Molecular modifications in factor VIII concentrates produced from different plasma pools

We defined the main cause for the increased immunogenicity of the commercia l factor VIII (fVIII) plasma-derived concentrates reported to induce format ion of inhibitory antibodies in haemophilia A patients in Germany and Belgi um. Formation of these antibodies directed against the C2 domain of fVIII w as previously attributed to the use of solvent/detergent (S/D) treatment an d pasteurisation for virus inactivation of fVIII concentrate. Since fVIII c oncentrates associated with increased immunogenicity were prepared from pla sma pools characterised by elevated levels of coagulation markers, we exami ned whether the plasma source or S/D treatment and pasteurisation are respo nsible for structural changes within the C2 domain causing its abnormal imm unogenicity. We found that samples of fVIII concentrate that originated fro m the abnormal plasma pool had a reduced ability to bind to phospholipid an d conformationally sensitive anti-C2 domain antibodies, this effect being m ostly pronounced in the samples that underwent both S/D treatment and paste urisation. Thus, our study suggests that insufficient quality of the starti ng plasma pools is the major factor determining the structural alterations in the C2 domain of fVIII, whereas combination of S/D treatment and pasteur isation aggravates these changes. (C) 2001 Elsevier Science Ltd. All rights reserved.