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INHIBITOR TO ANTIHEMOPHILIC FACTOR Djajadiman Gatot Division of Hematology Oncology Department of Child Health FMUI - CMGH.

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Presentation on theme: "INHIBITOR TO ANTIHEMOPHILIC FACTOR Djajadiman Gatot Division of Hematology Oncology Department of Child Health FMUI - CMGH."— Presentation transcript:

1 INHIBITOR TO ANTIHEMOPHILIC FACTOR Djajadiman Gatot Division of Hematology Oncology Department of Child Health FMUI - CMGH

2 What is inhibitor? (to factor VIII)  Inhibitor are polyclonal allo-antibodies of the IgG molecules predominantly of the IgG4 subclass that directed to FVIII  Highly heterogeneous among patients  Display changes in epitope specificity over time  Its synthesis requires activated CD4+ cells  Neutralized the procoagulant activity of FVIII and render infusion of FVIII inefficient

3 How do inhibitor develop? FVIII is a soluble glycoprotein; its adminis- tration to an individual with normal immunocompetence will results in immune response The FVIII genotype has major influence for the development of inhibitors

4 Who will develop inhibitor? FVIII genotype and the risk of developing inhibitor: - large deletion (  88%) - nonsense mutations (  60%) - intron-22 inversion (  21%) - small deletions/insertions (  20%) - missense mutations (  5%)

5 Inhibitor Location of major factor VIII inhibitory epitopes

6 Who will develop inhibitor? HLA and the risk of developing inhibitor  ethnic group, African-American 2x than whites  family history of antibodies to FVIII  inherited predisposition hemophilic siblings >> extended hemophilic relatives  any severe hemophilia

7 When will inhibitor develop? The majority of inhibitors develop during childhood, at an average of 12 years Reported studies:  Inhibitor development occurred between the age of 1 – 2 yrs, after an average of 10 treatments with rFVIII  Inhibitor risk is greatest during the first 50 exposures to rFVIII

8 What is the incidence of inhibitor? Inhibitors of FVIII develop in up to 30% of hemophilia A patients and significantly more frequent in severe hemophilia

9 Why ‘only’ 30% of hemophilia patients have inhibitor? There are several possible mechanisms: 1)anti-FVIII antibodies are neutralized in the periphery, 2)B cells (and T cells) can be rendered anergic by intrinsic mechanism, 3)any antibodies produced are primarily directed towards sites of the FVIII molecule that are not involved in its function

10 InhibitorClassificationTreatment Low titer (< 5 BU) Higher/more frequent dose of factor concentrate High titer (> 5 BU) By-passing agent Immune tolerance induction Rituximab (?) Haemophilia 2006;12:7–18. Haemophilia 2006;12:218–22.

11 Management of bleeding in patient with inhibitor The ultimate goals of treatment are: 1.Resolution of bleeding diathesis 2.The elimination of the inhibitor

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21 Resolution of Bleeding Diathesis Replacement therapy: ~ human FVIII (high-dose) ~ recombinant FVIII (2 nd and 3 rd generation) ~ porcine FVIII Bypass therapy: ~ prothrombin complex concentrate (PCC) ~ activated PCC ~ recombinant FVIIa

22 Contact activation XIa IXa+VIII APC TM TF-VIIa Xa+V IIaFibrinFibrinolysis TAFI TFPI TM

23 The elimination of inhibitor Immune tolerance induction (ITI), - may take up to 1 – 3 years to achieve tolerance - very high cost - successfully eradicating up to 90% of FVIII inhibitor Immunomodulation, + cytostatics: cyclophosphamide, 6-mercaptopurine + immunosuppressant: azathioprine, cyclosporin + corticosteroids + gamma globulin + plasmapheresis

24 Immune tolerance induction The dose: High level inhibitors (>100 BU), treated with high-dose regimen: IU kg -1 day -1 Low titer inhibitors (5-100 BU), treated either with high- or low-dose regimen: 50 IU kg -1, 3 times per week

25 Immune tolerance induction The cost:  British: 0.25 – 1 million £ per patient  Italy: 18,000 € per patient, monthly  USA: 1,7 million $ per patient

26 Thank You


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