Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis

J Thromb Haemost. 2018 Jan;16(1):39-43. doi: 10.1111/jth.13888. Epub 2017 Nov 16.


Essentials Recombinant factor VIII (rFVIII) was contrasted with plasma-derived FVIII (pdFVIII). In previously untreated patients with hemophilia A, rFVIII led to more inhibitors than pdFVIII. Inhibitors with rFVIII developed earlier, and the peak rate was higher than with pdFVIII. Inhibitors with rFVIII were more severe (higher titre) than with pdFVIII.

Summary: Background The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe hemophilia A. Recently, a randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) demonstrated a 2-fold higher risk of inhibitor development in children treated with recombinant FVIII (rFVIII) products than with plasma-derived FVIII (pdFVIII) during the first 50 exposure days (EDs). Objective/Methods In this post-hoc SIPPET analysis we evaluated the rate of inhibitor incidence over time by every 5 EDs (from 0 to 50 EDs) in patients treated with different classes of FVIII product, made possible by a frequent testing regime. Results The highest rate of inhibitor development occurred in the first 10 EDs, with a large contrast between rFVIII and pdFVIII during the first 5 EDs: hazard ratio 3.14 (95% confidence interval [CI], 1.01-9.74) for all inhibitors and 4.19 (95% CI, 1.18-14.8) for high-titer inhibitors. For patients treated with pdFVIII, the peak of inhibitor development occurred later (6-10 EDs) and lasted for a shorter time. Conclusion These results emphasize the high immunologic vulnerability of patients during the earliest exposure to FVIII concentrates, with the strongest response to recombinant FVIII products.

Keywords: antibodies; factor VIII; hemophilia A; inhibitor; plasma.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing / blood*
  • Antibodies, Neutralizing / immunology
  • Child, Preschool
  • Coagulants / administration & dosage*
  • Coagulants / adverse effects
  • Coagulants / immunology
  • Factor VIII / administration & dosage*
  • Factor VIII / adverse effects
  • Factor VIII / immunology
  • Hemophilia A / blood
  • Hemophilia A / diagnosis
  • Hemophilia A / drug therapy*
  • Hemophilia A / immunology
  • Humans
  • Male
  • Randomized Controlled Trials as Topic
  • Recombinant Proteins / administration & dosage
  • Time Factors
  • Treatment Outcome


  • Antibodies, Neutralizing
  • Coagulants
  • Recombinant Proteins
  • F8 protein, human
  • Factor VIII