Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion.

Patients with an unexplained mild to moderate bleeding tendency are diagnosed with bleeding disorder of unknown cause (BDUC), a classification reached after ruling out other mild to moderate bleeding disorders (MBD) including von Willebrand disease (VWD), platelet function defects (PFDs), coagulation factor deficiencies (CFDs), and non-hemostatic causes for bleeding. This review outlines our diagnostic approach to BDUC, a diagnosis of exclusion, drawing on current guidelines and insights from the Vienna Bleeding Biobank (VIBB). According to guidelines, we diagnose VWD based on VWF antigen and/or activity levels ≤50 IU/dL, with repeated VWF testing if VWF levels are <80 IU/dL. This has been introduced in our clinical routine after our findings of diagnostically relevant fluctuations of VWF levels in a high proportion of MBD patients. PFDs are identified through repeated abnormalities in light transmission aggregometry (LTA), flow cytometric mepacrine fluorescence, and glycoprotein expression analysis. Nevertheless, we experience diagnostic challenges with regard to reproducibility and unspecific alterations of LTA. For factor (F) VIII and FIX deficiency, a cutoff of 50% is utilized to ensure detection of mild hemophilia A or B. We apply established cutoffs for other rare CFD being aware that these do not clearly reflect the causal role of the bleeding tendency. Investigations into very rare bleeding disorders due to hyperfibrinolysis or increase in natural anticoagulants are limited to cases with a notable family history or distinct bleeding phenotypes considering cost-effectiveness. While the pathogenesis of BDUC remains unknown, further explorations of this intriguing area may reveal new mechanisms and therapeutic targets.
Competing Interests: D.M. received honoraria for advisory board meetings and lectures from CSL Behring, a research grant from CSL Behring (Prof. Heimburger award) and travel support by Sobi, Novo Nordisk, Pfizer, and Roche.J.G. received research grants from CSL Behring, Sobi, Takeda, Amgen, and Novartis for the Medical University of Vienna; honoraria for lectures and advisory board meetings from CSL Behring, Sobi, Novartis, and Amgen.I.P. received a grant from CSL Behring for the Medical University of Vienna; honoraria from CSL Behring, Sobi, Takeda, Pfizer, for lectures and advisory board meetings; as well as travel support by Sobi.
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