Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A
Antonino Cannavò, Carla Valsecchi, Isabella Garagiola, Roberta Palla, Pier Mannuccio Mannucci, Frits R Rosendaal, Flora Peyvandi, SIPPET study group, Amal El-Beshlawy, Mohsen Elalfy, Vijay Ramanan, Peyman Eshghi, Suresh Hanagavadi, Ramabadran Varadarajan, Mehran Karimi, Mamta V. Manglani, Cecil Ross, Guy Young, Tulika Seth, Shashikant Apte, Dinesh M. Nayak, Elena Santagostino, Maria Elisa Mancuso, Adriana C. Sandoval Gonzalez, Johnny N. Mahlangu, Santiago Bonanad Boix, Monica Cerqueira, Nadia P. Ewing, Christoph Male, Tarek Owaidah, Veronica Soto Arellano, Nathan L. Kobrinsky, Suvankar Majumdar, Rosario Perez, Anupam Sachdeva, Mindy Simpson, Mathew Thomas, Ezio Zanon, Bulent Antmen, Kaan Kavakli, Marilyn J. Manco-Johnson, Monica Martinez, Esperanza Marzouka, Maria Gabriella Mazzucconi, Daniela Neme, Angeles Palomo Bravo, Rogelio Paredes Aguilera, Alessandra Prezotti, Klaus Schmitt, Brian M. Wicklund, Bulent Zulfikar, Antonino Cannavò, Carla Valsecchi, Isabella Garagiola, Roberta Palla, Pier Mannuccio Mannucci, Frits R Rosendaal, Flora Peyvandi, SIPPET study group, Amal El-Beshlawy, Mohsen Elalfy, Vijay Ramanan, Peyman Eshghi, Suresh Hanagavadi, Ramabadran Varadarajan, Mehran Karimi, Mamta V. Manglani, Cecil Ross, Guy Young, Tulika Seth, Shashikant Apte, Dinesh M. Nayak, Elena Santagostino, Maria Elisa Mancuso, Adriana C. Sandoval Gonzalez, Johnny N. Mahlangu, Santiago Bonanad Boix, Monica Cerqueira, Nadia P. Ewing, Christoph Male, Tarek Owaidah, Veronica Soto Arellano, Nathan L. Kobrinsky, Suvankar Majumdar, Rosario Perez, Anupam Sachdeva, Mindy Simpson, Mathew Thomas, Ezio Zanon, Bulent Antmen, Kaan Kavakli, Marilyn J. Manco-Johnson, Monica Martinez, Esperanza Marzouka, Maria Gabriella Mazzucconi, Daniela Neme, Angeles Palomo Bravo, Rogelio Paredes Aguilera, Alessandra Prezotti, Klaus Schmitt, Brian M. Wicklund, Bulent Zulfikar
Abstract
The development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) is the major complication in hemophilia A. Nonneutralizing antibodies (NNAs) have been detected in hemophilia patients and also in unaffected individuals. The aim of this study was to assess the prevalence of NNAs and to evaluate whether their presence is associated with the development of inhibitors in a cohort of previously untreated or minimally treated patients with hemophilia A; 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 observed for the development of neutralizing antibodies. NNAs were found in 18 (7.6%) of 237 patients at screening, and there was a clear age gradient. Of those with NNAs, 7 patients subsequently developed an inhibitor for a cumulative incidence of 45.4% (95% confidence interval [CI], 19.5% to 71.3%); among the 219 patients without NNAs, 64 (29%) developed an inhibitor (cumulative incidence, 34.0%; 95% CI, 27.1%-40.9%). In Cox regression analyses, patients with NNAs at screening had an 83% higher incidence of inhibitor development than patients without NNAs (hazard ratio [HR], 1.83; 95% CI, 0.84-3.99). For high-titer inhibitors, the incidence rate had an almost threefold increase (HR, 2.74; 95% CI, 1.23-6.12). These associations did not materially change after adjustment. The presence of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII concentrates is associated with an increased incidence of inhibitors.
© 2017 by The American Society of Hematology.
Source: PubMed