Genetics and hemophilia

Genetic Differences Influence Inhibitor Development

Research examines inhibitors in blacks vs. whites
Author: Sarah Aldridge

Researchers have known for years that certain factors, including genetics, increase the likelihood of inhibitor development. Now they have preliminary evidence that genetic differences may help account for nearly double the rate of inhibitor development in blacks with hemophilia A, or factor VIII (FVIII) deficiency, vs. whites. A study published in the April 16, 2009, issue of The New England Journal of Medicine showed that slight differences in the FVIII protein may be the problem.

Inhibitors develop in approximately 20% to 30% of patients with severe hemophilia A. Once they occur, alternative strategies must be developed to either bypass the need for factor VIII product or desensitize the immune system through immune tolerance induction. Although successful in most patients, immune tolerance induction can be expensive and time consuming (see “Inhibitors Cause Complications,” HemAware September/October 2007, page 47).

The research study was conducted from 2003 to 2006 at four hemophilia treatment centers (HTCs) in Region IV South: the University of Alabama at Birmingham; Emory University, Atlanta; the Medical College of Georgia, Augusta; and the University of Mississippi Medical Center, Jackson. Of the black patients with hemophilia A who were being treated at those centers, 78 enrolled in the study. The average age was 17.5 years. The breakdown of the severity of the diagnosis was 63% severe, 22% moderate and 14% mild. Blood samples were drawn to test for inhibitors, and the FVIII gene was sequenced for each subject.

Two of the investigators, Kevin R. Viel, PhD, and Tom E. Howard, MD, PhD, had shown in a previous study on people without hemophilia that blacks and whites differed in the haplotypes, or naturally occurring genetic variations involving the FVIII chromosome. Although both displayed H1 and H2 haplotypes, only blacks had three other haplotypes—H3, H4 and H5, which is rare. A sixth haplotype, H6, was found in Asians.

It turns out that haplotypes may matter when it comes to factor product. When the patients in the HTCs were divided into two groups based on haplotype, the data revealed that those in the H3/H4 group, 24% of the subjects, were 3.4 times more likely to develop inhibitors than those in the H1/H2 group.

Inhibitor development was not related to the severity of hemophilia or the age of the patients. The triggering agent may be the factor product itself. Because all current recombinant and plasma-derived products are made from H1/H2 versions of the FVIII protein, the immune systems of black patients with the H3/H4 haplotypes could recognize it as new and foreign. To defend itself against what it perceives as an “attack” by the unfamiliar H1/H2 haplotypes, the immune systems in black patients produce inhibitors, antibodies to the infused product.

“These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti-factor VIII alloantibodies,” the researchers wrote.

But before manufacturers change the FVIII formulations, more data need to be collected. “This is the first report of how the type of naturally occurring haplotype might be important in making a product,” says Thomas C. Abshire, MD, one of the study investigators. He is director of the Emory/Children’s Comprehensive Hemostasis and Thrombosis Program in Atlanta. “It should be one of the things that might be taken into consideration, along with the other known factors of inhibitor development.” A larger study that reproduces the results also needs to be conducted to confirm this study’s initial findings, he says.