Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A.

Single missense mutations in the F8 gene encoding the coagulation protein factor VIII (FVIII) give rise predominantly to non-severe hemophilia A. Despite only a single amino acid sequence difference between the replacement, therapeutic FVIII (tFVIII) and the patient's endogenous FVIII, tFVIII may still be perceived as foreign by the recipient's immune system and trigger an immune response (inhibitor). Inhibitor formation is a life-long risk for non-severe hemophilia A patients treated with tFVIII, but remains difficult to predict. The aim of this study was to understand whether fortuitous, primary sequence cross-matches between tFVIII and proteins in the human proteome are the reason why certain F8 mutations are not associated with inhibitor formation. We predicted which tFVIII differences are potentially perceived as foreign by helper T cells a necessary precursor to inhibitor development and then scanned potentially immunogenic peptides against more than 100,000 proteins in the proteome. As there are hundreds of disease-causing F8 missense mutations and the Human Leucocyte Antigen gene complex governing peptide presentation to helper T cells is highly polymorphic, these calculations pose a huge combinatorial challenge that we addressed computationally. We identify that cross-matches between tFVIII and the human proteome are commonplace and have a profound impact on the predicted risk of inhibitor development. Our results emphasize the importance of knowing both the F8 missense mutation and the Human Leucocyte Antigen alleles of a patient with missense mutation hemophilia A if his underlying risk of inhibitor development is to be estimated