Factor VIII Inhibitors in Previously Treated Haemophilia A Patients with a Double Virus-inactivated Plasma Derived Factor VIII Concentrate

Abstract

SummaryAntibodies to factor VIII (inhibitors) are usually produced at the beginning of treatment with factor VIII and are rare in multitransfused patients. Such antibodies are deemed to be patient-related, as supported by the description of a number of associated risk factors. However, a second category of inhibitors has recently been identified, namely antibodies occurring in multitransfused patients as a result of exposure to a particular factor VIII concentrate. A first outbreak of product-related inhibitors was recently described. The present paper describes the second well-documented occurrence of such inhibitors.Eight out of 140 multitransfused patients with severe haemophilia A developed an inhibitor to factor VIII shortly after changing treatment to a double-virus inactivated plasma-derived factor VIII concentrate. In addition to solvent-detergent treatment, this concentrate was pasteurised at 63° C for 10 hours. Exposure to the pasteurised product before inhibitor detection ranged from 9 to 45 days. Inhibitor titers varied between 2.2 and 60 Bethesda Units and recovery of transfused factor VIII ranged from 0.21 to 0.68 (expressed as IU/dl factor VIII rise per IU/kg administered). In contrast to usual inhibitors in haemophilia A patients, these product-related inhibitors showed complex inhibition kinetics. They were found specific for the factor VIII light chain. The inhibitors gradually declined when exposure to the pasteurised product was stopped, despite further treatment with other factor VIII concentrates. The present data stress the importance of carefully monitored clinical studies, both in previously treated and previously untreated patients, before introduction of a new or modified clotting factor concentrate.

Clotting factor concentrate switching and inhibitor development in hemophilia A

“…We can reasonably answer "no" to this important question: it must be appreciated that even after the outbreak of inhibitors caused in the 1990s in The Netherlands and in Belgium, the majority of the inhibitors detected were transient. 12,43,57,58 …”

Prevention of bleeds in hemophilia patients with inhibitors: Emerging data and clinical direction

“…Other host factors that are associated with the development of inhibitors may include genetically determined immunologic traits [9,10], age at first exposure to FVIII (with those exposed before age 6 months more likely to develop inhibitors than those exposed later) [11,12], and race (with African Americans 2 times more likely than Caucasians to develop inhibitors) [1,13,14]. That nonhost factors may play a role has been shown by rare instances in which a particular FVIII concentrate has resulted in unusually high inhibitor development [15][16][17].…”

The Role of Immunomodulation in the Management of Factor VIII Inhibitors

“…In terms of FVIII concentrate and product administration variables, rare "outbreaks" of FVIII inhibitors have occurred with concentrates that have likely experienced structural changes during production, 12,13 and there is good evidence to suggest that FVIII delivery into an immunological environment primed by inflammation or tissue trauma will also be more prone to generate an inhibitor response. This type of environment is, of course, more likely to occur at the time of surgery, when many patients will receive continuous high-dose infusions of FVIII, thus raising the question of whether this form of intensive exposure to the protein might be more likely to stimulate inhibitor development.…”