Factor VIII Inhibitors in Previously Treated Haemophilia A Patients with a Double Virus-inactivated Plasma Derived Factor VIII Concentrate^[*]

Summary

Antibodies to factor VIII (inhibitors) are usually produced at the beginning of treatment with factor VIII and are rare in multitransfused patients. Such antibodies are deemed to be patient-related, as supported by the description of a number of associated risk factors. However, a second category of inhibitors has recently been identified, namely antibodies occurring in multitransfused patients as a result of exposure to a particular factor VIII concentrate. A first outbreak of product-related inhibitors was recently described. The present paper describes the second well-documented occurrence of such inhibitors.

Eight out of 140 multitransfused patients with severe haemophilia A developed an inhibitor to factor VIII shortly after changing treatment to a double-virus inactivated plasma-derived factor VIII concentrate. In addition to solvent-detergent treatment, this concentrate was pasteurised at 63° C for 10 hours. Exposure to the pasteurised product before inhibitor detection ranged from 9 to 45 days. Inhibitor titers varied between 2.2 and 60 Bethesda Units and recovery of transfused factor VIII ranged from 0.21 to 0.68 (expressed as IU/dl factor VIII rise per IU/kg administered). In contrast to usual inhibitors in haemophilia A patients, these product-related inhibitors showed complex inhibition kinetics. They were found specific for the factor VIII light chain. The inhibitors gradually declined when exposure to the pasteurised product was stopped, despite further treatment with other factor VIII concentrates. The present data stress the importance of carefully monitored clinical studies, both in previously treated and previously untreated patients, before introduction of a new or modified clotting factor concentrate.

This study was supported in part by research grant 3.0266.95 from the Belgian F.G.W.O. and by convention BR 1/4-255/138 from the IRSIA

• References

• 1 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: 1402-1406
• 2 McMillan CW, Shapiro SS, Whitehurts D, Hoyer LW, Rao V, Lazerson J. the Haemophilia Study Group The natural history of factor VIII:C inhibitors in patients with haemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988; 71: 344-348
• 3 Hoyer LW. Annotation. Why do so many haemophilia A patients develop an inhibitor. Br J Haematol 1995; 90: 498-501
• 4 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: 115-118
• 5 Rosendaal FR, Nieuwenhuis HK, Van denBerg HM, Heijboer H, Mauser-Bunschoten EP, van derMeerJ, Smit C, Strengers PFW. the Dutch Haemophilia Study Group A sudden increase in Factor VIII inhibitor development in multitransfused haemophilia A patients in The Netherlands. Blood 1993; 81: 2180-2186
• 6 Guérois C, Laurian Y, Rothschild C, Parquet-Gernez A, Duclos A-M, Négrier C, Vicariot M, Fimbel B, Fressinaud E, Fiks-Sigaud M, Derlon A, Berthier A-M, Gaillard S, Bertrand M-A. Incidence of factor VIII inhibitor development in severe haemophilia A patients treated only with one brand of highly purified plasma-derived concentrate. Thromb Haemost 1995; 73: 215-218
• 7 Vermylen J, Peerlinck K. Review of the hepatitis A epidemics in haemophiliacs in Europe. Vox Sang 1994; 67: 8-11
• 8 Ruymann FB, Krill CE, Halpin TJ, Churchill WH, Ewenstein B, DeMaria A, MancoJohnson MJ, Hoffman RE. Hepatitis A among persons with haemophilia who received clotting factor concentrate. MMWR 1996; 45: 29-32
• 9 Robinson S, Schwinn H, Josic D, Nur I, Stadler M, Bal F, Gehringer W, Schütz R. Development and biochemical characterization of a double-virus-inactivated factor VIII preparation. Blood Coagulat Fibrinol 1995; 06: 40-47
• 10 Effenberer W, Oldenburg J, Budde U, Paffenholz M, Hanfland P, Brack-man H-H. Entwicklung von Faktor VIII-Hemmkörpem bei vorher behandelten (PTP) Hämophilie A-Patienten unter der Anwendung eines doppelt virusinaktivierten plasmatischen Faktor VIII-Konzentrates (Octavi SD plus). Hamburger Hamophiliesymposium. Hamburg, Germany: 1995. (in press)
• 11 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 EysJ. A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869
• 12 Langdell RD, Wagner RH, Brinkhous KM. Effect of antihemophilic factor on one-stage clotting tests: a presumptive test for haemophilia and a simple one-stage antihemophilic factor assay procedure. J Lab Clin Med 1953; 41: 637-647
• 13 Gilles JG, Arnout J, Peerlinck K, Vermylen J, Saint-Remy JM. Antifactor VIII antibodies of haemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction. Blood 1993; 82: 2452-2461
• 14 Peerlinck K, FR Rosendaal, Vermylen J. Incidence of inhibitor development in a group of young haemophilia A patients treated exclusively with lyophilized cryoprecipitate. Blood 1993; 81: 3332-3335
• 15 Biggs R, Austen DEG, Denson KWE, Rizza CR, Borrett R. The mode of action of antibodies which destroy factor VIII. I. Antibodies which have second-order concentration graphs. Br J Haematol 1972; 23: 125-155
• 16 Gawryl MS, Hoyer LW. Inactivation of factor VIII coagulant activity by two different types of human antibodies. Blood 1982; 60: 1103-1109
• 17 Kasper CK. Laboratory diagnosis of factor VIII inhibitors. In: Acquired haemophilia. Kessler C. ed. Excerpta Medica Inc; 1995. p 9
• 18 Briët E, Rosendaal FR, Kreuz W, Rasi V, Peerlinck F, Vermylen J, Ljung R, Rocino A, Addiego J, Lorenzo JI, Pabinger I. High titer inhibitors in severe haemophilia A. A meta-analysis based on eight long-term follow-up studies concerning inhibitors associated with crude or intermediate purity factor VIII products. Thromb Haemost 1994; 72: 162-164
• 19 Tuddenham EGD, Schwaab R, Seehafer J, Millar DS, Gitschier J, Higuchi M, Bidichandani S, Connor JM, Hoyer LW, Yoshioka A, Peake IR, Olek K, Kazazian HH, Lavergne J-M, Giannelli F, Antonarakis SE, Cooper DN. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acids Research 1994; 22: 3511-3545
• 20 Antonorakis SE, Rossiter JP, Young M, Horst J, De MoerlooseP, Sommer SS, Ketterling RP, Kazazian Jr HH, Négrier C, Vinciguerra C, Gitschier J, Goossens M, Girodon E, Ghanem N, Plassa F, Lavergne JM, Vidaud M, Costa JM, Laurian Y, Lin S-W, Lin S-R, Shen M-C, Lillicrap D, Taylor SAM, Windsor S, Valleix SV, Nafa K, Sultan Y, Delpech M, Vnencak-Jones CL, Philips III 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 E, Baiget M, Domenech M, Altisent C, Tussel J, Beneyto M, Lorenzo JJ, Gaucher C, Mazurier C, Peerlinck K, Matthys G, Cassiman JJ, Vermylen J, Mori PG, Acquila M, Caprino D, Inaba H. Factor VIII Gene Inversions in Severe Haemophilia A: Results of an International Consortium Study. Blood 1995; 86: 2206-2212
• 21 Aly AM, Aledort LM, Lee TD, Hoyer LM. Histocompatibility antigen pattern in haemophiliac patients with factor VIII antibodies. Br J Haematology 1990; 76: 238-241
• 22 Scandella D, Mattingly G, de GraafS, Fuller CA. Localization of epitopes for human factor VIII inhibitor antibodies by immunoblotting and antibody neutralization. Blood 1989; 74: 1618-1626
• 23 Gilles JG, Amout J, Peerlinck K, Vermylen J, Saint-Remy J-M. A sudden outbreak of inhibitors during treatment with a particular pasteurized factor VIII concentrate (FVIII-CPS-P): characterization of specific antibodies. Thromb Haemost 1993; 69: 557 (abstract)
• 24 Mauser-Bunschoten EP, Rosendaal FR, Nieuwenhuis HK, Roosendaal G, Briët E, Vandenberg HM. Clinical course of factor VIII inhibitors developed after exposure to a pasteurized Dutch concentrate compared to classic inhibitors in haemophilia A. Thromb Haemost 1994; 71: 703-706