Thromb Haemost 1999; 81(01): 39-44
DOI: 10.1055/s-0037-1614415
Review Article
Schattauer GmbH

Inhibitors in German Hemophilia A Patients Treated with a Double Virus Inactivated Factor VIII Concentrate Bind to the C2 Domain of FVIII Light Chain

R. Laub
1   From the Red Cross, Brussels, Belgium
,
Di M. Giambattista
1   From the Red Cross, Brussels, Belgium
,
P. Fondu
2   Hôpital Universitaire Brugmann, Brussels
,
H.-H. Brackmann
3   University of Bonn, Germany, Rockville, MD, USA
,
H. Lenk
4   University of Leipzig, Germany, Rockville, MD, USA
,
E. L. Saenko
5   American Red Cross, Rockville, MD, USA
,
M. Felch
5   American Red Cross, Rockville, MD, USA
,
D. Scandella
5   American Red Cross, Rockville, MD, USA
› Author Affiliations
Further Information

Correspondence to:

Dr. D. Scandella
American Red Cross
15601 Crabbs Branch Way
Rockville, MD 20855, USA
Phone: +1 301 738 0750   
Fax: +1 301 738 0794

Publication History

Received04 May 1998

Accepted after revision15 September 1998

Publication Date:
08 December 2017 (online)

 

Summary

To reduce the risk of transmission of hepatitis A virus, an Octaphar-ma produced factor VIII (fVIII) concentrate treated with solvent detergent (FVIII-SD) was further pasteurized after purification. This product, Octavi SDPlus (FVIII-SDP), was marketed in Europe in 1993 to 1995. Inhibitors appeared from September to October, 1995, in 12 of 109 previously treated German hemophilia A patients. A study of similarly treated Belgian patients, who also developed inhibitors, had shown antibodies to the fVIII light chain (domains A3-C1-C2) only. In the present study, the epitope specificity of 8 German inhibitor plasmas was also found to be restricted to the light chain. In radioimmunoprecipitation assays to localize the light chain epitope(s), antibody binding to heavy chain (domains A1-A2-B) was 11-148 fold lower than to the C2 domain, and binding to recombinant A3-C1 was barely detectable. These results were supported by >95% neutralization of a high responder inhibitor titer by the C2 domain.


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  • References

  • 1 Bray GL, Gomperts ED, Courter S, Gruppo R, Gordon EM, Manco-John-son M, Shapiro A, Scheibel E, White III G, Lee M. and the Recombinate Study Group. A multicenter study of recombinant factor VIII (Recombinate): Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 1994; 83: 2428-35.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 Mannucci PM, Santagostino E, Di Bona E, Gentili G, Ghirardini A, Chiavoni M, Mele A. The outbreak of hepatitis A in Italian patients with hemophilia: facts and fancies. Vox Sang 1994; 67: 31-5.
  • 6 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.
  • 7 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Oppermann H, Keck R, Lawn RM, Capon DJ. Structure of human factor VIII. Nature 1984; 312: 337-42.
  • 8 Sawamoto Y, Prescott R, Zhong D, Saenko EL, Mauser-Bunschoten E, Peerlinck K, van den Berg M, Scandella D. 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. Thromb Haemost 1998; 79: 62-8.
  • 9 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.
  • 10 Vlot AJ, Koppelman SJ, van den Berg MH, Bouma BN, Sixma JJ. The affinity and stoichiometry of binding of human factor VIII to von Willebrand factor. Blood 1995; 85: 3150-7.
  • 11 Nesheim M, Pittman DD, Giles AR, Fass DN, Wang JH, Slonosky D, Kauf-man RJ. The effect of plasma von Willebrand factor on the binding of human factor VIII to thrombin-activated human platelets. J Biol Chem 1991; 266: 17815-26.
  • 12 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.
  • 13 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.
  • 14 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.
  • 15 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.
  • 16 Zhong D, Saenko EL, Felch M, Scandella D. Some human inhibitor antibodies interfere with factor VIII binding to factor IX. Blood 1998; 92: 136-42.
  • 17 Thompson AR, Murphy MEP, Liu ML, Saenko EL, Healey JF, Lollar P, Scandella D. Loss of tolerance to exogenous and endogenous factor VIII in a mild hemophilia A patient with an Arg593 to Cys mutation. Blood 1997; 90: 1902-10.
  • 18 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.
  • 19 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.
  • 20 Hoyer LW. The incidence of factor VIII inhibitors in patients with severe hemophilia A. Adv Exp Biol Med 1995; 386: 35-45.
  • 21 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.
  • 22 Hay CRM, Ollier W, Pepper L, Cumming A, Keeney S, Goodeve AC, Col-vin BT, Hill FGH, Preston FE, Peake IR. et al HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. Thromb Haemost 1997; 77: 234-7.
  • 23 Raut S, Di Giambattista M, Bevan SA, Hubbard AR, Barrowcliffe TW, Laub R. Modification of FVIII in therapeutic concentrates after virus inactivation by solvent-detergent and pasteurisation. Thromb Haemost 1998; 80: 624-31.
  • 24 Josic D, Stadler M, Buchacher A, Pock K, Robinson S, Schwinn H. Degradation products of factor VIII which can lead to increased immunogenicity.. Thromb Haemost 1997. Suppl. 576.
  • 25 Rosendaal FR. Factor VIII inhibitors on a SD-treated and pasteurized concentrate associated with specific batches and batch characteristics.. Thromb Haemost 1997. Suppl. 590.
  • 26 Pittman DD, Alderman EM, Tomkinson KN, Wang JH, Giles AR, Kauf-man RJ. Biochemical, Immunological, and In Vivo Functional Characterization of B-Domain-Deleted Factor VIII. Blood 1993; 81: 2925-35.
  • 27 Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian Jr. HH. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nature Genet 1995; 10: 10119-21.

Correspondence to:

Dr. D. Scandella
American Red Cross
15601 Crabbs Branch Way
Rockville, MD 20855, USA
Phone: +1 301 738 0750   
Fax: +1 301 738 0794

  • References

  • 1 Bray GL, Gomperts ED, Courter S, Gruppo R, Gordon EM, Manco-John-son M, Shapiro A, Scheibel E, White III G, Lee M. and the Recombinate Study Group. A multicenter study of recombinant factor VIII (Recombinate): Safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 1994; 83: 2428-35.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 Mannucci PM, Santagostino E, Di Bona E, Gentili G, Ghirardini A, Chiavoni M, Mele A. The outbreak of hepatitis A in Italian patients with hemophilia: facts and fancies. Vox Sang 1994; 67: 31-5.
  • 6 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.
  • 7 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Oppermann H, Keck R, Lawn RM, Capon DJ. Structure of human factor VIII. Nature 1984; 312: 337-42.
  • 8 Sawamoto Y, Prescott R, Zhong D, Saenko EL, Mauser-Bunschoten E, Peerlinck K, van den Berg M, Scandella D. 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. Thromb Haemost 1998; 79: 62-8.
  • 9 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.
  • 10 Vlot AJ, Koppelman SJ, van den Berg MH, Bouma BN, Sixma JJ. The affinity and stoichiometry of binding of human factor VIII to von Willebrand factor. Blood 1995; 85: 3150-7.
  • 11 Nesheim M, Pittman DD, Giles AR, Fass DN, Wang JH, Slonosky D, Kauf-man RJ. The effect of plasma von Willebrand factor on the binding of human factor VIII to thrombin-activated human platelets. J Biol Chem 1991; 266: 17815-26.
  • 12 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.
  • 13 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.
  • 14 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.
  • 15 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.
  • 16 Zhong D, Saenko EL, Felch M, Scandella D. Some human inhibitor antibodies interfere with factor VIII binding to factor IX. Blood 1998; 92: 136-42.
  • 17 Thompson AR, Murphy MEP, Liu ML, Saenko EL, Healey JF, Lollar P, Scandella D. Loss of tolerance to exogenous and endogenous factor VIII in a mild hemophilia A patient with an Arg593 to Cys mutation. Blood 1997; 90: 1902-10.
  • 18 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.
  • 19 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.
  • 20 Hoyer LW. The incidence of factor VIII inhibitors in patients with severe hemophilia A. Adv Exp Biol Med 1995; 386: 35-45.
  • 21 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.
  • 22 Hay CRM, Ollier W, Pepper L, Cumming A, Keeney S, Goodeve AC, Col-vin BT, Hill FGH, Preston FE, Peake IR. et al HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. Thromb Haemost 1997; 77: 234-7.
  • 23 Raut S, Di Giambattista M, Bevan SA, Hubbard AR, Barrowcliffe TW, Laub R. Modification of FVIII in therapeutic concentrates after virus inactivation by solvent-detergent and pasteurisation. Thromb Haemost 1998; 80: 624-31.
  • 24 Josic D, Stadler M, Buchacher A, Pock K, Robinson S, Schwinn H. Degradation products of factor VIII which can lead to increased immunogenicity.. Thromb Haemost 1997. Suppl. 576.
  • 25 Rosendaal FR. Factor VIII inhibitors on a SD-treated and pasteurized concentrate associated with specific batches and batch characteristics.. Thromb Haemost 1997. Suppl. 590.
  • 26 Pittman DD, Alderman EM, Tomkinson KN, Wang JH, Giles AR, Kauf-man RJ. Biochemical, Immunological, and In Vivo Functional Characterization of B-Domain-Deleted Factor VIII. Blood 1993; 81: 2925-35.
  • 27 Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian Jr. HH. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nature Genet 1995; 10: 10119-21.