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Table of contents
I. INTRODUCTION
I.1. Hemophilia A
I.1.1. Generalities
I.1.1.1. Historical aspects
I.1.1.2. Phenotypic aspects
I.1.1.3. Genetic aspects
I.1.1.4 Bleeding complications in Hemophilia A
I.1.2 The coagulation cascade
I.1.2.1 Primary haemostasis
I.1.2.2 Secondary haemostasis
I.1.2.2.1 The extrinsic pathway
I.1.2.2.2 The intrinsic pathway
I.2.2.3 Pro-coagulant factor VIII
I.2.2.3.1 Synthesis, structure and post-traductional modifications
I.2.2.3.2 Activation of FVIII
I.2.2.3.3 Life cycle of FVIII, catabolic receptors, in vivo distribution, site of elimination
I.2.2.3.4 Catabolic receptors for FVIII
I.2.2.3.5 In vivo distribution of FVIII
I.1.3 Prevention or treatment of bleeding episodes in patients with hemophilia A
I.1.3.1 Factor VIII products
I.1.3.2 Infusion regiment
I.1.3.3 Complications of the treatment
I.1.3.4 Treatment of patients with FVIII inhibitors
I.2 The anti-factor VIII immune response
I.2.1 FVIII as seen by the immune system in patients with hemophilia A
I.2.2 Antigen-presenting cells
I.2.2.1 Dendritic cells
I.2.2.2 Macrophages
I.2.2.3 B cells
I.2.3 The spleen
I.2.4 The anti-FVIII immune response in hemophilia A patients
I.2.4.1 T-cell activation
I.2.4.2 B-cell activation
I.3 Risk factors
I.3.1 The danger signal theory
I.3.1.1 Exogenous danger signals
I.3.1.2 Endogenous danger signals
I.3.2 Genetic risk factors
I.3.2.1 FVIII mutations
I.3.2.2 HLA haplotype
I.3.2.3 Polymorphisms in immune-related genes
I.3.3 Non-genetic risk factors
I.3.3.1 Age at the start of treatment
I.3.3.2 Mode and intensity of FVIII administration
I.3.3.3 State of the immune system at the time of FVIII infusion
I.4 Purpose of the PhD work
II. RESULTS
II.1. Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphism in the HMOX1 promoter
II.2. Hemarthrosis and arthropathies do not favor the development of factor VIII inhibitors in hemophilia A mice
II.3. Restoration of the oxidative balance in factor VIII-deficient mice reduces the immunogenicity of therapeutic factor VIII
II.4. Oxidation of therapeutic factor VIII aggravates its immunogenicity in factor-VIII deficient mice
III. DISCUSSION
IV. REFERENCES
V. ANNEXES
