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Thromb Haemost 1998; 80(05): 779-783
DOI: 10.1055/s-0037-1615358
Review Article
Schattauer GmbH

French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

C. Rothschild
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
Y. Laurian
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
E. P. Satre
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
A. Borel Derlon
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
H. Chambost
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
P. Moreau
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
J. Goudemand
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
A. Parquet
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
J. Peynet
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
M. Vicariot
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
P. Beurrier
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
S. Claeyssens
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
A. Durin
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
A. Faradji
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
E. Fressinaud
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
S. Gaillard
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
V. Guérin
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
C. Guérois
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
G. Pernod
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
P. Pouzol
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
J. F. Schved
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
,
C. Gazengel
1   From the Hemophilia Centers of Paris-Necker, Bicêtre, Montmorency, Caen, Marseille, Le Mans, Lille, Versailles, Brest, Angers, Toulouse, Lyon, Strasbourg, Nantes, Limoges, Bordeaux, Tours, Grenoble, Reims and Montpellier, France
› Author Affiliations
Further Information

Publication History

Received 17 March 1998

Accepted after resubmission 04 August 1998

Publication Date:
07 December 2017 (online)

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Summary

Fifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

 

  • References

  • 1 Bray GL, Gomperts ED, Courter S, Gruppo R, Gordon EM, Manco-Johnson M, Shapiro A, Scheibel E, White G, Lee M. 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.
    PubMedGoogle Scholar
  • 2 Lusher JM, Arkin S, Abilgaard CF, Schwartz RS. and the Kogenate Previously Untreated Patient Study Group. Recombinant factor VIII for the treatment of previously untreated patients with Haemophilia A. N Engl J Med 1993; 328: 453-9.
    CrossrefPubMedGoogle Scholar
  • 3 Addiego J, Kasper C, Abildgaard C, Hiltgartner M, Lusher J, Glader B, Aledort L. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993; 342: 462-4.
    CrossrefPubMedGoogle Scholar
  • 4 De Biasi R, Rocino A, Papa ML, Salerno E, Mastrullo L, De Blasi D. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma-derived concentrates. Thromb Haemost 1994; 71: 544-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-8.
    CrossrefPubMedGoogle Scholar
  • 6 Guérois C, Laurian Y, Rothschild C, Parquet-Gernez A, Duclos AM, Négrier C, Vicariot M, Fimbel B, Fressinaud E, Fiks-Sigaud M, Derlon A, Berthier AM, Gaillard S, Bertrand MA. Incidence of factor VIII inhibitor development in severe hemophilia A patients treated only with one brand of highly purified plasma-derived concentrate. Thromb Haemost 1995; 73: 215-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Addiego JE, Gomperts E, Liu SL, Bailey P, Courter SG, Lee ML, Neslund GG, Kingdon HS, Griffith MJ. Treatment of hemophilia A with a highly purified factor VIII concentrate prepared by anti-FVIIIc immunoaffinity chromatography. Thromb Haemost 1992; 67: 19-27.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Yee TT, Williams MD, Hill FGH, Lee CA, Pasi KJ. Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product. Thromb Haemost 1997; 78: 1027-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Langdell RD, Wagner RH, Brinkhous KM. Effect of antihemophilic factor on one-stage clotting test. J Lab Clin Med 1953; 41: 637-47.
    PubMedGoogle Scholar
  • 10 Kasper CK, Aledort LM, Counts RB, Edson JR, Fratantoni J, Green D, Hampton JW, Hilgartner MW, Lazerson J, Levine PH, McMillan CW, Pool JG, Shapiro SS, Shulman NR, van Eys J. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869-72.
    PubMedGoogle Scholar
  • 11 Lakish D, Kazazian H, Antonarakis S, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature Genet 1993; 5: 236-41.
    CrossrefPubMedGoogle Scholar
  • 12 Kaplan EL, Meier P. Non parametric estimation from incomplete observations. JAMA 1958; 53: 456-81.
    PubMedGoogle Scholar
  • 13 Rothschild C, Laurian Y, Satre EP, Borel-Derlon A, Chambost H, Moreau P, Goudemand J, Parquet A, Vicariot M, Beurrier P, Claeyssens S, Durin A, Faradji A, Fressinaud E, Gaillard S, Guérin V, Guérois C, Pernod G, Peynet J, Pouzol P, Schved JF, Gazengel C. Inhibitor incidence in previously untreated patients (PUPs) with severe hemophilia A receiving recombinant factor VIII (rFVIII). Thromb Haemost 1997; 78 (Suppl. 01) 2654a.
    PubMedGoogle Scholar
  • 14 Lusher J, Arkin S, Abildgaard CF, Hurst D. and the Kogenate PUP study group. Recombinant FVIII (Kogenate) treatment of previously untreated patients (PUPS) with hemophilia A: update of safety, efficacity, and inhibitor development after five study years. Thromb Haemost 1995; 73 (Suppl. 01) 1012a.
    PubMedGoogle Scholar
  • 15 Bray GL, Schroth P, Lynes M, Buckwalter C, Lee ML, and Gomperts ED. for the Recombinate Study Group. Results from the Recombinate® (recombinant factor VIII) study of previously untreated patients with hemophilia A: a 4.5 year follow-up report. Thromb Haemost 1995; 73 (Suppl. 01) 1013a.
    PubMedGoogle Scholar
  • 16 Peerlinck K, Arnout J, Gilles JG, Saint-Remy JMR, Vermylen J. A higher than expected incidence of facteur 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
  • 17 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
  • 18 Rosendaal FR, Nieuwenhuis HM, van den Berg HM, Heijboer H, MauserBunschoten 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
  • 19 Aledort L. Inhibitors in hemophilia patients: Current status and management. Am J Hematol 1994; 47: 208-17.
    CrossrefPubMedGoogle Scholar
  • 20 Hoyer LW. Factor VIII inhibitors. Curr Opin Hematol 1995; 2: 365-71.
    CrossrefPubMedGoogle Scholar
  • 21 Tizzano EF, Altisent C, Domènech M, Cornet M, Tusell J, Baiget M. Inhibitor Development in Haemophilia A Patients with Inversion of the Intron 22 of the Factor VIII Gene. Thromb Haemost 1996; 76: 124-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Schwaab R, Brackmann HH, 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
  • 23 Antonarakis SE, Rossiter JP, Young M, Horst J, de Moerloose P, Sommer SS, Ketterling RP, Kazazian HH, Négrier C, Vinciguerra C, Gitschier J, Goossens M, Girodon E, Ghanem N, Plassa F, Lavergne JM, Vidaud M, Costa JM, Laurian Y, Lin SW, Lin SR, Shen MC, Lillicrap D, Taylor SAM, Windsor S, Valleix SV, Nafa K, Sultan Y, Delpech M, Vnencak-Jones CL, Phillips JA, Ljung RCR, Koumbarelis E, Gialeraki A, Mandalaki T, Jenkins PV, Collins PW, Pasi KJ, Goodeve A, Peake I, Preston FE, Schwartz M, Scheibel E, Ingerslev J, Cooper DN, Millar DS, Kakkar VV, Giannelli F, Naylor JA, Tizzano EF, Baiget M, Domenech M, Altisent C, Tusell J, Beneyto M, Lorenzo JI, Gaucher C, Mazurier C, Peerlinck K, Matthijs G, Cassiman JJ, Vermylen J, Mori PG, Acquila M, Caprino D, Inaba H. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood 1995; 86: 2206-12.
    PubMedGoogle Scholar
  • 24 Millar DS, Kakkar VV, Cooper DN. Screening for inversions in the factor VIII (F8) gene causing severe haemophilia A. Blood Coagulation Fibrinolysis 1994; 5: 239-42.
    CrossrefPubMedGoogle Scholar
  • 25 Addiego JE, Kasper C, Abildgaard C, Lusher J, Hilgartner M, Glader B, Aledort L, Hurst D, Bray G. Increased frequency of inhibitors in African American hemophilia A patients. Blood 1994; 84 (Suppl. 01) 943a.
    PubMedGoogle Scholar
  • 26 Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G, van den Berg HM. Low-Dose Immune Tolerance Induction in Hemophilia A patients with inhibitors. Blood 1995; 86: 983-8.
    PubMedGoogle Scholar
  • 27 Kreuz W, Ehrenforth S, Funk M, Auerswald G, Mentzer D, Joseph-Steiner J, Beeg T, Klarmann D, Scharrer I, Kornhuber B. Immune tolerance therapy in paediatric haemophiliacs with factor VIII inhibitors: 14 years follow-up. Haemophilia 1995; 1: 24-32.
    PubMedGoogle Scholar
  • 28 DiMichele DM, Kroner BL. Analysis of the North American Immune Tolerance Registry (NAITR) (1993-1997): Current practice implications. Blood 1997; 90 (Suppl. 01) 156a.
    PubMedGoogle Scholar
  • 29 Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors-Twenty Years “Bonn Protocol”. Vox Sang 1996; 70: 30-5.
    PubMedGoogle Scholar
  • 30 DiMichele DM. Immune tolerance: a synopsis of the international experience. Haemophilia 1998; 4: 568-73.
    CrossrefPubMedGoogle Scholar
  • 31 Mariani G, Ghirardini A, Bellocco R. Immune tolerance in hemophilia. Principal results from the international registry. Thromb Haemost 1994; 72: 155-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Spence K, Beresford-Webb VM, Lawn M, Savidge GF. Immune tolerance as a cure for FVIII antibodies. Haemophilia 1996 2 (Suppl. 01) 126a.
    PubMedGoogle Scholar