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Hamostaseologie 2024; 44(04): 287-297
DOI: 10.1055/a-2263-5706
Review Article

Bleeding Disorder of Unknown Cause: A Diagnosis of Exclusion

Dino Mehic
1   Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
,
Johanna Gebhart
1   Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
,
Ingrid Pabinger
1   Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
› Author Affiliations Funding The Vienna Bleeding Biobank is supported by an unrestricted grant of CSL Behring, the Medical-Scientific Fund of the Mayor of the Federal Capital Vienna (grant number 20023), and the Anniversary Fund of the Austrian National Bank (grant number 18500).
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Abstract

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.

Keywords

von Willebrand disease - von Willebrand factor - hemophilia A/B - inherited platelet disorders - hemostasis

Authors' Contribution

D.M., J.G., and I.P. performed a literature review, wrote and revised the manuscript.




Publication History

Received: 20 November 2023

Accepted: 07 February 2024

Article published online:
27 February 2024

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