Bleeding Disorder of Unknown Cause in the Netherlands

NCT07454161 | Recruiting DMC

• 1 other identifier: NL87370.068.24
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 8

Brief Summary

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. 1.What are the mechanisms underlying the bleeding tendency in BDUC?
2. 2.How do bleeding symptoms affect patients' daily functioning and overall health-related quality of life?
3. 3.How is care delivered to individuals with BDUC, and how can this be improved?

Conditions

Hemorrhagic Disorders; Bleeding Disorder of Unknown Cause

Keywords

Bleeding disorder of unknown cause; Hemostasis; Diagnosis; Management; Pathofysiology; Quality of life; Prospective

Outcome Measures

Primary Outcomes (2)

• Health-related quality of life

  Using the Patient-Reported Outcomes Measurement Information System (PROMIS) in adults and the Pediatric Quality of Life Inventory (PedsQL) in children. PROMIS: responses are converted into T-scores, where higher scores indicate a greater level of the concept being measured (e.g., higher physical function or greater pain, depending on the domain). PedsQL: range 0-100 scale, with higher scores indicating better HRQoL.

  From enrollment to the end at 10 years

• Diagnostic yield

  The diagnostic yield of advanced platelet function, hemostasis and fibrinolytic testing in individuals with BDUC, by examining the frequency and nature of the identified hemostasis abnormalities and their potential relevance to the bleeding phenotype.

  At baseline

Secondary Outcomes (19)

• Bleeding symptoms

  From enrollment to the end at 10 years

• Bleeding severity

  From enrollment to the end at 10 years

• Physical activity

  From enrollment to the end at 10 years

• Patient activation

  From enrollment to the end at 10 years

• Diagnostic delay

  At baseline

Study Arms (1)

Bleeding Disorder of Unknown Cause

This cohort consists of patients aged ≥12 years presenting with a clinically relevant increased bleeding tendency, as determined by a medical specialist or indicated by an elevated ISTH Bleeding Assessment Tool (ISTH-BAT) score, who remain without a definitive hemostatic diagnosis after extensive laboratory evaluation. These individuals are classified as having a bleeding disorder of unknown cause (BDUC). The bleeding phenotype in this cohort is generally similar to that of patients with established coagulation disorders. Participants frequently experience an increased risk of bleeding during daily life (e.g., heavy menstrual bleeding) and during medical procedures such as surgery, dental interventions, or childbirth, as well as following trauma. In this study, participants will undergo blood sampling for advanced hemostasis and genetic analysis, complete questionnaires, and be followed longitudinally to assess the impact of bleeding on health-related quality of life.

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals aged ≥12 years with a clinically relevant increased bleeding tendency, based on an elevated ISTH Bleeding Assessment Tool (ISTH-BAT) score or the clinical view of a (pediatric) hemostasis specialist, who remain undiagnosed following comprehensive laboratory investigation and are consequently classified as having a bleeding disorder of unknown cause (BDUC), will be identified at one of the six Hemophilia treatment centers in the Netherlands and approached for study participation by their treating physician.

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Maastricht University Medical Center: lead
• Sanquin Research & Blood Bank Divisions: collaborator

Study Sites (8)

Radboud University Medical Center

Nijmegen, Gelderland, 6525 GA, Netherlands

NOT YET RECRUITING

Maastricht University Medical Center

Maastricht, Limburg, 6228 HX, Netherlands

RECRUITING

Maxima Medical Center

Veldhoven, North Brabant, 5504 DB, Netherlands

NOT YET RECRUITING

Amsterdam University Medical Center

Amsterdam, North Holland, 1105 AZ, Netherlands

NOT YET RECRUITING

University Medical Center Groningen

Groningen, Provincie Groningen, 971 GZ, Netherlands

NOT YET RECRUITING

Leiden University Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

NOT YET RECRUITING

Erasmus Medisch Centrum

Rotterdam, South Holland, 3015 GD, Netherlands

NOT YET RECRUITING

University Medical Center Utrecht

Utrecht, Utrecht, 3584 CX, Netherlands

NOT YET RECRUITING

Related Publications (9)

• 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(8):102625. doi: 10.1016/j.rpth.2024.102625. eCollection 2024 Nov.

  PMID: 39687924 BACKGROUND

• 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. Epub 2025 May 27.

  PMID: 40421900 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 disorder of unknown cause: communication from the SSC of the ISTH. J Thromb Haemost. 2024 Jul;22(7):2059-2070. doi: 10.1016/j.jtha.2024.03.005. Epub 2024 Mar 20.

  PMID: 38518896 BACKGROUND

• 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 2019 Nov 20.

  PMID: 31747136 BACKGROUND

• Thomas W, Downes K, Desborough MJR. Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management. Haemophilia. 2020 Nov;26(6):946-957. doi: 10.1111/hae.14174. Epub 2020 Oct 23.

  PMID: 33094877 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples will be collected for advanced hemostasis testing and DNA analysis. Biospecimens, including plasma and whole blood, will be stored in accordance with informed consent and applicable regulations.

MeSH Terms

Conditions

Hemorrhagic Disorders; Disease

Condition Hierarchy (Ancestors)

Hematologic Diseases; Hemic and Lymphatic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• F.C.J.I. Heubel-Moenen, Dr.

  Maastricht University Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr. F.C.J.I. Heubel-Moenen

CONTACT

+31 (0)43 3876543; floor.moenen@mumc.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 10 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2026
• First Posted: March 6, 2026
• Study Start: May 1, 2026
• Primary Completion (Estimated): March 1, 2039
• Study Completion (Estimated): March 1, 2039
• Last Updated: April 27, 2026

Record last verified: 2026-04

Locations

NL (8)