1. WFH Bangkok 2004 Factor VIII - Von Willebrand Factor Inhibitors and Immune Tolerance The Key Issue in Haemophilia A

2. WFH Bangkok 2004 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 times greater than for those without an inhibitor” (Rosendaal et al, 1989)

3. WFH Bangkok 2004 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. WFH Bangkok 2004 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. WFH Bangkok 2004 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. WFH Bangkok 2004 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. WFH Bangkok 2004 Inhibitor Development in PUP’s: Product (2) Rothschild C et al, French Multicentre Study. ISTH Congress, 12-18 July 2003, Birmingham Haemophilia Severity (residual factor VIII activity) Inhibitor Incidence based on Factor VIII Preparation Used Plasma-Derived FVIII- VWF Concentrate Recombinant PUPs6386 Inhibitors7 (11.1 %)27 (31.4 %) Total34/149 (22.8 %)

8. WFH Bangkok 2004 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

9. WFH Bangkok 2004 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)

10. WFH Bangkok 2004 Inhibitor Management Strategies Priority: Treatment of acute bleeding episodes –Haemorrhage –Surgery

11. WFH Bangkok 2004 Haemorrhage Management in Inhibitors Treatment options in acute bleeding episodes –Mild bleeding in low titre, low responders (< 10 BU) Human FVIII Bypassing agents, i.e. PCC, APCC Porcine FVIII discontinued

12. WFH Bangkok 2004 Haemorrhage Management in Inhibitors Treatment options in acute bleeding episodes –Serious bleeding in low titre, low responders Human FVIII, 100-200 IU/kg until bleeding controlled and APTT corrected

13. WFH Bangkok 2004 Haemorrhage Management in Inhibitors Treatment options in acute bleeding episodes –Patients with inhibitor titre > 10 BU/ml PCC APCC † Recombinant factor VIIa (rFVIIa) Plasmapheresis / Immune adsorption Immunosuppressive drugs † High doses of APCC’s have been associated with DIC, thrombosis and myocardial infarction. Caution: APCC’s contain a small amount of FVIII and may exert anamnestic effect

14. WFH Bangkok 2004 Surgery –Low Titre (Inhibitor < 10 BU) FVIII 100-200 IU/kg until FVIII:C > 50 % APCC –High Titre (Inhibitor > 10 BU) APCC rFVIIa Haemorrhage Management in Inhibitors

15. WFH Bangkok 2004 Inhibitor Management Strategies Eradication of Inhibitor –Immune Tolerance Induction (ITI) : Info