Blood Res.  2013 Mar;48(1):58-62. 10.5045/br.2013.48.1.58.

Characterization of anti-factor VIII antibody in a patient with acquired hemophilia A

• Oh J
• Lim Y
• Jang MJ
• Huh JY
• Shima M
• Oh D

• KMID: 2270729
• DOI: http://doi.org/10.5045/br.2013.48.1.58

Abstract

Acquired hemophilia A (AHA) is a bleeding disorder caused by the development of an auto-antibody against endogenous factor VIII (FVIII). In this study, the epitope of the autoantibody was identified in a 67-year-old female patient with AHA. A prolonged activated partial thromboplastin time (77.4 s) that failed to correct in an incubation mixing test (68.2 s), a decreased FVIII activity, and a high FVIII inhibitor (14.6 Bethesda units/mL) were observed. Enzyme-linked immunosorbent assay demonstrated that the antibody belonged to the immunoglobulin G4 subclass. An immunoblotting assay revealed the light chain (A3/C1/C2 domain) of FVIII as the binding region of the antibody. The bleeding experienced by our patient resulted from the interference of FVIII binding to both FIX by anti-A3 antibodies and phospholipids and von Willebrand factor by anti-C2 antibodies. To the best of our knowledge, this is the first study in Korea characterizing an autoantibody in the context of AHA.

Keyword

Acquired hemophilia A; Factor VIII autoantibody; Epitope

MeSH Terms

Antibodies
Enzyme-Linked Immunosorbent Assay
Factor VIII
Female
Hemophilia A
Hemorrhage
Humans
Immunoblotting
Immunoglobulins
Korea
Light
Partial Thromboplastin Time
Phospholipids
von Willebrand Factor
Antibodies
Factor VIII
Immunoglobulins
Phospholipids
von Willebrand Factor

Figure

• 

  Fig. 1 Clinical course of our patient. This graph shows FVIII (%), aPTT (s), and FVIII Ab (BU, Bethesda unit) levels. Abbreviations: rFVIIa, recombinant activated factor VII; Pd, prednisolone; Aza, azathioprine; HD, hospital day.

• 

  Fig. 2 The APTT waveform analysis of the patient's plasma. Minor hemostatic effect by infusion. Abbreviations: Patient Pre, Pre-treatment; Patient Post, Post-treatment; NP, normal pooled plasma; Coag, coagulation.

• 

  Fig. 3 Immunoblotting assay. Lane No.1 shows an 80-kDa immune complex band (indicating that the antibody against a light chain of FVIII exists in the patient's serum). Lane No.2 shows a cleaved 72-kDa band after activation by thrombin.

• 

  Fig. 4 Structure of factor VIII and reported epitopes of factor VIII inhibitors. Epitope regions are indicated by arrows. In this case, the dominant IgG subclass is IgG4, and the binding region is the 72-kDa A3/C1/C2 domain of the light chain. FIXa and FXa indicate activated factor IX and X, respectively. Abbreviations: VWF, von Willebrand factor; APC, activated protein C.

Reference

1. Collins P, Macartney N, Davies R, Lees S, Giddings J, Majer R. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol. 2004; 124:86–90. PMID: 14675412.

2. Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood. 2007; 109:1870–1877. PMID: 17047148.

3. Franchini M, Montagnana M, Lippi G. Clinical, laboratory and therapeutic aspects of platelet-type von Willebrand disease. Int J Lab Hematol. 2008; 30:91–94. PMID: 18333841.

4. Meiklejohn DJ, Watson HG. Acquired haemophilia in association with organ-specific autoimmune disease. Haemophilia. 2001; 7:523–525. PMID: 11554945.

5. Sallah S, Wan JY. Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients. Cancer. 2001; 91:1067–1074. PMID: 11267950.

6. Solymoss S. Postpartum acquired factor VIII inhibitors: results of a survey. Am J Hematol. 1998; 59:1–4. PMID: 9723568.

7. Defendenti C, Atzeni F, Spina MF, et al. Clinical and laboratory aspects of Ro/SSA-52 autoantibodies. Autoimmun Rev. 2011; 10:150–154. PMID: 20854935.

8. Lavigne-Lissalde G, Schved JF, Granier C, Villard S. Anti-factor VIII antibodies: a 2005 update. Thromb Haemost. 2005; 94:760–769. PMID: 16270627.

9. Lavigne-Lissalde G, Rothschild C, Pouplard C, et al. Characteristics, mechanisms of action, and epitope mapping of anti-factor VIII antibodies. Clin Rev Allergy Immunol. 2009; 37:67–79. PMID: 19172415.

10. Scandella D, Mattingly M, de Graaf S, Fulcher CA. Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization. Blood. 1989; 74:1618–1626. PMID: 2477082.

11. Fulcher CA, de Graaf Mahoney S, Roberts JR, Kasper CK, Zimmerman TS. Localization of human factor FVIII inhibitor epitopes to two polypeptide fragments. Proc Natl Acad Sci U S A. 1985; 82:7728–7732. PMID: 2415970.

12. Scandella D, Gilbert GE, Shima M, et al. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site. Blood. 1995; 86:1811–1819. PMID: 7544643.

13. Bray GL, Kroner BL, Arkin S, et al. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the Multi-Center Hemophilia Cohort Study. Am J Hematol. 1993; 42:375–379. PMID: 8493988.

14. Reding MT, Lei S, Lei H, Green D, Gill J, Conti-Fine BM. Distribution of Th1- and Th2-induced anti-factor VIII IgG subclasses in congenital and acquired hemophilia patients. Thromb Haemost. 2002; 88:568–575. PMID: 12362225.

15. The Korean Society on Thrombosis and Hemostasis. The guidelines of Hemophilia. 2011. Seoul, Korea: Han Kuk Medical Publisher;p. 115–120.

16. Song MH, Ahn SJ, Yoo SH, Kim BH, Park JH. Total knee arthroplasty-associated acquired hemophilia: a case report. J Korean Orthop Assoc. 2006; 41:167–169.

17. Chung BH, Kim YJ, Kim MS, et al. A case of acquired hemophilia detected after influenza vaccination. Korean J Med. 2004; 66:298–301.

18. Lee N, Yoon SH, Lim W, et al. Post-operative bleeding due to acquired hemophilia successfully treated with recombinant factor VIIa: case report. Korean J Hematol. 2009; 44:163–167.

19. Hwang HW, Kong JH, Yu DW, Kim WT, Kim HS, Lee CI. A patient with acquired hemophilia A induced by clopidogrel. Korean J Hematol. 2012; 47:80–82. PMID: 22479283.