Bleeding Disorder of Unknown Cause In the Netherlands (BDUC-iN Study)
Trial Snapshot
- Phase
- Not Applicable
- Status
- Not yet recruiting
- Enrollment
- 500
- Locations
- 8
- Primary Endpoint
- The prevalence of bleeding disorders
Study Overview
Brief Summary
The purpose of the BDUC-iN study is to learn more about unexplained bleeding in individuals with bleeding disorder of unknown cause (BDUC). We aim 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:
- What are the mechanisms underlying the bleeding tendency in BDUC?
- How do bleeding symptoms affect patients' daily functioning and overall health-related quality of life?
- 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 haemophilia treatment centers in the Netherlands. They 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 affects 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 for the bleeding tendency, there is currently no clear guideline or consensus available for treatment of persons with BDUC. The lack of a clear diagnosis of BDUC is therefore challenging for both the individual and the treating physician.
Objectives: The BDUC-iN study 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: We have designed a multicenter, observational cohort study involving 500 individuals with BDUC registered at or investigated in one of the six Haemophilia 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 Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 12 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Referred to a (pediatric) hemostasis specialist for evaluation of bleeding tendency.
- •Increased bleeding tendency based on: Abnormal 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
- •PT and aPTT: within local reference range, or prolonged without explanatory factor deficiency
- •Fibrinogen activity, VWF antigen & activity, Factor VIII, IX, XI and XIII: within local reference range or abnormal but not explaining bleeding phenotype
- •Light transmission aggregometry: Not diagnostic for a platelet function
- •Kidney function: EGFR > 45 ml/min
- •Liver function: ALAT, bilirubin < 3 x ULN
Exclusion Criteria
- •Use of medication interfering with laboratory hemostasis tests which cannot be stopped before blood withdrawal (e.g. anticoagulant or antiplatelet therapy, NSAID's, SSRI's)
- •Pregnancy or lactation at moment of inclusion
- •Presence of a known bleeding disorder
- •Presence of an acquired cause or another explanation for the increased bleeding tendency
- •Inability to provide informed consent
Arms & Interventions
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.
Outcomes
Primary Outcomes
The prevalence of bleeding disorders
Time Frame: At baseline
To determine the prevalence of identifiable bleeding disorders in persons with BDUC using advanced hemostasis testing and proteomic analyses. The primary outcome reflects the proportion of participants in whom a hemostatic abnormality is detected.
Health-related quality of life
Time Frame: From enrollment to the end at 10 years
To assess health-related quality of life (HRQoL) in persons with BDUC using validated questionnaires, and to evaluate changes over time in relation to bleeding symptoms and their impact on physical functioning and social participation. Questionnaires will be administered at multiple time points during follow-up.
Secondary Outcomes
- Clinical characteristics and bleeding phenotype in BDUC(From enrollment to the end at 10 years)
- Care pathways for persons with BDUC(From enrollment to the end at 10 years)
- Perceived quality of care in BDUC(From enrollment to the end at 10 years)
- Distribution of identified bleeding disorder subtypes(At baseline)
- Longitudinal changes in hemostatic parameters(From enrollment to the end at 10 years)
- Identification of genetic and proteomic variants contributing to BDUC(From enrollment to the end at 10 years)
- Stratification of BDUC subgroups based on blood cell parameters(At baseline)
- Endothelial cell function in haemostasis in BDUC(From enrollment to the end at 10 years)
- In vitro effectiveness and safety of targeted therapeutic strategies(From enrollment to the end at 10 years)
- Data-driven prediction and diagnostic tools for BDUC(From enrollment to the end at 10 years)