Haemophilia A: Inhibitors

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

'Basics to Brilliance: Haematology Podcast' has been accredited for CPD credit by the Royal College of Pathologists UK.

Medical professionals and clinical scientists holding career-grade positions, who are registered with any of the Royal Colleges for CPD, will be eligible to earn 1 credit for every hour of learning.

Email: basicstobrilliancehaem@gmail.com

Insta: BasicstoBrilliance

X: @basics_2_brill

Send us your feedback!