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; Midori Shima; Shogo Morichika; John McVey; Edward G. D. Tuddenham; Ichiro Tanaka; Hiroshi Suzuki; Keiji Nogami; Yohko Minamoto; Takaaki Hato; Evgueni L. Saenko; Dorothea Scandella; Akira Yoshioka

doi:10.1055/s-0037-1614042

Thrombosis and Haemostasis, Table of Contents

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

Authors

Masaru Shibata

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

¹From 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

Abstract

Summary

We report the development of a FVIII inhibitor in a patient with severe, cross reacting material reduced (CRM^R) 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

Full Text

References

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