Congenital haemophilia A is a chromosome-linked recessive disorder caused by the deficiency or reduction of factor VIII (FVIII) pro-coagulant activity. During treatment, some patients develop alloantibodies (FVIII inhibitors) that neutralize the action of exogenously administered FVIII. Currently, the presence of these inhibitors is the most serious adverse event found in replacement therapy. Some studies have suggested that genetic factors influence the development of the FVIII coagulation inhibitors. To identify the class I and II alleles that may be influencing the formation of inhibitors in severe haemophilic patients. Genotyping of the class I (HLA-A, -B and -C) and class II (HLA-DRB1, -DQA1 and -DQB1) alleles of 122 patients with severe haemophilia A, including 36 who had developed antibodies to factor VIII, was performed. After the comparison of the group without inhibitors and the group with inhibitors, HLA-C*16 [Odds ratio (OR) = 7.73; P = 0.0092] and HLA-DRB1*14 (OR = 4.52; P = 0.0174) were found to be positively associated with the formation of the inhibitors. These results confirm that HLA alleles are involved in inhibitor production and could be used as a tool for recognition of groups at high risk of possible inhibitor development in Southern Brazilian haemophilic patients.
Hemophilia A is a disease caused by a deficiency of coagulation factor VIII resulting
from genetic inheritance linked to chromosome X. One treatment option is the
administration of plasma or recombinant FVIII. However, some patients develop
inhibitors or antibodies against this factor. Inhibitors are alloantibodies that bind
to the epitope of factor VIII causing it to be recognized by the immune system as a
foreign peptide. This is the most serious complication in hemophilia patients in
respect to replacement therapy. Some studies have suggested that genetic factors
influence the development of factor VIII inhibitors such as ethnicity, family
history, mutations in the factor VIII gene and in genes of the immune system. The aim
of this study was to conduct a literature review to assess the influence of genetic
factors of immune response genes, especially genes of the major histocompatibility
complex and cytokines, which may be related to the development of factor VIII
inhibitors in hemophilia A patients. Understanding these risk factors will help to
determine future differential treatment in the control and prevention of the
development of inhibitors.
This suggests that polymorphisms in INFG and in TGFB1 genes are related to risk of developing inhibitor, and could contribute to a genetic profile of the individual HA for the risk of inhibitors development to FVIII.
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