Inhibitors of factor VIII in black patients with hemophilia.
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.
Southwest Foundation for Biomedical Research, San Antonio, TX, USA.
Kevin R
KR
Viel
Afshin
A
Ameri
Thomas C
TC
Abshire
Rathi V
RV
Iyer
Raymond G
RG
Watts
Charles
C
Lutcher
Cynthia
C
Channell
Shelley A
SA
Cole
Karl M
KM
Fernstrom
Shelley
S
Nakaya
Carol K
CK
Kasper
Arthur R
AR
Thompson
Laura
L
Almasy
Tom E
TE
Howard
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000906:Antibodies; D044383:Black People / Q000235:genetics*; D019774:Blood Coagulation Factor Inhibitors / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D006239:Haplotypes; D006467:Hemophilia A / Q000208:ethnology* / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007518:Isoantibodies; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D055815:Young Adult
D000906:Antibodies; D019774:Blood Coagulation Factor Inhibitors; D007518:Isoantibodies; C078147:F8 protein, human; D005169:Factor VIII