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Non-neutralizing antibodies against factor VIII and risk of inhibitor development in patients with severe hemophilia A

Antonino Cannavò, Carla Valsecchi, Isabella Garagiola, Roberta Palla, Pier Mannuccio Mannucci, Frits R. Rosendaal and Flora Peyvandi

Key points

  • Non-neutralizing antibodies against factor VIII are detected in untreated or minimally treated patients with hemophilia A.

  • The presence of non-neutralizing antibodies is associated with a substantially increased risk of inhibitor development.

Abstract

The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Non-neutralizing antibodies (NNAs) have not only been detected in hemophilia patients but also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs in a cohort of previously untreated or minimally treated patients with hemophilia A, and to evaluate whether their presence is associated with the development of inhibitors. Plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected before any exposure to FVIII concentrates and analyzed for the presence of anti-FVIII NNAs. Patients were followed for the development of neutralizing antibodies. NNAs were found in 18/237 (7.6%) of patients at screening, with a clear age gradient. Of those with NNAs, seven patients subsequently developed an inhibitor, for a cumulative incidence of 45.4% (95% confidence interval (CI95) 19.5-71.3%), whereas among those without NNAs 64/219 (29%) developed an inhibitor (cumulative incidence 34.0%, CI95 27.1-40.9%). In Cox regression, patients with NNAs at screening had a 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio (HR) 1.83, CI95 0.84-3.99). For high-titer inhibitors, the rate was almost 3-fold increased (HR 2.74, CI95 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors.

  • Submitted June 6, 2016.
  • Accepted December 15, 2016.