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

April 23, 2026 updated by: Maastricht University Medical Center

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

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.

Study Overview

Status

Recruiting

Conditions

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.

Study Type

Observational

Enrollment (Estimated)

500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Netherlands
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6525 GA
        • Not yet recruiting
        • Radboud University Medical Center
    • Limburg
      • Maastricht, Limburg, Netherlands, 6228 HX
        • Recruiting
        • Maastricht University Medical Center
        • Contact:
    • North Brabant
      • Veldhoven, North Brabant, Netherlands, 5504 DB
        • Not yet recruiting
        • Maxima Medical Center
    • North Holland
      • Amsterdam, North Holland, Netherlands, 1105 AZ
        • Not yet recruiting
        • Amsterdam University Medical Center
    • Provincie Groningen
      • Groningen, Provincie Groningen, Netherlands, 971 GZ
        • Not yet recruiting
        • University Medical Center Groningen
    • South Holland
      • Leiden, South Holland, Netherlands, 2333 ZA
        • Not yet recruiting
        • Leiden University Medical Center
      • Rotterdam, South Holland, Netherlands, 3015 GD
        • Not yet recruiting
        • Erasmus Medisch Centrum
    • Utrecht
      • Utrecht, Utrecht, Netherlands, 3584 CX
        • Not yet recruiting
        • University Medical Center Utrecht

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Health-related quality of life
Time Frame: From enrollment to the end at 10 years
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
Time Frame: At baseline
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bleeding symptoms
Time Frame: From enrollment to the end at 10 years
Prevalence of bleeding symptoms in patients with BDUC.
From enrollment to the end at 10 years
Bleeding severity
Time Frame: From enrollment to the end at 10 years
Bleeding severity, using the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT). Range 0 to 56, with higher scores indicating a greater number and/or severity of bleeding symptoms.
From enrollment to the end at 10 years
Physical activity
Time Frame: From enrollment to the end at 10 years
Physical activity using the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH). Responses are converted into a total activity score, with higher scores indicating higher levels of physical activity.
From enrollment to the end at 10 years
Patient activation
Time Frame: From enrollment to the end at 10 years
Patient activation measured using the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH). Responses are converted into a total activity score, with higher scores indicating higher levels of physical activity.
From enrollment to the end at 10 years
Diagnostic delay
Time Frame: At baseline
The time (in years) between the onset of bleeding symptoms and the establishment of a BDUC diagnosis.
At baseline
Outcomes of hemostatic challenges
Time Frame: From enrollment to the end at 10 years
Occurrence of bleeding complications after surgery and childbirth.
From enrollment to the end at 10 years
Care pathways
Time Frame: From enrollment to the end at 10 years
Visualisation of the care pathway in BDUC including diagnostic procedures and follow up strategies.
From enrollment to the end at 10 years
Patient satisfaction with care
Time Frame: From enrollment to the end at 10 years
Patient satisfaction with current care will be assessed using semi-structured interviews and focus groups, and analyzed using thematic analysis to generate overarching themes reflecting patient satisfaction, reported as qualitative themes.
From enrollment to the end at 10 years
Platelet function disorder
Time Frame: At baseline
Number of patients with a (flow-dependent) platelet function disorder.
At baseline
Rare factor deficiency
Time Frame: At baseline
Number of patients with a rare factor deficiency.
At baseline
Fibrinolytic disorders
Time Frame: At baseline
Number of patients with a fibrinolytic disorder.
At baseline
Anticoagulant abundance
Time Frame: At baseline
Number of patients with an anticoagulant abundance.
At baseline
Endothelial dysfunction
Time Frame: From enrollment to the end at 10 years
Number of patients with signs of endothelial dysfunction, using ex vivo patient-derived cellular models.
From enrollment to the end at 10 years
Genetic and proteomic variants
Time Frame: At baseline
Identification of proteoforms and genetic variants associated with BDUC, including the detection of novel proteoforms and haemostatic modifiers that may contribute to the bleeding phenotype.
At baseline
Stratification of BDUC subgroups
Time Frame: From enrollment to the end at 10 years
Subgroups classification of persons with BDUC based on abnormalities in platelet, hemoglobin, and leukocyte parameters using rich full blood count data, in combination with clinical and laboratory characteristics.
From enrollment to the end at 10 years
Tranexamic acid supplementation
Time Frame: From enrollment to the end at 10 years
In vitro difference in thrombus formation before and after supplementation of tranexamic acid.
From enrollment to the end at 10 years
Platelet supplementation
Time Frame: From enrollment to the end at 10 years
In vitro difference in thrombus formation before and after supplementation of platelets.
From enrollment to the end at 10 years
von Willebrand factor/factor VIII supplementation
Time Frame: From enrollment to the end at 10 years
In vitro difference in thrombus formation before and after supplementation of von Willebrand factor/factor VIII.
From enrollment to the end at 10 years
AI driven prediction model for bleeding
Time Frame: From enrollment to the end at 10 years
Development of AI driven prediction model for bleeding in patients with BDUC, leveraging patient clinical profiles and biomarker data.
From enrollment to the end at 10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Maastricht University Medical Center

Collaborators

Sanquin Research & Blood Bank Divisions

Investigators

  • Principal Investigator: F.C.J.I. Heubel-Moenen, Dr., Maastricht University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2026

Primary Completion (Estimated)

March 1, 2039

Study Completion (Estimated)

March 1, 2039

Study Registration Dates

First Submitted

March 2, 2026

First Submitted That Met QC Criteria

March 2, 2026

First Posted (Actual)

March 6, 2026

Study Record Updates

Last Update Posted (Actual)

April 27, 2026

Last Update Submitted That Met QC Criteria

April 23, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL87370.068.24

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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