Inhibitors of factor VIII in black patients with hemophilia

Kevin R. Viel, Afshin Ameri, Thomas C. Abshire, Rathi V. Iyer, Raymond G. Watts, Charles Lutcher, Cynthia Channell, Shelley A. Cole, Karl M. Fernstrom, Shelley Nakaya, Carol K. Kasper, Arthur R. Thompson, Laura Almasy, Tom E. Howard

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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.

Original languageEnglish (US)
Pages (from-to)1618-1627
Number of pages10
JournalNew England Journal of Medicine
Volume360
Issue number16
DOIs
StatePublished - Apr 16 2009

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Factor VIII
Hemophilia A
Haplotypes
Isoantibodies
Mutation
Proteins
Logistic Models
Odds Ratio
Confidence Intervals
Incidence
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Viel, K. R., Ameri, A., Abshire, T. C., Iyer, R. V., Watts, R. G., Lutcher, C., ... Howard, T. E. (2009). Inhibitors of factor VIII in black patients with hemophilia. New England Journal of Medicine, 360(16), 1618-1627. https://doi.org/10.1056/NEJMoa075760

Inhibitors of factor VIII in black patients with hemophilia. / Viel, Kevin R.; Ameri, Afshin; Abshire, Thomas C.; Iyer, Rathi V.; Watts, Raymond G.; Lutcher, Charles; Channell, Cynthia; Cole, Shelley A.; Fernstrom, Karl M.; Nakaya, Shelley; Kasper, Carol K.; Thompson, Arthur R.; Almasy, Laura; Howard, Tom E.

In: New England Journal of Medicine, Vol. 360, No. 16, 16.04.2009, p. 1618-1627.

Research output: Contribution to journalArticle

Viel, KR, Ameri, A, Abshire, TC, Iyer, RV, Watts, RG, Lutcher, C, Channell, C, Cole, SA, Fernstrom, KM, Nakaya, S, Kasper, CK, Thompson, AR, Almasy, L & Howard, TE 2009, 'Inhibitors of factor VIII in black patients with hemophilia', New England Journal of Medicine, vol. 360, no. 16, pp. 1618-1627. https://doi.org/10.1056/NEJMoa075760
Viel KR, Ameri A, Abshire TC, Iyer RV, Watts RG, Lutcher C et al. Inhibitors of factor VIII in black patients with hemophilia. New England Journal of Medicine. 2009 Apr 16;360(16):1618-1627. https://doi.org/10.1056/NEJMoa075760
Viel, Kevin R. ; Ameri, Afshin ; Abshire, Thomas C. ; Iyer, Rathi V. ; Watts, Raymond G. ; Lutcher, Charles ; Channell, Cynthia ; Cole, Shelley A. ; Fernstrom, Karl M. ; Nakaya, Shelley ; Kasper, Carol K. ; Thompson, Arthur R. ; Almasy, Laura ; Howard, Tom E. / Inhibitors of factor VIII in black patients with hemophilia. In: New England Journal of Medicine. 2009 ; Vol. 360, No. 16. pp. 1618-1627.
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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.",
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T1 - Inhibitors of factor VIII in black patients with hemophilia

AU - Viel, Kevin R.

AU - Ameri, Afshin

AU - Abshire, Thomas C.

AU - Iyer, Rathi V.

AU - Watts, Raymond G.

AU - Lutcher, Charles

AU - Channell, Cynthia

AU - Cole, Shelley A.

AU - Fernstrom, Karl M.

AU - Nakaya, Shelley

AU - Kasper, Carol K.

AU - Thompson, Arthur R.

AU - Almasy, Laura

AU - Howard, Tom E.

PY - 2009/4/16

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N2 - 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.

AB - 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.

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