1 / 14

Inhibitors

Inhibitors. Why they happen What are they How to control them Treatment options. Why Inhibitors H appen. Genetics Hemophilia severity More common in severe hemophilia FVIII mutations Mutations in intron 22 and 1 (regions inside a gene) Nonsense mutations Stop codon

tyrell
Download Presentation

Inhibitors

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Inhibitors Why they happen What are they How to control them Treatment options

  2. Why Inhibitors Happen • Genetics • Hemophilia severity • More common in severe hemophilia • FVIII mutations • Mutations in intron 22 and 1 (regions inside a gene) • Nonsense mutations • Stop codon • Inversion mutations • DNA is reversed in (breaks off DNA and reinserts in reverse) • Family History • Higher chance of family member developing inhibitor if in family • Race/Ethnicity • Subtypes of FVIII (different types in different race/ethnicity, rFVIII is based on white FVIII) 3X higher

  3. Environmental • Environmental • Intensive FVIII exposure • Continuous infusions • surgery --Immunological/inflammatory/infectious events Stimulation of immune system to produce antibodies • Use of rFVIII products • 27% in PUPs (Previously Untreated Patients)

  4. Types of Inhibitors • Hemophilia A and B inhibitors • FVIII • FIX • Acquired Hemophilia • The body's natural clotting process is disrupted • The body produces antibodies that fight its own blood-clotting proteins (auto-immune) • Not genetic, no family history

  5. What are Inhibitors • Epitopes • A binding site on the antigen • Inhibitors are antibodies • Antibodies are produced by your body in response to disease (viral or bacteria) • Antigen • Foreign object in body

  6. Antibody/Antigen site

  7. Presentation of Inhibitor • Uncontrolled bleeding in patient • Patient is given factor with bleed • Bleeding is not controlled with factor Breakthrough bleeding on prophy --Signs of bleeding while on regular treatment of factor VIII or IX

  8. Bethesda/Nijmegen Assay • Bethesda is the test performed to measure inhibitors • One BU is the amount of inhibitor needed to inactivate 50% of FVIII in pooled normal plasma • Nijmegen assay • Low level antibodies • Antibody/Elisa test • Short half life

  9. Classifications of Inhibitors • Low titer • 5 BU or less • High titer • 5 BU or higher • Low-responding • Never rise above 5 BU (not anamnestic) • High-responding • Above 5 BU (sharp rise in antibody titer within 5-6 days of fVIII exposure

  10. Immune Tolerance Induction • Goal-To restore normal replacement of factor • BONN • High responding-FVIII 100-150 IU/KG every 12 hours • Van Creveld/Dutch Protocol • FVIII given 25IU/KG every other day • Malmo Protocol • BONN protocol with immunosuppressant w/corticosteroids and cyclophosphamide, IVIG

  11. Treatment Options • NovoSeven • rFVIIa • Intrinsic pathway • Induces hemostasis by activating sufficient FX on activated platelet surface thrombin generation • Feiba • aPCC (prothrombin complex concentrate) • Promotes hemostasis by providing prothrombin (factor 2) and activated factor X (FX) converts prothrombin to thrombin (clot formation)

  12. Clotting Cascade

  13. FVIII domain

  14. Conclusion • Inhibitors are the most serious complication in hemophilia • Researchers are looking at the time to start replacing clotting factor in PUPs • Family History • Use of other FVIII subtypes (human plasma, Europe)

More Related