Factor VIII Inhibitors in Two Families with Mild Haemophilia A: Structural Analysis of the Mutations

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Abstract
The development of inhibitory antibodies against coagulation factor VIII (FVIII) in patients with mild haemophilia A is uncommon. We describe here two families in which three or two members have developed inhibitors, suggesting a familial predisposition. The mutations found, in the A2 (Arg593Cys) and C1 domains (Tyr2105Cys), have been reported to give rise to inhibitor development in single individuals in addition to the family cluster we describe, strongly suggesting that these amino acid substitutions give rise to a more immunogenic protein. The analysis of structural models of activated factor VIII revealed that Arg593 is solvent-exposed and involved in a network of electrostatic interactions while Tyr2105 is partially buried and has hydrophobic interactions essentially with Ile2144. All these residues are strictly conserved in the FVIII amino acid sequence from man, pig and mouse, suggesting, at least, that they have structural roles. We propose that the two mutations in these families could cause mild haemophilia A because they induce local conformational changes (and possible secretion or intermolecular interaction problems, e.g., with von Willebrand factor) compatible with immunogenicity and production of inhibitors against the infused wild-type FVIII.