The Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B

Study Overview
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Brief Summary
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There are large inter-individual differences in the bleeding pattern of patients with moderate or mild hemophilia. The major determinant of bleeding phenotype is the level of coagulant factor VIII or IX. In hemophilia A, studies addressing the association between factor VIII level and the clinical bleeding pattern yield conflicting results. In hemophilia B such studies have not yet been performed. The primary aim of this project is to analyze the association between factor VIII and factor IX levels and the bleeding phenotype. The secondary aim is to analyze potential differences in phenotype between hemophilia A and B. The project is a multicentre observational cohort study. We will include 500 patients with moderate or mild hemophilia A (FVIII 0.02-0.35 IU/mL) and 500 patients with moderate or mild hemophilia B (FIX 0.02-0.35 IU/mL) who are 12 to 55 years old. The main cohort study consists of clinical data collection, one blood sample and an online questionnaire for patients. Data will be collected on the nature and duration of all bleeding episodes, disease and treatment characteristics, physical activity level and musculoskeletal status. One blood withdrawal will be performed for centralized laboratory assays for FVIII or FIX levels (both one-stage and chromogenic assays) and genetic analysis for the most prevalent prothrombotic mutations. The online questionnaire for patients focuses on bleeds experienced in the past. A subset of 200 patients aged 24 years or older (100 with moderate or mild hemophilia A and 100 with moderate or mild hemophilia B) will be investigated in more detail by longitudinal data collection including analysis of physical joint status, MRI imaging of joints and biomarkers for joint damage. This longitudinal observation will consist of two time points that lie two years apart, allowing us to identify any changes that occur over the observed time period with respect to joint status.

Official Title
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The Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B

Conditions
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Hemophilia

Intervention / Treatment
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* Other: Blood sample
* Other: Questionnaire
* Other: MRI-imaging
* Other: Physical examination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Moderate or mild hemophilia A (FVIII:C 0.02-0.35 IU/mL) or hemophilia B (FIX:C 0.02-0.35 IU/mL) Age from 12 up to and including 55 years Exclusion Criteria: Other clotting disorder Participation in another trial with an investigational product Comorbidity affecting the musculoskeletal status Clinically relevant inhibitor status at present or in the past Hemophilia B Leyden Use of anticoagulants

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort study population<br>For the main cohort study, we will include 500 patients with moderate or mild hemophilia A and 500 patients with moderate or mild hemophilia B. | Other: Blood sample<br>* Blood withdrawal.<br>Other: Questionnaire<br>* Online questionnaire about the bleeds that patients experienced in the past.<br>|
| Sub study population<br>A subset of 200 patients of the cohort study population will be investigated in more detail by longitudinal data collection. | Other: Blood sample<br>* Blood withdrawal.<br>Other: MRI-imaging<br>* MRI imaging of joints.<br>Other: Physical examination<br>* Physical examination of joint status.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding phenotype | Annual bleeding rate, annual major bleeding rate, annual spontaneous joint bleeding rate, annual joint bleeding rate | Retrospective 10 years |