Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives

• Published in: Research and practice in thrombosis and haemostasis 2024-11, Vol.8 (8), p.102625, Article 102625
• Main Authors: Monard, Amaury L.L., Mussert, Caroline M.A., van Duijl, Tirsa T., Kruip, Marieke J.H.A., Henskens, Yvonne M.C., van den Biggelaar, Maartje, Schutgens, Roger E.G., Schols, Saskia E.M., Fijnvandraat, Karin J., Meijer, Karina, den Exter, Paul L., Nieuwenhuizen, Laurens, van Moort, Iris, Baker, Ross I., O’Donnell, James S., Cnossen, Marjon H., Heubel-Moenen, Floor C.J.I.
• Format: Article
• Language: English
• Subjects: bleeding disorder of unknown cause; diagnosis; hemostasis; Illustrated Review; review; treatment
• ISSN: 2475-0379; 2475-0379
• DOI: 10.1016/j.rpth.2024.102625

In more than half of the individuals with a clinically relevant bleeding tendency who are referred to hemostasis experts, no biological etiology can be found after extensive laboratory testing. These persons are diagnosed with an unexplained bleeding tendency or “bleeding disorder of unknown cause” (BDUC). The mucocutaneous bleeding phenotype of individuals with BDUC is generally comparable to that of individuals with inherited bleeding disorders such as von Willebrand disease or platelet function disorders. BDUC definitions applied in literature are heterogeneous, but all comprise 2 main criteria: (1) there is an increased bleeding tendency based on the clinical view of the physician and/or an increased bleeding score; (2) no abnormalities are found with available hemostasis laboratory tests. This is reflected in the recent published BDUC definition by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, stating that BDUC is a diagnosis of exclusion, characterized by normal hemostatic investigations despite a clinically significant bleeding tendency. Importantly, other nonhemostatic and acquired causes of bleeding should be excluded, but details on exclusion criteria and associated diagnostic testing remain undefined. Patients and health care providers are challenged by the uncertainty and lack of formal diagnosis particularly as there is no clear consensus regarding treatment. Research on the diagnostic value of new laboratory tests in individuals with BDUC has not yet been productive. In this illustrative review, the current practice and knowledge gaps in BDUC are addressed, previous research on BDUC is outlined and future directions with outstanding questions for future research in BDUC are highlighted. •Bleeding Disorder of Unknown Cause (BDUC) is defined by a positive personal and/or family history of bleeding with normal laboratory test results.•More than half of patients with bleeding symptoms seen in hemostasis clinics are diagnosed with BDUC.•There are major knowledge gaps and lack of consensus on the approach to treatment.•Research is critically required to better understand the impact and determinants of BDUC.