Characteristics of patients with bleeding disorder of unknown cause in a cohort of patients with mild to moderate bleeding disorders

Introduction: Bleeding disorder of unknown cause (BDUC) represents a diagnosis of exclusion in patients with a clinically relevant bleeding tendency but without laboratory correlates [1]. Currently, the underlying mechanisms in BDUC remain elusive. Investigating differences between BDUC patients and patients with established diagnoses of mild to moderate bleeding disorders (MBD) might yield important clues towards the underlying pathophysiology of BDUC and could reveal patient sub-cohorts with a particularly high rate of BDUC.

Method: Patients from the Vienna Bleeding Biobank (VIBB) were analyzed for this study. Overall study design, in- and exclusion criteria of the VIBB and diagnostic criteria for established MBD diagnoses (including platelet function defects (PFD), von Willebrand disease (VWD) and coagulation factor deficiencies (CFD)) and BDUC have been published previously [2].

Results: In total,967 MBD patients were investigated. Detailed characteristics of the study cohort are outlined in [Fig. 1]. Of included patients, 364 were diagnosed with an established MBD (265 (28%) had PFD, 77 (8%) had VWD and 22 (2%) had CFD), with the remaining 603 patients (62%) having been classified as BDUC patients. BDUC patients showed a significantly higher proportion of women (p<0.001) and a higher median age (p<0.001) than patients with established MBD. Blood group O (BGO) was significantly more common in established MBD (p=0.009), mainly due to VWD patients, among whom 71% had BGO. Family history of bleeding was similar in BDUC and established MBD patients (p=0.425). In multivariate regression ([Fig. 2]), female sex and higher age were significantly associated with the diagnosis of a BDUC (odds ratio [OR]: 1.79, 95% confidence interval [CI]: 1.25-2.56, and OR: 1.02 [1.01-1.02], respectively). BGO was associated with the diagnosis of an established MBD (OR: 1.44 [1.11-1.90]), while family history of bleeding was not associated with either BDUC or an established MBD. Comparison of the median ISTH-BAT score, as a measurement of overall bleeding phenotype, between BDUC patients (ISTH-BAT 6, interquartile range [IQR]: 4-8) and patients with established MBD diagnoses (ISTH-BAT 6 [4-9]) showed no significant difference, p=0.743. In line, BDUC patients reported a similar number of bleeding symptoms (3 [2-4]) than other MBD patients (3 [2-4]), p=0.198. However, upon adjustment for age, sex and BGO in multivariate regression, a higher number of bleeding symptoms was slightly associated with an established MBD (OR: 0.92 [0.85-0.99]).

Fig. 1 Patient and cohort characteristics. Significances of categorical data are results of X ²-tests and Fisher’s exact tests for group sizes<6. Non-normally distributed continues and ordinal data was compare using the Wilcoxon-test. P-values are reported after correction for multiple testing using the Bonferroni-Holm-Method.

Fig. 2 Results of uni- and multivariate logistic regressions.*Multivariate logistic regression adjusted for age, sex and blood group O.

Conclusion: Female sex and higher age were associated with BDUC, while BGO showed an association with an established MBD diagnosis. Our data show a generally similar bleeding phenotype in BDUC patients compared to those with a MBD diagnosis. Taken together, BDUC seems to primarily affect women of higher age, possibly hinting towards sex- or hormone-related mechanisms underlying or aggravating the bleeding tendency.

Publikationsverlauf

Artikel online veröffentlicht:
13. Februar 2025

• References

• 1 Baker RI, Choi P, Curry N, Gebhart J, Gomez K, Henskens Y. et al. Standardisation of Definition and Management for Bleeding Disorder of Unknown Cause: Communication from the SSC of the ISTH. J Thromb Haemost 2024 S1538783624001636
• 2 Mehic D, Gebhart J, Pabinger I.. Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion. Hämostaseologie 2024; a-2263 5706