Abstract
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.
Keywords: bleeding disorder of unknown cause, diagnosis, hemostasis, review, treatment
Essentials
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Bleeding Disorder of Unknown Cause (BDUC) is defined by a positive personal and/or family history of bleeding with normal laboratory test results.
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More than half of patients with bleeding symptoms seen in hemostasis clinics are diagnosed with BDUC.
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There are major knowledge gaps and lack of consensus on the approach to treatment.
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Research is critically required to better understand the impact and determinants of BDUC.
Acknowledgments
Figures are created in BioRender.com
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author contribution
A.L.L.M. and C.M.A.M. share first authorship and wrote original draft, designed the capsule, and reviewed the process. T.T.v.D., M.J.H.A.K., Y.M.C.H., M.v.d.B., R.E.G.S., S.E.M.S., K.J.F., K.M., P.L.d.E., L.N., I.v.M., R.I.B., and J.S.O’D. reviewed and edited the manuscript. M.H.C. and F.C.J.I.H-M. reviewed, edited, and supervised the study.
Relationship disclosure
TTvD has received research funding from the Bertus Kem Stipendium (GNGH).
MJHAK has received an investigator-initiated research grant from Dutch Research Council (NWO), The Netherlands Organisation for Health Research and Development (ZonMw), Netherlands thrombosis foundation and Sobi, and speaker fees from Roche, Sobi and BMS. All payments go to the Erasmus MC as an institution. YMCH is professor of clinical chemistry, in particular hemostasis. In this position she collaborates with and tests reagents and equipment from IVD companies in the field of hemostasis (Werfen, Siemens, Roche, Nodia, Stago). She is also an advisor of Promicol. REGS has received research funding from Bayer, CSL Behring, Hemab, NovoNordisk, Novartis, Octapharma, Sanofi, and Sobi. All payments go to the institution. MHC has received researcher initiated research and travel grants from the Dutch Research Council (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch Healthcare Insurers Innovation Fund, Pfizer, Baxter/Baxalta/Shire/Takeda, Bayer Schering Pharma, CSL Behring, Sobi, Novo Nordisk, Novartis, Nordic Pharma, Roche and Octapharma and has served as a board member for Roche and Bayer. All scholarships, prizes and reimbursements go to Erasmus MC as an institution. FCJIH-M has received a research grant from Octapharma. All other authors have no conflict of interest to disclose.
Footnotes
Handling Editor: Michelle Sholzberg
Amaury L.L. Monard and Caroline M.A. Mussert share the first authorship and contributed equally to this work.
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