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Factor VIII - Von Willebrand Factor

Factor VIII - Von Willebrand Factor. Inhibitors and Immune Tolerance The Key Issue in Haemophilia A. Inhibitors. Haemophilia treatment has brought with it two serious complications: viral infection and inhibitory antibody induction

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Factor VIII - Von Willebrand Factor

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  1. Factor VIII - Von Willebrand Factor Inhibitors and Immune Tolerance The Key Issue in Haemophilia A

  2. Inhibitors • Haemophilia treatment has brought with it two serious complications: viral infection and inhibitory antibody induction • Double virus inactivated preparations now fulfil clinical virus safety requirements • “The development of an inhibitory antibody is the most common and serious complication arising from the treatment of haemophilia Mortality of haemophiliacs with inhibitors is 5.3 timesgreater than for those without an inhibitor” (Rosendaal et al, 1989)

  3. Inhibitors • Incidence (literature): • Haemophilia A 0 ~ 30 % • Haemophilia B 1 – 5 % • In haemophilia B, cause for concern as allergic reactions and nephrotic symptom known • Inhibitors are less likely to arise in patients with mild or moderate haemophilia

  4. Inhibitor Development • Inhibitors usually develop at an early age • In a total of 309 studied patients with inhibitors, antibodies developed in • 31 % before 5 years of age • 44 % before 10 years of age • 66 % before 20 years of age • Most inhibitors appear within the first 10-20 exposure days (ED) with a median of 11 ED • Development after 50 ED is rare • Transient inhibitors disappear spontaneously • Around 20 % of all inhibitors persist

  5. Inhibitor Development Risk Factors (FVIII) • Genetic predisposition • Intron 22 inversion • Race • Sibling with inhibitors • Age • Mode of application (venepuncture; subcutaneous introduction of factor) • Product

  6. Inhibitor Development Risk Factors: Product (1) • Factor VIII concentrates which do not contain von Willebrand factor are a risk for increased incidence of inhibitor formation

  7. Measurement of Inhibitors • An inhibitor unit is defined as the reciprocal of the dilution of patient plasma that neutralises a specified amount of FVIII / FIX, under given conditions of time and temperature • The common today test is the Bethesda method, in which 1 inhibitor unit (BU) is defined as the amount that destroys half the FVIII / FIX activity in an equal mixture of patient and normal plasma at 37 °C after 2 h

  8. Inhibitor Classification • Titre • Low titre inhibitors  10 BU • High titre Inhibitors > 10 BU • Response • About 50% Low-responders: Inhibitor levels do not rise after exposure to FVIII / FIX • About 50 % High-responders: Rapid increase in antibody level following exposure to FVIII / FIX (anamnesis)

  9. Inhibitor Management Strategies • Priority: Treatment of acute bleeding episodes • Haemorrhage • Surgery

  10. Inhibitor Management Strategies • Eradication of Inhibitor • Immune Tolerance Induction (ITI) : Info

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