuable intellectual guidance and technical support for this study. This work was supported by the National Natural Science Foundation of China, 82260027. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.