Bleeding Disorder of Unknown Cause in the Netherlands

Official title

Bleeding Disorder of Unknown Cause In the Netherlands (BDUC-iN Study)

Overview

The purpose of the Bleeding Disorder of Unknown Cause in the Netherlands study (BDUC-iN) is to learn more about unexplained bleeding in individuals with a bleeding disorder of unknown cause (BDUC). The study aims to better understand why these individuals have increased bleeding and how it affects their health and daily life. The main questions of this study are: 1. What are the mechanisms underlying the bleeding tendency in BDUC? 2. How do bleeding symptoms affect patients' daily functioning and overall health-related quality of life? 3. How is care delivered to individuals with BDUC, and how can this be improved? Participants with increased bleeding tendency who remain undiagnosed after standard coagulation testing and are consequently classified as having BDUC will be enrolled across the Hemophilia treatment centers in the Netherlands. Participants will undergo blood sampling for advanced hemostasis testing and genetic analysis. In addition, participants will complete validated questionnaires to assess bleeding symptoms and health-related quality of life. Participants will be followed longitudinally to evaluate how bleeding symptoms affect daily activities, medical procedures, and overall health-related quality of life.

Detailed description

Background: Despite advances in laboratory diagnostics, current standard hemostasis tests only identify a hemostatic defect in about 25-50% of individuals who are referred to a hemostasis specialist for evaluation of bleeding symptoms. Individuals presenting with an increased bleeding tendency and in whom no abnormalities can be found with standard laboratory hemostasis tests, and who have no other identifiable cause for their bleeding phenotype, are classified as having a bleeding disorder of unknown cause (BDUC). Persons with BDUC suffer from similar bleeding symptoms and clinical manifestations as those observed in persons with a diagnosed bleeding disorders such as von Willebrand Disease (VWD) or platelet function disorders (PFDs). In daily life, frequently experienced bleeding symptoms in patients with BDUC such as heavy menstrual bleeding or epistaxis are known to have a major impact on social functioning, school or work-related activities, and consequently result in reduced health-related quality of life. Due to a lack of knowledge about the underlying pathophysiological cause of the bleeding tendency, there is currently no clear guideline or consensus available for treating persons with BDUC. The lack of a clear diagnosis of BDUC is therefore challenging for both the individual and the treating physician.

Objectives: The Bleeding Disorder of Unknown Cause in the Netherlands study (BDUC-iN) aims to improve diagnostic accuracy and optimize treatment strategies in persons with BDUC, by evaluating the pathophysiological mechanisms underlying the bleeding tendency. Additionally, the BDUC-iN study aims to identify and evaluate healthcare delivery, patient outcomes and health-related quality of life among persons with BDUC.

Methods: This study is a multicenter, observational cohort study involving 500 individuals with BDUC registered at or investigated in one of the six Hemophilia Treatment Centers in the Netherlands. Diagnostic, therapeutic and fundamental research questions are organized into eleven dedicated work packages. Clinical data is collected over a 10-year follow-up period to evaluate changes over time. The impact of bleeding symptoms on health-related quality of life is assessed using validated questionnaires. Advanced hemostasis and fibrinolytic testing, platelet function assessments and proteogenomics analysis are performed to characterise bleeding phenotypes and identify hemostasis defects. In addition, targeted therapeutic interventions are tested in vitro to assess their impact on platelet adhesion, thrombus formation and thrombin generation. A care pathway framework is developed, which will incorporate findings from the collected clinical, laboratory and patient-reported data, as well as additional focus groups with patients and treating physicians, with the aim of identifying areas for improvement in diagnosis and treatment management.

Primary outcome measures

• Health-related quality of life [Time frame: From enrollment to the end at 10 years]
• Diagnostic yield [Time frame: At baseline]

Secondary outcome measures (12)

• Bleeding symptoms [Time frame: From enrollment to the end at 10 years]
• Bleeding severity [Time frame: From enrollment to the end at 10 years]
• Physical activity [Time frame: From enrollment to the end at 10 years]
• Patient activation [Time frame: From enrollment to the end at 10 years]
• Diagnostic delay [Time frame: At baseline]
• Outcomes of hemostatic challenges [Time frame: From enrollment to the end at 10 years]
• Care pathways [Time frame: From enrollment to the end at 10 years]
• Patient satisfaction with care [Time frame: From enrollment to the end at 10 years]
• Platelet function disorder [Time frame: At baseline]
• Rare factor deficiency [Time frame: At baseline]
• Fibrinolytic disorders [Time frame: At baseline]
• Anticoagulant abundance [Time frame: At baseline]

Eligibility criteria

Inclusion criteria

• Referred to a (pediatric) hemostasis specialist for evaluation of bleeding tendency.
• Increased bleeding tendency based on: Abnormal International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) score (≥ 5 in women age 18-30; ≥ 6 in women age 31-51, ≥ 7 in women age 52 or older; ≥4 in men and ≥ 3 in children) OR Clinical gestalt according to the investigating physician
• Absence of diagnostic test results for a bleeding disorder in standard laboratory hemostasis tests:
• Complete blood count: Hemoglobin > 6.0 mmol/L; thrombocyte count > 100 x10\^9/L
• Prothrombin (PT) and activated Partial Thromboplastin Time (aPTT): within local reference range, or prolonged without explanatory factor deficiency
• Fibrinogen activity, von Willebrand Factor (VWF) antigen \& activity, Factor VIII, IX, XI and XIII: within local reference range or abnormal but not explaining bleeding phenotype
• Light transmission aggregometry (LTA): Not diagnostic for a platelet function
• Kidney function: eGFR > 45 ml/min
• Liver function: ALAT, bilirubin < 3 x upper limit of normal

Exclusion criteria

• Use of medication interfering with laboratory hemostasis tests which cannot be stopped before blood withdrawal
• Pregnancy or lactation at moment of inclusion
• Presence of an established bleeding disorder
• Presence of an acquired cause or another explanation for the increased bleeding tendency
• Inability to provide informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Netherlands · 8 centers

• Radboud University Medical Center — Nijmegen
• Maastricht University Medical Center — Maastricht
• Maxima Medical Center — Veldhoven
• Amsterdam University Medical Center — Amsterdam
• University Medical Center Groningen — Groningen
• Leiden University Medical Center — Leiden
• Erasmus Medisch Centrum — Rotterdam
• University Medical Center Utrecht — Utrecht

Publications

• Monard ALL, Mussert CMA, van Duijl TT, Kruip MJHA, Henskens YMC, van den Biggelaar M, Schutgens REG, Schols SEM, Fijnvandraat KJ, Meijer K, den Exter PL, Nieuwenhuizen L, van Moort I, Baker RI, O'Donnell JS, Cnossen MH, Heubel-Moenen FCJI. Bleeding disorder of unknown cause: an illustrated review on current practice, knowledge gaps, and future perspectives. Res Pract Thromb Haemost. 2024 Nov 13;8( PMID 39687924
• Mussert CMA, Monard ALL, van Duijl TT, Henskens YMC, van den Biggelaar M, Schutgens REG, Schols SEM, Fijnvandraat KJ, Meijer K, den Exter PL, Nieuwenhuizen L, van Moort I, Kruip MJHA, Cnossen MH, Heubel-Moenen FCJI; BDUC-iN study group. Current Practice Regarding Bleeding Disorders of Unknown Cause in the Netherlands: A National Survey. Haemophilia. 2025 Jul;31(4):752-760. doi: 10.1111/hae.70065. PMID 40421900
• Monard ALL, Hellenbrand D, Verhezen P, Beckers EAM, Henskens YCM, Heubel-Moenen FCJI. tPA-ROTEM identifies hyperfibrinolytic profile in a significant proportion of patients with bleeding disorder of unknown cause (BDUC). Thromb Res. 2025 Sep;253:109404. doi: 10.1016/j.thromres.2025.109404. Epub 2025 Jul 16. PMID 40680469
• Mehic D, Schwarz S, Shulym I, Ay C, Pabinger I, Gebhart J. Health-related quality of life is impaired in bleeding disorders of unknown cause: results from the Vienna Bleeding Biobank. Res Pract Thromb Haemost. 2023 Aug 22;7(6):102176. doi: 10.1016/j.rpth.2023.102176. eCollection 2023 Aug. PMID 37720482
• van Duijl TT, Gouw S, Kronevska I, Kooiker A, Kopatz WF, Freato N, Beijlevelt M, Hamer HM, Fijnvandraat K, Meijers JCM, van den Biggelaar M. F9 missense variant hot spots associated with qualitative protein defects causing hemophilia B. Blood Vessel Thromb Hemost. 2025 Jul 18;2(4):100095. doi: 10.1016/j.bvth.2025.100095. eCollection 2025 Nov. PMID 41356341
• Heubel-Moenen FCJI, Brouns SLN, Herfs L, Boerenkamp LS, Jooss NJ, Wetzels RJH, Verhezen PWM, Machiels P, Megy K, Downes K, Heemskerk JWM, Beckers EAM, Henskens YMC. Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time. Br J Haematol. 2022 Mar;196(6):1388-1400. doi: 10.1111/bjh.18003. Epub 2022 Jan 10. PMID 35001370
• Baker RI, Choi P, Curry N, Gebhart J, Gomez K, Henskens Y, Heubel-Moenen F, James P, Kadir RA, Kouides P, Lavin M, Lordkipanidze M, Lowe G, Mumford A, Mutch N, Nagler M, Othman M, Pabinger I, Sidonio R, Thomas W, O'Donnell JS; ISTH SSC Von Willebrand Factor, Platelet Physiology, and Women's Health Issues in Thrombosis and Haemostasis. Standardization of definition and management for bleeding disor PMID 38518896
• MacDonald S, Wright A, Beuche F, Downes K, Besser M, Symington E, Kelly A, Thomas W. Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment. Int J Lab Hematol. 2020 Apr;42(2):116-125. doi: 10.1111/ijlh.13124. Epub 20 PMID 31747136

Identifiers

NCT: NCT07454161 · NL87370.068.24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗