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.