Bleeding Disorder of Unknown Cause, Hemorrhagic Disorders
Conditions
Keywords
Bleeding disorder of unknown cause, Hemostasis, Diagnosis, Management, Pathofysiology, Quality of life, Prospective
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. 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.
Interventions
None listed
Sponsors
Maastricht University Medical Center
Sanquin Research & Blood Bank Divisions
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Health-related quality of life | 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. |
| Diagnostic yield | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bleeding symptoms | From enrollment to the end at 10 years | Prevalence of bleeding symptoms in patients with BDUC. |
| Bleeding severity | 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. |
| Physical activity | 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. |
| Patient activation | 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. |
| Diagnostic delay | At baseline | The time (in years) between the onset of bleeding symptoms and the establishment of a BDUC diagnosis. |
| Outcomes of hemostatic challenges | From enrollment to the end at 10 years | Occurrence of bleeding complications after surgery and childbirth. |
| Care pathways | From enrollment to the end at 10 years | Visualisation of the care pathway in BDUC including diagnostic procedures and follow up strategies. |
| Patient satisfaction with care | 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. |
| Platelet function disorder | At baseline | Number of patients with a (flow-dependent) platelet function disorder. |
| Rare factor deficiency | At baseline | Number of patients with a rare factor deficiency. |
| Fibrinolytic disorders | At baseline | Number of patients with a fibrinolytic disorder. |
| Anticoagulant abundance | At baseline | Number of patients with an anticoagulant abundance. |
| Endothelial dysfunction | From enrollment to the end at 10 years | Number of patients with signs of endothelial dysfunction, using ex vivo patient-derived cellular models. |
| Genetic and proteomic variants | 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. |
| Stratification of BDUC subgroups | 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. |
| Tranexamic acid supplementation | From enrollment to the end at 10 years | In vitro difference in thrombus formation before and after supplementation of tranexamic acid. |
| Platelet supplementation | From enrollment to the end at 10 years | In vitro difference in thrombus formation before and after supplementation of platelets. |
| von Willebrand factor/factor VIII supplementation | From enrollment to the end at 10 years | In vitro difference in thrombus formation before and after supplementation of von Willebrand factor/factor VIII. |
| AI driven prediction model for bleeding | 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. |
Countries
Netherlands
Contacts
CONTACTDr. F.C.J.I. Heubel-Moenen
PRINCIPAL_INVESTIGATORF.C.J.I. Heubel-Moenen, Dr.
Maastricht University Medical Center
Outcome results
None listed