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; Di M. Giambattista; P. Fondu; H.-H. Brackmann; H. Lenk; E. L. Saenko; M. Felch; D. Scandella

doi:10.1055/s-0037-1614415

Thrombosis and Haemostasis, Table of Contents

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

¹From the Red Cross, Brussels, Belgium

,

Di M. Giambattista

¹From the Red Cross, Brussels, Belgium

,

P. Fondu

²Hôpital Universitaire Brugmann, Brussels

,

H.-H. Brackmann

³University of Bonn, Germany, Rockville, MD, USA

,

H. Lenk

⁴University of Leipzig, Germany, Rockville, MD, USA

,

E. L. Saenko

⁵American Red Cross, Rockville, MD, USA

,

M. Felch

⁵American Red Cross, Rockville, MD, USA

,

D. Scandella

⁵American Red Cross, Rockville, MD, USA

› Author Affiliations

Abstract

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

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.