Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A

SIPPET Study Group, Shermarke Hassan, Roberta Palla, Carla Valsecchi, Isabella Garagiola, Amal El-Beshlawy, Mohsen Elalfy, Vijay Ramanan, Peyman Eshghi, Mehran Karimi, Samantha Claudia Gouw, Pier Mannuccio Mannucci, F. R. Rosendaal, Flora Peyvandi

Research output: Contribution to journalArticlepeer-review


Background: There is a need to identify patients with haemophilia who have a very low or high risk of developing inhibitors. These patients could be candidates for personalized treatment strategies. Aims: The aim of this study was to externally validate a previously published prediction model for inhibitor development and to develop a new prediction model that incorporates novel predictors. Methods: The population consisted of 251 previously untreated or minimally treated patients with severe haemophilia A enrolled in the SIPPET study. The outcome was inhibitor formation. Model discrimination was measured using the C-statistic, and model calibration was assessed with a calibration plot. The new model was internally validated using bootstrap resampling. Results: Firstly, the previously published prediction model was validated. It consisted of three variables: family history of inhibitor development, F8 gene mutation and intensity of first treatment with factor VIII (FVIII). The C-statistic was 0.53 (95% CI: 0.46–0.60), and calibration was limited. Furthermore, a new prediction model was developed that consisted of four predictors: F8 gene mutation, intensity of first treatment with FVIII, the presence of factor VIII non-neutralizing antibodies before treatment initiation and lastly FVIII product type (recombinant vs. plasma-derived). The C-statistic was 0.66 (95 CI: 0.57–0.75), and calibration was moderate. Using a model cut-off point of 10%, positive- and negative predictive values were 0.22 and 0.95, respectively. Conclusion: Performance of all prediction models was limited. However, the new model with all predictors may be useful for identifying a small number of patients with a low risk of inhibitor formation.

Original languageEnglish
Pages (from-to)e441-e449
Issue number4
Publication statusPublished - 2021


  • factor VIII
  • haemophilia A
  • immunogenicity
  • inhibitors
  • prediction

ASJC Scopus subject areas

  • Hematology
  • Genetics(clinical)


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