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Haemophilia. 2017 Mar;23(2):292-299. doi: 10.1111/hae.13105. Epub 2016 Nov 8.

Anti-factor VIII antibodies in brothers with haemophilia A share similar characteristics.

Author information

1
Department of Paediatrics, Clinical and Molecular Haemostasis and Immunodeficiency, University Hospital Frankfurt, Frankfurt am Main, Germany.
2
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA, USA.
3
Department of Biostatistics, Rho Inc., Chapel Hill, NC, USA.
4
Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden.

Abstract

INTRODUCTION:

The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is currently the most serious complication for patients with haemophilia A undergoing FVIII replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development.

AIM:

To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors.

METHODS:

The domain specificity of FVIII-specific IgG was analysed by antibody binding to FVIII fragments and homologue-scanning mutagenesis (HSM). The FVIII-specific IgG subclasses were measured by direct ELISA.

RESULTS:

Of the 16 patient analysed with both methods, 12 had A2- and 13 had C2-specific IgG. The presence of A1-, A3- or C1-specific IgG was identified in nine of 14 patients analysed by HSM. IgG1, IgG2 and IgG4 subclasses contributed to the anti-FVIII IgG response, and the amount of FVIII-specific IgG1 (r = 0.66) and IgG4 (r = 0.69) correlated significantly with inhibitor titres. Patients with high concentrations of total anti-FVIII IgG (r = 0.69) or high inhibitor titres (r = 0.52) had a high proportion of FVIII-specific IgG4. Statistical analysis revealed trends/evidence that the subclass distribution (P = 0.0847) and domain specificity to HC/LC (P = 0.0883) and A2/C2 (P = 0.0011) of anti-FVIII IgG were more similar in brothers compared to unrelated subjects.

CONCLUSION:

Overall, our data provide a first hint that anti-FVIII IgG characteristics are comparable among haemophilic brothers with inhibitors. Whether genetic factors also influence the nature of patients' antibodies needs to be confirmed in a larger study population.

KEYWORDS:

IgG subclasses; anti-factor VIII antibodies; epitope mapping; factor VIII inhibitors; haemophilia A

PMID:
27862687
DOI:
10.1111/hae.13105
[Indexed for MEDLINE]

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