title: Recombinant porcine factor VIII for high-risk surgery in paediatric congenital haemophilia A with high-titre inhibitor.
abstract: BACKGROUND
  High-titre factor VIII (FVIII) inhibitors complicate peri-operative haemostasis. Recombinant porcine FVIII (r-pFVIII) may provide an alternative haemostatic agent for high-risk procedures and allow FVIII activity monitoring.
  
  
  OBJECTIVE
  Devise an effective haemostatic plan for repair of a progressively symptomatic aortic coarctation in a 5-year-old male with immune tolerance induction (ITI) refractory high-titre FVIII inhibitors.
  
  
  METHODS
  Preprocedure human FVIII inhibitor titre was 58 Bethesda Units mL-1(BU) and cross-reacted to neutralize porcine FVIII at 30 BU. Daily ITI with plasma-derived FVIII concentrate was supplemented with anti-B-cell and anti-plasma cell immunotherapy to reduce FVIII inhibitor titres. Potential haemostatic agents were evaluated in comparative ex vivo thrombin generation assays (TGA).
  
  
  RESULTS
  Four weeks after immunosuppression, human and porcine inhibitor titres declined to 16 and 2 BU respectively. TGA with r-pFVIII was less robust than with activated prothrombin complex concentrate (aPCC); however, r-pFVIII was selected for cardiac surgery to secure the ability to assay FVIII levels throughout this high-bleeding risk procedure. Haemostasis with r-pFVIII was excellent; initial trough FVIII activity levels ranged from 0.81-1.17 IU mL-1. On postoperative day 3, peak and trough levels markedly declined suggesting a rising porcine inhibitor titre. Postprocedure prophylaxis was transitioned to aPCC, informed by TGA.
  
  
  CONCLUSIONS
  R-pFVIII provided effective peri-procedural haemostasis with no adverse events. Rapid neutralization of r-pFVIII after the first 60 hours, despite intensive immune suppression, accentuates the importance of careful monitoring. Use of TGA can support bypassing agent selection for convalescence. The comparative cost of r-pFVIII may limit its use to high morbidity clinical scenarios.
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Croteau
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Abajas
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: B I
authors.initials: BI
authors.lastname: Nielsen
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Marx
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Baird
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Neufeld
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Monahan
mesh_terms: D000818:Animals; D002675:Child, Preschool; D005169:Factor VIII / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D013552:Swine
chemical_list: D011994:Recombinant Proteins; C427184:recombinant factor VIII SQ; D005169:Factor VIII
keywords: FEIBA; Obizur; bypassing agents; recombinant activated factor VII; recombinant porcine factor VIII