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00:52 Intro
02:10 Definition
- Common: Alloantibody neutralizes FVIII
- Rare: causes increased clearance of FVIII
- 1/3 of Severe Haemophilia A patients
- Median time 10-15 emergency doses
- RF: Mutation types (INSIGHT study), <5 or >60, African/Hispanic, HIVneg, large rFVIII doses, FVIII + inflammatory stimulus
07:05 Inhibitor classifications
- Titres: Low (<5 BU) vs. High (>5 BU)
- Responder: Low vs High
- Time: Dependent (FVIII inh.) vs Independent (FIX inh.)
09:50 Presentation in practice
- Treatment failure, change in bleeding pattern, anaphylaxis
- Screening: prior to invasive procedures, before/after treatment changes
- Routine surveillance:
- Mild- moderate: Yearly + 2-3 wks after emergency treatment
- Severe: Every 3rd emergency dose or 3 monthly
13:55 Tests (needs repeat)
- Mixing study
- FVIII assay (48 hours post dose)
- Bethesda assay (if 80-100% residual FVIII = no inhibitor)
- Specialist: ELISA, In-vivo recovery
- Most sensitive: FVIII half-life studies
- Inhibitor Assays (Bovine chromogenic assay)
19:45 Preventative measures?
- Mild to moderate: DDAVP when possible
- Severe: prophylaxis
23:40 Treatments
- Bypass agent: skips intrinsic pathway, straight to extrinsic
- F.I.B.A: activated PCC (II, VIII, IX, X)
- Onset 15-30 mins
- Dose: 50-100IU/kg
- Half life 8-12 hrs
- NB: Plasma derived: FVIII contamination, infection
- Contraindicated: Emicizimab
- NovoSeven: activated rFVIIa
- Peak 15 mins
- Dose: 270ug/kg, fixed dose, can’t titrate
- NB: Half life 2 hours, can’t titrate
- Obizor: Porcine rVIII
- Peak 30 mins
- Dose: 200IU/kg and titrateable
- Porcine Bethesda before use
34:35 Prophylaxis
- Emicizumab
- Immune tolerance induction pts: Emicizumab, NovoSeven > FIBA
- Breakthrough bleeding: increase frequency
38:22 Immune Tolerance Induction: start ASAP if inhibitor present
- UKHCDO: Long term FVIII tolerance induction and maintenance is key for severe Haemophilia A - don't rely on Emicizumab
- Success rate: 70%, consistent treatment, fewer emergency doses prior to starting, Historic peak titre <200 BU, <10 BU titres at the start, < 5yrs from inhibitor presentation
- Super responder antibody, >500 BU titres
46:20 International Immune Tolerance Study (Hay, DiMichele)- Blood 2012
47:50 Monitoring and Response Assessment
- Success:
- FVIII half-life >7 hours
- BU negative
- Measurable trough levels at 48 hours
- Failure: escalated to max rFVIII but still uptrending titres or fall of <20% in 6 months (alternative systemic agents)
- NB: rule out intercurrent infection
50:33 VerITI-8 trial
51:28 Golden Nuggets
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