bleeding disorder coagulation disorder
Conditions
Interventions
Sponsors
Universitair Medisch Centrum Utrecht
Eligibility
Age
2 Years to 64 Years
Inclusion criteria
Inclusion criteria: - Age: 6 years and older - Previously confirmed Hemophilia A - Previously and frequently (> 50 ED) treated with factor VIII - Willing and be able to understand the study information and sign the informed consent form;Different subgroups: * 10 adults with an inhibitor (5 patients with mild or moderate hemophilia A, 5 patients with severe hemophilia A) * 10 adults without an inhibitor after successful ITI * 20 patients (10 adults, 10 children age > 6 years) without an inhibitor and without a history of ITI
Exclusion criteria
Exclusion criteria: - Documented history of persisting severe anaemia (defined as haemoglobin
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| - Immunologic analysis with a comparison between patients with and without inhibitor: * Amount and phenotype of FVIII specific B-cells, ie B-naïve, B-memory, B plasma cell. * Amount of regulatory B-cells * Amount of myeloid derived suppressor cells (MDSCs) * Amount and phenotype of FVIII specific CD4-cells (T-cells), ie T effector vs. T regulator. * Activation and proliferation status of CD4+ T-cells * Function of regulatory T-cells * Amount and type of FVIII antibodies * Cytokine production (pro- versus anti-inflammatory) With the abovementioned analyses we will test what will cause tolerance, i.e. on one side the elimination or absence of FVIII-specific effector B- and T-cells or on the other hand the induction of regulatory cells (regulatory B- and T-cells and MDSCs). Moreover some functional assays will be performed to evaluate not only differences in quantity, but also possible differences in the function / quality of effector and regulatory T-cells, Finally the role of pro- vs. anti-inflammatory cytokines will be evaluated (which is also indirectly related tot the ratio between pro-inflammatory and regulatory cells). | — |
Secondary
| Measure | Time frame |
|---|---|
| - Creating an in-vitro human model of ITI and testing different factor VIII products with regard to their potency to generate an inflammatory or more tolerogenic respons * Co-culture of CD4+ T-cells (naive or FVIII-specific) with B-LCL (EBV immortalized B-cells, acting as antigen presenting cells) and addition of different types of FVIII producs * After 24 hours measurement of T-cell response: 1) Amount and subtype of CD4+ T-cells (effector vs. regulatory T-cells) 2) T-cel activation and proliferation status 3) Cytokine profile (pro- vs. anti-inflammatory) | — |
Countries
The Netherlands
Outcome results
None listed