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N Engl J Med. 2016 May 26;374(21):2054-64. doi: 10.1056/NEJMoa1516437.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

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From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico (F.P., P.M.M., E.S., M.E.M.), and Department of Pathophysiology and Transplantation, Università degli Studi di Milano (F.P., P.M.M., I.G.), Milan, Clinica Medica II, Azienda Ospedaliera di Padova, Centro Emofilia, Padua (E.Z.), and Ematologia, Unità Operativa Diagnostica Speciale e Terapia delle Malattie dell'Emostasi e della Trombosi, Università Sapienza, Policlinico Umberto I, Rome (M.G.M.) - all in Italy; the Pediatric Hematology Department, Cairo University Pediatric Hospital (A.E.-B.), and Department of Pediatrics, Faculty of Medicine, Ain Shams University (M.E.), Cairo; Jehangir Clinical Development Center, Department of Hematology, Jehangir Hospital Premises (V.R.), and Sahyadri Speciality Hospital (S.A.), Pune, Jagadguru Jayadeva Murugarajendra Medical College, Davangere (S.H.), Center for Blood Disorders, Chennai (R.V.), Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai (M.V.M.); St. John's Medical College Hospital, Bangalore (C.R.), All India Institute of Medical Sciences, Department of Hematology (T.S.), and Pediatric Hematology Oncology and Bone Marrow Transplantation, Institute for Child Health, Sir Ganga Ram Hospital (A.S.), New Delhi, Melaka-Manipal Medical College, Manipal University, Manipal (D.M.N.), and Kerala Institute of Medical Science, Trivandrum (M.T.) - all in India; the Congenital Pediatric Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran (P.E.), and Hematology Research Center, Shiraz University of Medical Sciences, Shiraz (M.K.) - both in Iran; Children's Hospital Los Angeles, Los Angeles (G.Y.), and City of Hope National Medical Center, Duarte (N.P.E.) - both in California; Hospital de Especialidades Unidad Médica de Alta Especialidad, Instituto Mexicano del Seguro Social, Monterrey (A.C.S.G.), an



The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy.


We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites.


Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00).


Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; number, NCT01064284; EudraCT number, 2009-011186-88.).

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