Low vitamin C status and hypermobility-related disorders in patients with bleeding disorder of unknown cause

INTRODUCTION: Bleeding disorder of unknown cause (BDUC) is a challenging diagnosis that predominantly affects women. Previous investigations into connective tissue disorders (CTD) and vitamin C have not been conducted.

AIM: To examine the association between hypermobility-related disorders, vitamin C status and BDUC.

METHODS: Patients were selected following laboratory and genetic screening that yielded negative results for known hemostasis disorders. Sixty patients with BDUC and an ISTH BAT score ≥ 10 underwent clinically examination for skin hyperextensibility and for hypermobility assessed by Beighton score. Vitamin C was analyzed by high-performance liquid chromatography. Genetic screening for causal variants in 42 CTD genes was performed.

RESULTS: The majority of patients were female (56/60). Median ISTH BAT score was 13 (range 10-23). Beighton score was positive in 29/60 patients compared to 1/20 healthy controls (HC) (p < .001). Hyperextensive skin was observed in (18/60) patients, and none (0/20) of the HC (p = .0041). Ten patients met the clinical diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS), and one patient was diagnosed with Noonan syndrome. Genetic screening excluded various subtypes of EDS with known genetic backgrounds. Average vitamin C level was adequate, but lower than in HC (55.9 vs. 70.4 μmol/L; p = .001). Suboptimal, or low vitamin C were identified in 19/60 compared to 1/20 HC (p = .018).

CONCLUSION: Our study demonstrates that BDUC is frequently associated with hypermobility disorders and low vitamin C status. Our results could pave the way for a randomized study of vitamin C supplementation in patients with BDUC.