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

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: 100-200 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