Ignite Creation Date:
2026-03-26 @ 3:14 PM
Ignite Modification Date:
2026-03-31 @ 2:16 AM
Study NCT ID:
NCT07454161
Status:
NOT_YET_RECRUITING
Last Update Posted:
2026-03-06
First Post:
2026-03-02
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Bleeding Disorder of Unknown Cause in the Netherlands
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2026-03-25'}, 'conditionBrowseModule': {'meshes': [{'id': 'D006474', 'term': 'Hemorrhagic Disorders'}, {'id': 'D004194', 'term': 'Disease'}], 'ancestors': [{'id': 'D006402', 'term': 'Hematologic Diseases'}, {'id': 'D006425', 'term': 'Hemic and Lymphatic Diseases'}, {'id': 'D010335', 'term': 'Pathologic Processes'}, {'id': 'D013568', 'term': 'Pathological Conditions, Signs and Symptoms'}]}}, 'protocolSection': {'designModule': {'bioSpec': {'retention': 'SAMPLES_WITH_DNA', 'description': '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.'}, 'studyType': 'OBSERVATIONAL', 'designInfo': {'timePerspective': 'PROSPECTIVE', 'observationalModel': 'COHORT'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 500}, 'targetDuration': '10 Years', 'patientRegistry': True}, 'statusModule': {'overallStatus': 'NOT_YET_RECRUITING', 'startDateStruct': {'date': '2026-03-01', 'type': 'ESTIMATED'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2026-03', 'completionDateStruct': {'date': '2039-03-01', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2026-03-02', 'studyFirstSubmitDate': '2026-03-02', 'studyFirstSubmitQcDate': '2026-03-02', 'lastUpdatePostDateStruct': {'date': '2026-03-06', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2026-03-06', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2039-03-01', 'type': 'ESTIMATED'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'The prevalence of bleeding disorders', 'timeFrame': 'At baseline', 'description': '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.'}, {'measure': 'Health-related quality of life', 'timeFrame': 'From enrollment to the end at 10 years', 'description': '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.'}], 'secondaryOutcomes': [{'measure': 'Clinical characteristics and bleeding phenotype in BDUC', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To describe demographic characteristics, bleeding history, bleeding scores, and prevalence of bleeding symptoms in persons with BDUC in the Netherlands.'}, {'measure': 'Care pathways for persons with BDUC', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To describe and visualize current care pathways, including diagnostic and treatment strategies used for bleeding episodes (i.e. surgical procedures and childbirth) in persons with BDUC, including the observed treatment responses.'}, {'measure': 'Perceived quality of care in BDUC', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To assess patient and healthcare professional experiences with BDUC care, including perceptions of diagnostic processes, information provision, communication, accessibility of care, and provided treatment.'}, {'measure': 'Distribution of identified bleeding disorder subtypes', 'timeFrame': 'At baseline', 'description': 'To describe the distribution of identified bleeding disorder subtypes among participants with a detected hemostatic abnormality, including , coagulation factor deficiencies, fibrinolytic disorders, (flow dependent) platelet function disorders, anticoagulant abundance, global hemostasis (dys)function, and endothelial or vascular dysfunction.'}, {'measure': 'Longitudinal changes in hemostatic parameters', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To evaluate changes in coagulation and hemostatic parameters over time in participants with BDUC during longitudinal follow-up.'}, {'measure': 'Identification of genetic and proteomic variants contributing to BDUC', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To identify proteoforms and genetic variants associated with BDUC, including the detection of novel proteoforms and haemostatic modifiers that may contribute to the bleeding phenotype.'}, {'measure': 'Stratification of BDUC subgroups based on blood cell parameters', 'timeFrame': 'At baseline', 'description': 'To classify subgroups 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.'}, {'measure': 'Endothelial cell function in haemostasis in BDUC', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To assess endothelial cell contributions in the hemostasic process in persons with BDUC using ex vivo patient-derived cellular models, including endothelial and platelet secretion profiles and identification of novel endothelial-related hemostatic modifiers.'}, {'measure': 'In vitro effectiveness and safety of targeted therapeutic strategies', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To evaluate the in vitro effects of targeted therapeutic strategies on haemostatic function, including platelet adhesion, activation, aggregation, thrombus formation, and thrombin generation, using agents such as tranexamic acid, platelet supplementation, and von Willebrand factor/factor VIII.'}, {'measure': 'Data-driven prediction and diagnostic tools for BDUC', 'timeFrame': 'From enrollment to the end at 10 years', 'description': 'To develop and evaluate data-driven models and algorithms to predict bleeding risk and support diagnostic evaluation in persons with BDUC, including identification of relevant biomarkers and clinical-haemostatic associations.'}]}, 'oversightModule': {'oversightHasDmc': True, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'keywords': ['Bleeding disorder of unknown cause', 'Hemostasis', 'Diagnosis', 'Management', 'Pathofysiology', 'Quality of life', 'Prospective'], 'conditions': ['Hemorrhagic Disorders', 'Bleeding Disorder of Unknown Cause']}, 'referencesModule': {'references': [{'pmid': '37720482', 'type': 'BACKGROUND', 'citation': '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': '40680469', 'type': 'BACKGROUND', 'citation': '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': '41356341', 'type': 'BACKGROUND', 'citation': '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': '35001370', 'type': 'BACKGROUND', 'citation': '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': '40421900', 'type': 'BACKGROUND', 'citation': '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': '38518896', 'type': 'BACKGROUND', 'citation': "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': '31747136', 'type': 'BACKGROUND', 'citation': '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': '33094877', 'type': 'BACKGROUND', 'citation': '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.'}]}, 'descriptionModule': {'briefSummary': "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.\n\nThe main questions of this study are:\n\n1. What are the mechanisms underlying the bleeding tendency in BDUC?\n2. How do bleeding symptoms affect patients' daily functioning and overall health-related quality of life?\n3. How is care delivered to individuals with BDUC, and how can this be improved?\n\nParticipants 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.", 'detailedDescription': '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.\n\nObjectives: 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.\n\nMethods: 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.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['CHILD', 'ADULT', 'OLDER_ADULT'], 'minimumAge': '12 Years', 'samplingMethod': 'NON_PROBABILITY_SAMPLE', 'studyPopulation': '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 haemophilia treatment centers in the Netherlands and approached for study participation by their treating physician.', 'healthyVolunteers': False, 'eligibilityCriteria': "Inclusion Criteria:\n\n* Referred to a (pediatric) hemostasis specialist for evaluation of bleeding tendency.\n* 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\n* Absence of diagnostic test results for a bleeding disorder in standard laboratory hemostasis tests:\n* Complete blood count: Hemoglobin \\> 6.0 mmol/L; thrombocyte count \\> 100 x10\\^9/L\n* PT and aPTT: within local reference range, or prolonged without explanatory factor deficiency\n* Fibrinogen activity, VWF antigen \\& activity, Factor VIII, IX, XI and XIII: within local reference range or abnormal but not explaining bleeding phenotype\n* Light transmission aggregometry: Not diagnostic for a platelet function\n* Kidney function: EGFR \\> 45 ml/min\n* Liver function: ALAT, bilirubin \\< 3 x ULN\n\nExclusion Criteria:\n\n* 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)\n* Pregnancy or lactation at moment of inclusion\n* Presence of a known bleeding disorder\n* Presence of an acquired cause or another explanation for the increased bleeding tendency\n* Inability to provide informed consent"}, 'identificationModule': {'nctId': 'NCT07454161', 'acronym': 'BDUC-iN', 'briefTitle': 'Bleeding Disorder of Unknown Cause in the Netherlands', 'organization': {'class': 'OTHER', 'fullName': 'Maastricht University Medical Center'}, 'officialTitle': 'Bleeding Disorder of Unknown Cause In the Netherlands (BDUC-iN Study)', 'orgStudyIdInfo': {'id': 'NL87370.068.24'}}, 'armsInterventionsModule': {'armGroups': [{'label': 'Bleeding Disorder of Unknown Cause', 'description': '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).\n\nThe 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.\n\nIn 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.'}]}, 'contactsLocationsModule': {'locations': [{'zip': '6525 GA', 'city': 'Nijmegen', 'state': 'Gelderland', 'country': 'Netherlands', 'facility': 'Radboud University Medical Center', 'geoPoint': {'lat': 51.8425, 'lon': 5.85278}}, {'zip': '6228 HX', 'city': 'Maastricht', 'state': 'Limburg', 'country': 'Netherlands', 'contacts': [{'name': 'F.C.J.I. Heubel-Moenen, Dr.', 'role': 'CONTACT', 'email': 'floor.moenen@mumc.nl', 'phone': '+31 (0)43 3876543'}], 'facility': 'Maastricht University Medical Center', 'geoPoint': {'lat': 50.84833, 'lon': 5.68889}}, {'zip': '5504 DB', 'city': 'Veldhoven', 'state': 'North Brabant', 'country': 'Netherlands', 'facility': 'Maxima Medical Center', 'geoPoint': {'lat': 51.41833, 'lon': 5.40278}}, {'zip': '1105 AZ', 'city': 'Amsterdam', 'state': 'North Holland', 'country': 'Netherlands', 'facility': 'Amsterdam University Medical Center', 'geoPoint': {'lat': 52.37403, 'lon': 4.88969}}, {'zip': '971 GZ', 'city': 'Groningen', 'state': 'Provincie Groningen', 'country': 'Netherlands', 'facility': 'University Medical Center Groningen', 'geoPoint': {'lat': 53.21917, 'lon': 6.56667}}, {'zip': '2333 ZA', 'city': 'Leiden', 'state': 'South Holland', 'country': 'Netherlands', 'facility': 'Leiden University Medical Center', 'geoPoint': {'lat': 52.15833, 'lon': 4.49306}}, {'zip': '3015 GD', 'city': 'Rotterdam', 'state': 'South Holland', 'country': 'Netherlands', 'facility': 'Erasmus Medisch Centrum', 'geoPoint': {'lat': 51.9225, 'lon': 4.47917}}, {'zip': '3584 CX', 'city': 'Utrecht', 'state': 'Utrecht', 'country': 'Netherlands', 'facility': 'University Medical Center Utrecht', 'geoPoint': {'lat': 52.09083, 'lon': 5.12222}}], 'centralContacts': [{'name': 'Dr. F.C.J.I. Heubel-Moenen', 'role': 'CONTACT', 'email': 'floor.moenen@mumc.nl', 'phone': '+31 (0)43 3876543'}], 'overallOfficials': [{'name': 'F.C.J.I. Heubel-Moenen, Dr.', 'role': 'PRINCIPAL_INVESTIGATOR', 'affiliation': 'Maastricht University Medical Center'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'UNDECIDED'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Maastricht University Medical Center', 'class': 'OTHER'}, 'collaborators': [{'name': 'Sanquin Research & Blood Bank Divisions', 'class': 'OTHER'}], 'responsibleParty': {'type': 'SPONSOR'}}}}