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Thromb Haemost 2000; 84(03): 442-448
DOI: 10.1055/s-0037-1614042
Commentary
Schattauer GmbH

An Alloantibody Recognizing the FVIII A1 Domain in a Patient with CRM Reduced Haemophilia A due to Deletion of a Large Portion of the A1 Domain DNA Sequence

Masaru Shibata
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Midori Shima
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Shogo Morichika
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
John McVey
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Edward G. D. Tuddenham
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Ichiro Tanaka
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Hiroshi Suzuki
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Keiji Nogami
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Yohko Minamoto
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Takaaki Hato
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Evgueni L. Saenko
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Dorothea Scandella
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
,
Akira Yoshioka
1   From the Department of Pediatrics, Nara Medical University, Kashihara, Nara; Department of the Internal Medicine I, School of Medicine, Ehime University, Ehime, Japan; Haemostasis Research Group, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London, U.K.; Holland Laboratory, American Red Cross, Rockville, MD, USA
› Author AffiliationsWe wish to thank Dr J. C. Giddings for his helpful suggestions.
Further Information

Publication History

Received 20 January 2000

Accepted after resubmission 14 April 2000

Publication Date:
14 December 2017 (online)

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Summary

We report the development of a FVIII inhibitor in a patient with severe, cross reacting material reduced (CRMR) haemophilia A. The level of Factor VIII antigen (FVIII:Ag) measured by ELISA using anti- C2 monoclonal and alloantibodies was 1.9 U/dl. This baseline FVIII:Ag level was increased to 8.3 U/dl after administration of DDAVP. The anti-FVIII inhibitor titer was 2.9 Bethesda U/ml. DNA analysis showed a large deletion of the FVIII gene from exon 4 to 7, corresponding to amino acid residues 111-317 included within the A1 domain. The size of the gene deletion was approximately 28 kb. 5' and 3' breakpoints were identified by sequencing in intron 3 and intron 7, respectively. FVIII mRNA was detected in the patient’s peripheral lymphocytes and the deletion spanning exon 4 to 7 was confirmed at the RNA level. Immunoprecipitation experiments using 125I labeled A1, A2 and light chain demonstrated that the inhibitor reacted only with the 54 kDa A1 domain. The inhibitor activity was more than 95% neutralized by A1 domain polypeptide. Our findings suggest a close relationship between the inhibitor epitope and the specific gene deletion with regard to the pathogenesis of the inhibitor in this patient.

Key words

Haemophilia A - inhibitor - A1 domain - gene deletion - factor VIII - cross-reacting material reduced
 

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