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Coagulation & its Disorders
Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A
Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):599-608
Daniel P. Hart,1,2 Nazmiye Uzun,3 Stuart Skelton,1,3 Alison Kakoschke,3 Jacob Househam,3 David S. Moss3 and Adrian J. Shepherd3
1Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London; 2The Royal London Hospital Haemophilia Centre, Barts Health NHS Trust, London; 3Department of Biological Sciences and Institute of Structural and Molecular Biology, Birkbeck, University of London, UK
ABSTRACT
Single missense mutations in the F8 gene encoding the coagulation protein factor VIII give rise predominantly to non-severe hemophil- ia A. Despite only a single amino acid sequence difference between the replacement, therapeutic factor VIII and the patient’s endogenous factor VIII, therapeutic factor VIII 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 patients with non-severe hemo- philia A treated with therapeutic factor VIII, but remains difficult to pre- dict. The aim of this study was to understand whether fortuitous, pri- mary sequence cross-matches between therapeutic factor VIII and pro- teins in the human proteome are the reason why certain F8 mutations are not associated with inhibitor formation. We predicted which thera- peutic factor VIII 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-caus- ing F8 missense mutations and the human leukocyte antigen gene com- plex governing peptide presentation to helper T cells is highly polymor- phic, these calculations pose a huge combinatorial challenge that we addressed computationally. We found that cross-matches between ther- apeutic factor VIII 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 leukocyte antigen alleles of a patient with mis- sense mutation hemophilia A if his underlying risk of inhibitor develop- ment is to be estimated.
Introduction
Subjects with all severities of hemophilia A are at risk of an alloimmune response (inhibitor formation) against infused, therapeutic FVIII (tFVIII) concentrate. It is well recognized that the more disruptive the F8 mutation, the more severe the hemophilia and the more likely it is that inhibitors will arise.1 Consequently, severe hemophilia A has been the priority for inhibitor-related research, surveillance and intervention over the past decades.2–5 However, it is also clear that only a single amino acid difference between an endogenous F8 genotype and the wild-type tFVIII sequence is sufficient to induce an immune response that results in clinically relevant inhibitors6–8 and that this risk is life-long in the context of non-severe hemophilia A.8
Hemophilia A caused by a missense mutation is typically associated with a less severe bleeding phenotype than that caused by incomplete F8 transcripts. In con- trast to boys and men with severe hemophilia A, those living with non-severe hemophilia A are more likely to remain hospital dependent for on-demand tFVIII administration throughout their lives in the event of injury or surgery. The treat-
Correspondence:
ADRIAN J. SHEPHERD
a.shepherd@mail.cryst.bbk.ac.uk
Received: April 20, 2018.
Accepted: September 27, 2018. Pre-published: September 28, 2018.
doi:10.3324/haematol.2018.195669
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/599
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haematologica | 2019; 104(3)
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