Inhibitors of Factor VIII in Black Patients with Hemophilia

Abstract

Background Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients. Methods We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors. Results Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P = 0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups. Conclusions These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti–factor VIII alloantibodies.

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence‐based approaches

“…It is known that patients carrying mutations precluding FVIII synthesis, defined as null mutations (i.e., large deletions, inversions and nonsense mutations), are more susceptible to developing inhibitors (Schwaab et al, 1995;Goodeve & Peake, 2003). More recently, it has been reported that specific F8 polymorphisms may play a role in the increased inhibitor risk observed in black patients (Viel et al, 2009). In addition, human leucocyte antigen (HLA) class II molecules and polymorphisms of immune-regulatory genes (IL10, TNF and CTLA4) have been shown to influence the risk of inhibitor formation (Astermark et al, 2006a(Astermark et al, ,b, 2007Pavlova et al, 2009).…”

Physical Functioning in Boys with Hemophilia in the U.S.

“…[11][12][13] Disparities are reported among adolescents 14 and among children with special healthcare needs (CSHCN). [15][16][17][18] Reports on the impact of race and ethnicity in hemophilia have been limited to the higher prevalence of African Americans who develop inhibitors, 19,20 septic arthritis, 21 and joint ROM limitations. 7 There are no comprehensive reports on the impact of race and ethnicity on the pediatric U.S. hemophilia population.…”

Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

“…This could explain the significantly higher inhibitor occurrence in the AfricanAmerican population, and is currently being investigated in detail. 18 …”