Mismatched Factor VIII proteins risk factor for alloantibodies in blacks with hemophilia A

Black patients with hemophilia A may develop more Factor VIII inhibitors due to mutations in their Factor VIII proteins, which subsequently increase the likelihood of a mismatch with normal replacement Factor VIII proteins during infusion.

In the preliminary study, researchers sequenced the Factor VIII gene from blood samples of 76 black patients with hemophilia A. Patients’ medical charts were reviewed for baseline severity of hemophilia, age at enrollment and biologic relationships. Results from previous Bethesda assays were also reviewed.

The hemophilic Factor VIII mutation was identified in 70 patients. Measurements of Factor VIII taken prior to the study indicated that 14% of patients had mild hemophilia, 22% had moderate hemophilia, and 63% had severe hemophilia.

Researchers identified H1, H2, H3 and H4 haplotypes in the patient population; 24% of patients had an H3 or H4 haplotype. However, there was no statistically significant difference among the frequency of mild, moderate or severe hemophilia related to different haplotypes (P=0.11).

When compared with patients with an H1 or H2 background haplotype, patients with an H3 or H4 haplotype had a higher prevalence of Factor VIII inhibitors (OR=3.4; 95% CI, 1.1-10.2). This increased prevalence remained after adjustment for age at enrollment and baseline severity of disease (OR=3.6; 95% CI 1.1-12.3).

Because of the small study population size, the researchers suggested that further research is needed to confirm their findings. “If our findings are confirmed, the possibility would arise that recombinant DNA technology could be used to develop additional replacement products that vary from endogenous factor VIII proteins only at a residue or residues required to correct clotting-factor deficits,” the researchers wrote. – by Jennifer Southall

Viel K. NEJM.2009; 360:1618-1627.

This is a very intriguing and important study and I am glad that it is being published. A longstanding observation is that black patients have a higher frequency of Factor VIII inhibitors than are seen in whites in the United States. The reasons for this are not clear, but the presence of an inhibitor complicates management of the disease and increases the expense of controlling it. There are four nonsynonymous polymorphisms in the Factor VIII gene. For example, the amino acid changes that don't affect the function of the molecule, but make one person's molecule slightly different from the molecule of someone with a different polymorphism at that site. Considering all four possible changes, the population can be divided into six haplotypes, each showing some particular combination of these polymorphisms. It turns out that the white population is mostly either H1 or H2 haplotype, while about 25% of the black population is H3-H5. It also turns out that the currently marketed products are either H1 or H2. This means that some black patients get a product that is not a match for their genetic background. Does this mean they are more likely to get an inhibitor? The statistical analysis in the paper suggests that this may be the case, although the numbers are small, and as the authors note, their study needs to be confirmed. However, this is an intriguing and important observation that may suggest that the incidence of inhibitors could be lower with a different product (ie, that matches H3 haplotype for example).

– Katherine A. High, MD

HemOnc Today Editorial Board member