Factor VIII inhibitors in two families with mild haemophilia A: Structuralanalysis of the mutations

The development of inhibitory antibodies against coagulation factor VIII (F VIII) in patients with mild haemophilia A is uncommon. We describe here two families in which three or two members have developed inhibitors, suggesti ng a familiar predisposition. The mutations found, in the A2 (Arg593Cys) an d C1 domains (Tyr2105Cys), have been reported to give rise to inhibitor dev elopment in single individuals in addition to the family cluster we describ e, strongly suggesting that these amino acid substitutions give rise to a m ore immunogenic protein. The analysis of structural models of activated fac tor VIII revealed that Arg593 is solvent-exposed and involved in a network of electrostatic interactions while Tyr2105 is partially buried and has hyd rophobic interactions essentially with IIe2144. All these residues are stri ctly conserved in the FVIII amino acid sequence from man, pig and mouse, su ggesting, at least, that they have structural roles. We propose that the tw o mutations in these families could cause mild haemophilia A because they i nduce local conformational changes (and possible secretion or intermolecula r interaction problems, e.g., with von Willebrand factor) compatible with i mmunogenicity and production of inhibitors against the infused wild-type FV III. Copyright (C) 2001 S. Karger AG, Basel.