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Research Update: Inhibitor Development in Blacks with Hemophilia A Linked to Genotypes

Blacks with hemophilia A are twice as likely to develop inhibitors to factor VIII proteins as whites, a phenomenon that until recently was a mystery.
In a study published in the April 2009 issue of The New England Journal of Medicine, Tom E. Howard, MD, PhD, Clinical Associate Professor, Department of Pathology Laboratory Medicine, Greater Los Angeles VA Healthcare System, and colleagues. looked closely at the genes of 78 black patients with hemophilia A to find any distinguishing characteristics. The patients were being treated at four hemophilia treatment centers. Of them, 63% had severe hemophilia A. Data was collected from 2003-2006.

Investigators “sequenced” the FVIII gene in each patient to identify specific mutations and the haplotypes where they were positioned. Haplotypes are groups of closely linked genetic markers found on one chromosome that tend to be inherited together as a unit.
A genetic marker, which can be a gene or a section of DNA with no discernable function, is a segment of DNA with an recognizable physical location on a chromosome whose inheritance can be tracked.

There are six possible “wild-type” FVIII protein haplotypes designated H1 through H6. While H1 and H2 are found in all racial groups, H3, H4 and H5 are present only in blacks. Of the 78 patients enrolled in the study, 24% had the H3 or H4 genetic markers. Howard and his colleagues also found that these patients were three times as likely to develop inhibitors at other patients. The investigators believe that the higher inhibitor rate might be linked to “mismatched” gene markers and recombinant FVIII products. Currently, these products are made with H1 and H2 haplotypes of FVIII—proteins that the immune systems of patients with H3 and H4 regard as foreign and create antibodies—the inhibitors—to them.

“These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti–factor VIII alloantibodies,” concluded researchers. Further studies with larger numbers of patients are needed to duplicate the study results. If they confirm these results, future FVIII products could be made that more closely match the H3/H4 proteins carried by the African-American patients, preventing inhibitor development.    

This multi-site study was funded by grants from the National Institutes of Health.

Source: Viel K, Ameri A, Abshire T, et al. Inhibitors of Factor VIII in Black Patients with Hemophilia. N Engl J Med 360:1618, April 16, 2009.



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