Bleeding Disorder of Unknown Cause in the Netherlands

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.

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