Risk factors for inhibitor formation in haemophilia: A prevalent case-control study

M. V. Ragni, O. Ojeifo, J. Feng, J. Yan, K. A. Hill, S. S. Sommer, M. N. Trucco, D. J. Brambilla, Doreen Brettler, Pat Forand, Peg Geary, Bruce Ewenstein, Carol Sweeney, Louis Aledort, Stephanie Seremetis, Joan McCarthy, Donna DiMichelel, Ilene Goldberg, Lloyd Barron, Arnette HamsGilbert White, Brenda Nielsen, Aime Grimsley, Joan Cox-Gill, Andrea Boyd, David Green, Lisa Boggio, Sandy Harris, Keith Hoots, Madeline Cantini, George Buchanan, Cynthia Rutherford, Patricia Dunnagan, William Haire, Elizabeth Hanlon, Thomas Kisler, Stabler Sally, Sheryl Giambartolomei, Gowthami Arepally, Marsha Shhwartz, Joseph Addiego, Alison Matsunaga, Beth Chase, Laurence Wolff, Gregg Thomas, Robina Ingram

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case-control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200U per exposure, P <0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.O%) vs. zero of 57 (0%), P <0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P <0.001, and survival was shorter, 14 vs. 38yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P >0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. ≥120BU/mL, six vs. 16 months, P <0.01, but unaffected by tolerizing dose regimen, P >0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies.

Original languageEnglish (US)
Pages (from-to)1074-1082
Number of pages9
JournalHaemophilia
Volume15
Issue number5
DOIs
StatePublished - 2009

Keywords

  • Central nervous system bleeding
  • Factor VIII
  • Haemophilia
  • Inhibitor

ASJC Scopus subject areas

  • Hematology
  • Genetics(clinical)

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    Ragni, M. V., Ojeifo, O., Feng, J., Yan, J., Hill, K. A., Sommer, S. S., Trucco, M. N., Brambilla, D. J., Brettler, D., Forand, P., Geary, P., Ewenstein, B., Sweeney, C., Aledort, L., Seremetis, S., McCarthy, J., DiMichelel, D., Goldberg, I., Barron, L., ... Ingram, R. (2009). Risk factors for inhibitor formation in haemophilia: A prevalent case-control study. Haemophilia, 15(5), 1074-1082. https://doi.org/10.1111/j.1365-2516.2009.02058.x