The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors

Abstract

During a 4-year multicenter cooperative study of acquired factor VIII inhibitors in persons with hemophilia A, new inhibitors were detected in 31 of 1,306 patients who entered the study without an inhibitor or the history of an inhibitor. The incidence of new inhibitors was eight per 1,000 patient-years of observation. The factor VIII:C level before inhibitor development was less than or equal to 0.03 U/mL in 29 individuals and 0.06 U/mL and 0.07 U/mL in the remaining two. Factor VIII:Ag levels were measured in 27 individuals and were less than 0.03 U/mL in 23 and 0.05 to 0.11 U/mL in the remaining four. Maximum inhibitor levels ranged from 1.0 to 9,044 Bethesda U/mL. In seven patients under the age of 20, relatively weak inhibitors (none higher than 4.3 Bethesda U/mL) were detected on only a single occasion despite continued factor VIII challenge. In the other 24 patients with inhibitors detected on multiple occasions, 50% had appeared by age 20 and 71% by age 30. Seventeen of the 31 inhibitors, including 12 of 15 with maximum values greater than 10 Bethesda U/mL, developed within 75 exposure days to factor VIII.

A postmarketing surveillance study of the safety and efficacy of ReFacto® (St Louis‐derived active substance) in patients with haemophilia A

“…The PTP inhibitor case was a patient with >100 prior ED that developed a high-titre inhibitor. The incidence of PTPs developing inhibitors in this study was in accordance with previously published results for ReFacto [8] and is consistent with recently published studies of haemophilia A patients treated with plasma-derived or rFVIII products that employed regular inhibitor testing as part of the protocol [8,17,31].…”

Development of inhibitors in patients with haemophilia from India

“…In this ®rst report on inhibitor development in a large number of patients from India with haemophilia, several interesting observations could be made. The overall prevalence of inhibitor development (8.2%) in patients with severe haemophilia A in this series is similar to the reports from western countries prior to the introduction of intensive highly puri®ed factor concentrate therapy [11,12]. In the present series, the de®nition of severe haemophilia was kept at the traditional FVIII or FIX level < 1% rather than < 2% as was done in some inhibitor studies in haemophilia patients receiving recombinant factor concentrates [13,14].…”

Safety and efficacy of solvent/detergent‐treated antihaemophilic factor with an added 80 °C terminal dry heat treatment in patients with haemophilia A

“…Moreover, FVIII recovery and half life did not change upon testing after 6 months treatment with Koate Ò -DVI. A decline in these parameters would have been expected if neutralizing or binding antibodies were formed [23]. The mean in vivo FVIII recovery observed for KoateÒ-DVI in the present study for HIV seronegative and seropositive patients is similar to the in vivo FVIII recovery of 2.0% IU kg ±1 reported by others for plasma-derived FVIII concentrates [11], and indicates that the heat treatment step did not alter biological activity.…”