Download PDF
Thromb Haemost 1998; 79(01): 62-68
DOI: 10.1055/s-0037-1614221
Review Article
Schattauer GmbH

Dominant C2 Domain Epitope Specificity of Inhibitor Antibodies Elicited by a Heat Pasteurized Product, Factor VIII CPS-P, in Previously Treated Hemophilia A Patients without Inhibitors

Yoshikatsu Sawamoto
1   From the American Red Cross, Rockville, MD, USA
,
Richard Prescott
1   From the American Red Cross, Rockville, MD, USA
,
Degang Zhong
1   From the American Red Cross, Rockville, MD, USA
,
Evgueni L. Saenko
1   From the American Red Cross, Rockville, MD, USA
,
Eveline Mauser-Bunschoten
2   van Creveld Kliniek, Utrecht, The Netherlands
,
Kathelijne Peerlinck
3   Katholieke Universiteit Leuven, Belgium
,
Marijke van den Berg
2   van Creveld Kliniek, Utrecht, The Netherlands
,
Dorothea Scandella
1   From the American Red Cross, Rockville, MD, USA
› Author Affiliations
Further Information

Publication History

Received 26 May 1997

Accepted after revision 11 August 1997

Publication Date:
08 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

From June, 1990, to November, 1991, in The Netherlands and Belgium, 16 previously treated severe hemophilia A patients (PTP) developed inhibitors after exposure to factor VIII CPS-P, a new heat pasteurized product. A previously untreated patient (PUP) also developed an inhibitor to CPS-P. In inhibitor neutralization assays with recombinant fVIII C2 and A2 domain polypeptides, plasmas from 14 PTPs were ≥79% neutralized by C2 and <10% by A2, but the PUP plasma was partially neutralized by C2 (48%) and A2 (28%). Immunoprecipitation assays of the PTP and PUP plasmas with the fVIII heavy chain and with recombinant C2 and A3-C1 polypeptides confirmed that the C2 dominant immune response to CPS-P was found only in the PTPs. Competition of the binding of 2 inhibitors to 125I-CPS-P by unlabeled CPS-P and another plasma fVIII was similar, demonstrating that the antibody response was not directed to epitopes only present in CPS-P. We propose that the immunogenicity of the CPS-P C2 domain was altered by heat pasteurization.

 

  • References

  • 1 Hoyer LW, Scandella D. Factor VIII inhibitors: structure and function in autoantibody and hemophilia A patients. Sem Hematol 1994; 31: 1-5.
    PubMedGoogle Scholar
  • 2 Schwaab R, Brackmann H-H, Meyer C, Seehafer J, Kirchgesser M, Haack A, Olek K, Tuddenham EGD, Oldenburg J. Haemophilia A: Mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74: 1402-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Hoyer LW, Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White GCI. eds. Inhibitors to coagulation factors. The incidence of factor VIII inhibitors in patients with severe hemophilia A. New York: Plenum Press; 1995. p. 35-45.
    Google Scholar
  • 4 Gill FM. The natural history of factor VIII inhibitors in patients with hemophilia A. Prog Clin Biol Res 1984; 150: 19-29.
    PubMedGoogle Scholar
  • 5 McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao AV, Lazerson J. Hemophilia Study Group.. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988; 71: 344-8.
    PubMedGoogle Scholar
  • 6 Peerlinck K, Arnout J, Gilles JG, Saint-Remy J-M, Vermylen J. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemost 1993; 69: 115-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Rosendaal FR, Nieuwenhuis HK, van den Berg HM, Heijboer H, Mauser-Bunschoten EP, van der Meer J, Smit C, Strengers PFW, Briët E. and the Dutch Hemophilia Study Group. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Blood 1993; 81: 2180-6.
    PubMedGoogle Scholar
  • 8 Mauser-Bunschoten EP, Rosendaal FR, Nieuwenhuis HK, Roosendaal G, Briët E, van den Berg HM. Clinical course of factor VIII inhibitors developed after exposure to a pasteurised Dutch concentrate compared to classic inhibitors in hemophilia A. Thromb Haemost 1994; 71: 703-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Peerlinck K, Arnout J, Di Giambattista M, Gilles JG, Laub R, Jacquemin M, Saint-Remy JMR, Vermylen J. Factor VIII inhibitors in previously treated haemophilia A patients with a double-virus inactivated plasma derived factor VIII concentrate. Thromb Haemost 1997; 77: 80-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Opper-mann H, Keck R, Lawn RM, Capon DJ. Structure of human factor VIII. Nature 1984; 312: 337-42.
    CrossrefPubMedGoogle Scholar
  • 11 van Dieijen G, Tans G, Rosing J, Hemker HC. The role of phospholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem 1981; 256: 3433-42.
    PubMedGoogle Scholar
  • 12 Scandella D, Mattingly M, Prescott R. A recombinant factor VIII A2 domain polypeptide quantitatively neutralizes human inhibitor antibodies which bind to A2. Blood 1993; 82: 1767-75.
    PubMedGoogle Scholar
  • 13 Scandella D, Gilbert GE, Shima M, Eagleson C, Felch M, Prescott R, Rajalakshmi KJ, Saenko E. Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino aicds 2248-2312 which overlap a phospholipid binding site. Blood 1995; 86: 1811-9.
    PubMedGoogle Scholar
  • 14 Foster PA, Fulcher CA, Houghten RA, de Graaf Mahoney S, Zimmerman TS. A murine monoclonal anti-factor VIII inhibitory antibody and two human factor VIII inhibitors bind to different areas within a twenty amino acid segment of the acidic region of factor VIII heavy chain. Blood Coag Fibrinol 1990; 1: 9-15.
    CrossrefPubMedGoogle Scholar
  • 15 Saenko EL, Shima M, Gilbert GE, Scandella D. Slowed release of thrombin-cleaved factor VIII from von Willebrand factor by a monoclonal and a human antibody is a novel mechanism for factor VIII inhibition. J Biol Chem 1996; 271: 27424-31.
    CrossrefPubMedGoogle Scholar
  • 16 Healey JF, Lubin IM, Saenko EL, Hoyer LW, Scandella D, Lollar P. Residues 484-508 contain a major determinant of the inhibitory epitope in the A2 domain of human factor VIII. J Biol Chem 1995; 270: 14505-9.
    CrossrefPubMedGoogle Scholar
  • 17 Lollar P, Parker ET, Curtis JE, Helgerson SL, Hoyer LW, Scott ME, Scan-della D. Inhibition of human factor VIIIa by human anti-A2 subunit antibodies. J Clin Invest 1994; 93: 2497-504.
    CrossrefPubMedGoogle Scholar
  • 18 Shima M, Nakai H, Scandella D, Tanaka I, Sawamoto Y, Kamisue S, Morichika S, Murakami T, Yoshioka A. Common inhibitory effects of human anti-C2 domain inhibitor alloantibodies on factor VIII binding to von Willebrand factor. Brit J Haematol 1995; 91: 714-21.
    CrossrefPubMedGoogle Scholar
  • 19 Lenting PJ, Donath M-JSH, van Mourik JA, Mertens K. Identification of a binding site for blood coagulation factor IXa on the light chain of human factor VIII. J Biol Chem 1996; 269: 7150-5.
    PubMedGoogle Scholar
  • 20 Zhong D, Scandella D. Epitope of a hemophilia A inhibitor antibody overlaps the factor VIII binding site for factor IX. Blood 1996; 88: 324a.
    PubMedGoogle Scholar
  • 21 Lenting PJ, van de Loo JHP, Donath M-JSH, van Mourik JA, Mertens K. The sequence Glu1811-Lys1818 of human blood coagulation factor VIII comprises a binding site for activated factor IX. J Biol Chem 1996; 271: 1935-40.
    CrossrefPubMedGoogle Scholar
  • 22 Shima M, Scandella D, Yoshioka A, Nakai H, Tanaka I, Kamisue S, Terada S, Fukui H. A factor VIII neutralizing monoclonal antibody and a human inhibitor alloantibody recognizing epitopes in the C2 domain inhibit factor VIII binding to von Willebrand factor and to phosphatidylserine. Thromb Haemost 1993; 69: 240-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Scandella D, Timmons L, Mattingly M, Trabold N, Hoyer LW. A soluble recombinant factor VIII fragment containing the A2 domain binds to some human anti-factor VIII antibodies that are not detected by immunoblotting. Thromb Haemost 1992; 67: 665-71.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Saenko EL, Shima M, Rajalakshmi KJ, Scandella D. A role for the C2 domain of factor VIII in binding to von Willebrand factor. J Biol Chem 1994; 269: 11601-5.
    PubMedGoogle Scholar
  • 25 Kasper CK, Aledort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH. et al. A more uniform measurement of factor VIII inhibitors. Thrombos Diathes haemorrh 1975; 34: 869-72.
    PubMedGoogle Scholar
  • 26 Saenko EL, Scandella D. A mechanism for inhibition of factor VIII binding to phospholipid by von Willebrand factor. J Biol Chem 1995; 270: 13826-33.
    CrossrefPubMedGoogle Scholar
  • 27 Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene 1989; 77: 51-9.
    CrossrefPubMedGoogle Scholar
  • 28 Kaufman RJ. Selection and coamplification of heterologous genes in mammalian cells. Methods Enzymol 1990; 185: 537-66.
    PubMedGoogle Scholar
  • 29 Lollar P, Fay PJ, Fass DN. Factor VIII and factor VIIIa. Methods Enzymol 1993; 222: 128-43.
    PubMedGoogle Scholar
  • 30 Lollar P, Parker CG, Tracy RP. Molecular characterization of commercial porcine factor VIII concentrate. Blood 1988; 71: 137-43.
    PubMedGoogle Scholar
  • 31 Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC. et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342-7.
    CrossrefPubMedGoogle Scholar
  • 32 Prescott R, Nakai H, Saenko EL, Scharrer I, Nilsson IM, Humphries J, Hurst D, Bray G, Scandella D. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Blood 1997; 89: 3663-71.
    PubMedGoogle Scholar
  • 33 Mauser-Bunschoten EP, Niewenhuis HK, Roosendaal G, van den Berg HM. Low-dose tolerance induction in hemophilia A patients with inhibitors. Blood 1995; 86: 983-8.
    PubMedGoogle Scholar
  • 34 Gilles JGG, Arnout J, Vermylen J, Saint-Remy J-MR. Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction. Blood 1993; 82: 2452-61.
    PubMedGoogle Scholar
  • 35 Gilles JGG, Peerlinck K, Arnout J, Vermylen J, Saint-Remy J-MR. Restricted epitope specificity of anti-fVIII antibodies that appeared during a recent outbreak of inhibitors. Thromb Haemost 1997; 77: 938-43.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 1988; 335: 256-9.
    CrossrefPubMedGoogle Scholar