Skip to main content
SpringerLink
Log in

Case Study: Immunogenicity of Factor VIII

  • Chapter
Book cover Immunogenicity of Biopharmaceuticals

Part of the book series: Biotechnology: Pharmaceutical Aspects ((PHARMASP,volume VIII))

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abshire, T. C., Brackmann, H. H., Scharrer, I., Hoots, K., Gazengel, C., Powell, J. S., Gorina, E., Kellermann, E., and Vosburgh, E. 2000. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy. Thromb. Haemost. 83:811–816.

    PubMed  CAS  Google Scholar 

  • Abshire, T. and Kenet, G. 2004. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J. Thromb. Haemost. 2:899–909.

    Article  PubMed  CAS  Google Scholar 

  • Addiego, J. E. Jr., Gomperts, E., Liu, S.-L., Bailey, P., Courter, S. G., Lee, M. L., Neslund, G. G., Kingdon, H. S., and Griffith, M. J. 1992. Treatment of hemophilia A with a highly purified factor VIII concentrate prepared by anti-FVIII immunoaffinity chromatography. Thromb. Haemost. 67:19–27.

    PubMed  Google Scholar 

  • Addiego, J. E., Kasper, C., Abildgaard, C., Hilgartner, M., Lusher, J., Glader, B., and Aledort, L. 1993. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 342:462–464.

    Article  PubMed  CAS  Google Scholar 

  • Addiego, J. E., Kasper, C., Abildgaard, C., Lusher, J., Hilgartner, M., Glader, B., Aledort, L., Hurst, D., and Bray, G. 1994. Increased frequency of inhibitors in African American hemophilic patients. Blood 1:293a.

    Google Scholar 

  • Aledort, L. M. 2004. Is the incidence and prevalence of inhibitors greater with recombinant products? Yes. J. Thromb. Haemost. 2:861–862.

    Article  CAS  Google Scholar 

  • Aledort, L. M. and DiMichele, D. M. 1998. Inhibitors occur more frequently in African-American and Latino haemophiliacs. Haemophilia 4:68.

    Article  PubMed  CAS  Google Scholar 

  • Ananyeva, N. M., Lacroix-Desmazes, S., Hauser, C. A. Shima, M., Ovanesov, M. V., Khrenov, A. V., and Saenko, E. L. 2004. Inhibitors in hemophilia A: mechanisms of inhibition, management and perspectives. Blood Coagul. Fibrinolysis 15: 109–124.

    Article  PubMed  CAS  Google Scholar 

  • Antonarakis, S. E., Kazazian, H. H., and Tuddenham, E. G. D. 1995. Molecular etiology of factor VIII deficiency in hemophilia A. Hum. Mutat. 5:1–22.

    Article  PubMed  CAS  Google Scholar 

  • Arkin, S., Cooper, H. A., Hutter, J. J., Miller, S., Schmidt, M. L., Seibel, N. L., Shapiro, A., and Warrier, I. 1998. Activated recombinant human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors. Results of the NovoSeven emergency-use program. Haemostasis 28: 93–98.

    Article  PubMed  CAS  Google Scholar 

  • Astermark, J. 2006. Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors. Haemophilia 12 (Suppl. 6):8–14.

    Article  PubMed  CAS  Google Scholar 

  • Astermark, J., Berntorp, E., White, G. C., and Kroner, B. L. 2001. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia 7:267–272.

    Article  PubMed  CAS  Google Scholar 

  • Astermark, J., Oldenburg, J., Escobar, M., White G. C., Berntorp E., and the MIBS Study Group. 2005. The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica 90:924–931.

    PubMed  CAS  Google Scholar 

  • Astermark, J., Oldenburg, J., Pavlova, A., Berntorp, E., Lefvert, A. K., and the MIBS Study Group. 2006. Polymorphisms in the IL-10 but not in the IL-1β and IL-4 genes are associated with inhibitor development in patients with haemophilia A. Blood 107:3167–3172.

    Article  PubMed  CAS  Google Scholar 

  • Barr, R. D., Saleh, M., Furlong, W., Horsman, J., Sek, J., Pai, M., and Walker, I. 2002. Health status and health-related quality of life associated with hemophilia. Am. J. Hematol. 71:152–160.

    Article  PubMed  Google Scholar 

  • Bech, R. M. 1996. Recombinant factor VIIa in joint and muscle bleeding episodes. Haemostasis 26:135–138.

    PubMed  CAS  Google Scholar 

  • Behrmann, M., Pasi, J., Saint-Remy, J. M., Kotitschke, R., and Kloft, M. 2002. Von Willebrand factor modulates factor VIII immunogenicity: comparative study of different factor VIII concentrates in a haemophilia A mouse model. Thromb. Haemost. 88:221–229.

    PubMed  CAS  Google Scholar 

  • Berntorp, E. 2003. Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations: is it of clinical importance? Haematologica 88:EREP03

    PubMed  Google Scholar 

  • Berntorp, E., Astermark, J., Donfield, S. M., Nelson, G. W., Oldenburg, J., Shapiro, A. D., DiMichele, D. M., Ewenstein, B. M., Gomperts, E. D., Winkler, C. A., and the Hemophilia Inhibitor Genetics Study. 2005. Haemophilia Inhibitor Genetics Study – evaluation of a model for studies of complex diseases using linkage and associated methods. Haemophilia 11:427–429.

    Google Scholar 

  • Berntorp, E. and Lefvert, A. 2006. A bi-allelic polymorphism in the promoter region of the TNF alpha gene influences the risk of inhibitor development in patients with hemophilia A. Haemophilia 12:abstract 14FP36

    Google Scholar 

  • Bolton-Maggs, P. H., Stobart, K., and Smyth, R. L. 2004. Evidence-based treatment of haemophilia. Haemophilia 10 (Suppl. 4):20–24.

    Article  PubMed  Google Scholar 

  • Brackmann, H. H., Effenberger, E., Hess, L., Schwaab, R., and Oldenburg, L. 2000. NovoSeven in immune tolerance therapy. Blood Coagul. Fibrinolysis 11 (Suppl. 1):S39–S44.

    PubMed  CAS  Google Scholar 

  • Brackmann, H. H., Oldenburg, J., and Schwaab, R. 1996. Immune tolerance for the treatment of FVIII inhibitors-twenty years of the Bonn protocol, Vox Sang. 70 (Suppl. 1):30–35.

    Google Scholar 

  • Bray, G. L., Gomperts, E. D., Courter, S., Gruppo, R., Gordon, E. M., Manco-Johnson, M., Shaprio, A., Scheibel, E., White, G. 3rd, and Lee, M. 1994. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy and inhibitor risk in previously untreated patients with hemophilia A. Blood 83:2428–2435.

    PubMed  CAS  Google Scholar 

  • Calvez, T. and Laurian, Y. 2006. Protective effect of prophylaxis on inhibitor development in children with haemophilia A: more convincing studies are required. Br. J. Haematol. 132:798–799.

    Article  PubMed  Google Scholar 

  • Chalmers, E. A., Brown, S. A., Keeling, D., Liesner, R., Richards, M., Stirling, D., Thomas, A., Vidler, V., Williams, M. D., and Young, D. on behalf of the Paediatric Working Party of UKHCDO, 2007. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 13: 149–155.

    Article  PubMed  CAS  Google Scholar 

  • Chuansumrit, A., Sri-Udomporn, N., Srimuninnimit, V., and Juntarukha, R. 2001. A single high dose of recombinant factor VIIa combining adjuvant therapy for controlling bleeding episodes in haemophiliacs with inhibitors. Haemophilia 7: 532–534.

    Article  PubMed  CAS  Google Scholar 

  • Cooper, H. A., Jones, C. P., Campion, E., Roberts, H. R., and Hedner, U. 2001. Rationale for the use of high dose rFVIIa in a high-titre inhibitor patient with haemophilia B during major orthopaedic procedures. Haemophilia 7:517–522.

    Article  PubMed  CAS  Google Scholar 

  • Courter, S. G. and Bedrosian, C. L. 2001. Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Semin. Hematol. 38:529.

    Google Scholar 

  • DiMichele, D. M. 1998. Immune tolerance: a synopsis of international experience. Haemophilia 4:568–573.

    Article  CAS  Google Scholar 

  • DiMichele, D. M. 2000. Inhibitors in haemophilia: a primer. Haemophilia 6 (Suppl. 1):38–40.

    Article  PubMed  Google Scholar 

  • DiMichele, D. 2002. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia 8:280–287.

    Article  PubMed  CAS  Google Scholar 

  • Dolan, G. 2005. ESOS: A European study on the orthopaedic status of patients with haemophilia and inhibitors. Haemophilia 11 (Suppl. 1):24–25.

    Article  PubMed  Google Scholar 

  • Ehrenforth, S., Kreuz, W., Scharrer, I., Linde, R., Funk, M., Güngör, T., Krackhardt, B., and Kornhuber, B. 1992. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 339:594–598.

    Article  PubMed  CAS  Google Scholar 

  • Ehrlich, H. J., Henzl, M. J., and Gomperts, E. D. 2002. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 8:83–90.

    Article  PubMed  CAS  Google Scholar 

  • Ettingshausen, C. E., Martinez Saguer, I., Funk, M. B., Klarmann, D., Stoll, H., Biller, R., and Kreuz, W. 2003. Long-term prophylaxis with FEIBA in patients with high-responding inhibitors. J. Thromb. Haemost. 1 (Suppl. 1):abstract P1628.

    Google Scholar 

  • Ettingshausen, C. E. and Kreuz, W. 2005. Role of von Willebrand factor in immune tolerance induction. Blood Coagul. Fibrinolysis 16 (Suppl. 1):S27–S31.

    Article  PubMed  CAS  Google Scholar 

  • Ettingshausen, C. E. and Kreuz, W. 2006. Recombinant vs. plasma-derived products, especially those with intact VWF, regarding inhibitor development. Haemophilia 12 (Suppl. 6):102–106.

    Article  PubMed  Google Scholar 

  • Fay, P. J. 2004. Activation of factor VIII and mechanisms of cofactor action. Blood Rev. 18:1–15.

    Article  PubMed  Google Scholar 

  • Fay, P. J., Anderson, M. T., Chavin, S. I., and Marder, V. J. 1986. The size of human factor VIII heterodimers and the effects produced by thrombin. Biochim. Biophys. Acta 871:268–278.

    Google Scholar 

  • Fay, P. J., Beattie, T. L., Regan, L. M., O’Brien, L. M., and Kaufman, R. J. 1996. Model for the factor VIIIa-dependent decay of the intrinsic factor Xase: role of subunit dissociation and factor IXa-catalyzed proteolysis. J. Biol. Chem. 271: 6027–6032.

    Article  PubMed  CAS  Google Scholar 

  • Federici, A. B. 2003. The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica 88:EREP02

    PubMed  Google Scholar 

  • Fontes, E., Carvalho, S., and Amorim, L. 2004. Age at the beginning of factor VIII replacement is not a risk factor for inhibitor development in hemophilia A. Haemophilia 10:55 abstract 12 OC 14.

    Article  Google Scholar 

  • Frommel, D., and Allain, J. P. 1977. Genetic predisposition to develop factor VIII antibody in classic hemophilia. Clin. Immunol. Immunopathol. 8:34–38.

    Article  PubMed  CAS  Google Scholar 

  • Frommel, D., Allain, J. P., Saint-Paul, E., Bosser, C., Noël, B., Mannucci, P. M., Pannicucci, F., Blombäck, M., Prou-Wartelle, O., and Muller, J. Y. 1981. HLA antigens and factor VIII antibody in classic hemophilia. European study group of factor VIII antibody. Thromb. Haemost. 46:687–689.

    CAS  Google Scholar 

  • Fulcher, C. A., de Graaf Mahoney, S., and Zimmerman, T. S. 1987. FVIII inhibitor IgG subclass and FVIII polypeptide specificity determined by immunoblotting. Blood 69:1475–1480.

    PubMed  CAS  Google Scholar 

  • Gill, J. C. 1999. The role of genetics in inhibitor formation. Thromb. Haemost. 82:500–504.

    PubMed  CAS  Google Scholar 

  • Gilles, J. G., Arnout, J., Vermylen, J., and Saint-Remy, J. M. 1993. Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction. Blood 82:2452–2461.

    PubMed  CAS  Google Scholar 

  • Goodeve, A. C., and Peake, I. R. 2003. The molecular basis of hemophilia A: genotype-phenotype relationships and inhibitor development. Seminars in Thrombosis and Hemostasis, 29:23–30.

    Google Scholar 

  • Goodeve, A. C., Williams, I., Bray, G. L., and Peake, I. R. 2000. Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (recombinate). Recombinate PUP Study Group. Thromb. Haemost. 83:844–848.

    CAS  Google Scholar 

  • Goudemand, J., Rothschild, C., Demiguel, V., Vinciguerrat, C., Lambert, T., Chambost, H., Borel-Derlon, A., Claeyssens, S., Laurian, Y., and Calvez, T. 2006. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A. Blood 107:46–51.

    Article  PubMed  CAS  Google Scholar 

  • Gouw, S. C., van der Bom, J. G., and van den Berg, H. M. 2007. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL Cohort Study. Blood 109:4693–4697.

    Article  PubMed  CAS  Google Scholar 

  • Green, D. 1999. Complications associated with the treatment of haemophiliacs with inhibitors. Haemophilia 5 (Suppl. 3):11–17.

    Article  PubMed  Google Scholar 

  • Gringeri, A., Mantovani, L., Scalone, L., Mannucci, P. M., and the COCIS Study Group. 2003. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 102:2358–2363.

    Google Scholar 

  • Gringeri, A., Monzini, M., Tagariello, G., Scaraggi, F. A., Mannucci, P. M., and the Emoclot 15 Study Members. 2006. Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate. Haemophilia 12:128–132.

    Google Scholar 

  • Hay, C. R. M. 2002. The 2000 United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) inhibitor guidelines. Pathophysiol Haemost Thromb 32 (Suppl. 1):19–21.

    Article  PubMed  Google Scholar 

  • Hay, C. R. M. 2006. The epidemiology of factor VIII inhibitors. Haemophilia 12 (Suppl. 6):23–29.

    Article  PubMed  CAS  Google Scholar 

  • Hay, C. R., Ludlam, C. A., Colvin, B. T., Hill, F. G., Preston, F. E., Wasseem, N., Bagnall, R., Peake, I. R., Berntorp, E., Mauser Bunschoten, E. P., Fijnvandraat, K., Kasper, C. K., White, G., and Santagostino, E. 1998. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation. Thromb. Haemost. 79:762–766.

    CAS  Google Scholar 

  • Hay, C. R., Ollier, W., Pepper, L. Cumming, A., Keeney, S., Goodeve, A. C., Colvin, B. T., Hill, F. G., Preston, F. E., and Peake, I. R. 1997. HLA class II profile: A weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party. Thromb. Haemost. 77:234–237.

    CAS  Google Scholar 

  • Hedner, U. 2003. Potential role of recombinant factor VIIa as a hemostatic agent. Clin. Adv. Hematol. Oncol. 1:112–119.

    PubMed  Google Scholar 

  • Hedner, U., Glazer, S., Pingel, K. Alberts, K. A., Blombäck, M., Schulman, S., and Johnsson, H. 1988. Successful use of recombinant factor VIIa in patient with severe hemophilia A during synovectomy. Lancet 2:1193.

    Article  PubMed  CAS  Google Scholar 

  • Hilgartner, M., Aledort, L., Andes, A., and Gill, J. 1990. Efficacy and safety of vapor-heated anti-inhibitor coagulant complex in hemophilia patients. FEIBA Study Group. Transfusion 30:626–630.

    CAS  Google Scholar 

  • Hilgartner, M., Knatterud, G. L. and the FEIBA Study Group. 1983. The use of factor VIII by-passing activity (FEIBA Immuno) product for treatment of bleeding episodes in haemophiliacs with inhibitor. Blood 61:36–40.

    PubMed  CAS  Google Scholar 

  • Hilgartner, W., Makipernaa, A., and DiMichele, D. M. 2003. Long-term FEIBA prophylaxis does not prevent progression of existing joint disease. Haemophilia 9:261–268.

    Article  PubMed  CAS  Google Scholar 

  • Hodge, G., Flower, R., and Han, P. 1999. Effect of factor VIII concentrate on leucocyte cytokine production: characterisation of TGF-beta as an immunomodulatory component in plasma derived factor VIII concentrate. Br. J. Haematol. 106:784–791.

    Article  PubMed  CAS  Google Scholar 

  • Hodge, G., Saxon, B., and Revesz, T. 2006. Effect of factor VIII concentrate on leucocyte cytokine receptor expression in vitro: relevance to inhibitor formation and tolerance induction. Haemophilia 12:133–139.

    Article  PubMed  CAS  Google Scholar 

  • Hoffman, M., Monroe, D. M. III, and Roberts, H. R. 1998. Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII. Blood Coagul. Fibrinolysis 9 (Suppl. 1):S61–S65.

    PubMed  CAS  Google Scholar 

  • Hoots, W. K. 2006. Urgent inhibitor issues: targets for expanded research. Haemophilia 12:107–113.

    Article  PubMed  CAS  Google Scholar 

  • Ingerslev, J., Freidman, D., Gastineau, D., Gilchrist, G., Johnsson, H., Lucas, G., McPherson, J., Preston, E., Scheibel, E., and Shuman, M. 1996. Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa. Haemostasis 26 (Suppl. 1):118–123.

    PubMed  CAS  Google Scholar 

  • Ingerslev, J., Knudsen, L., Hvid, I., Tange, M. R., Fredberg, U., and Sneppen, O. 1997. Use of recombinant factor VIIa in surgery in factor VII deficient patients. Haemophilia 3:215–218.

    Article  Google Scholar 

  • Johannessen, M., Andreasen, R., and Nordfang, O. 2000. Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven. Blood Coagul. Fbrinolysis 11:239–242.

    CAS  Google Scholar 

  • Jurlander, B., Thim, L., Klausen, N. K., Persson, E., Kjalke, M., Rexen, P., Jorgensen, T. B., Ostergaard, P. B., Erhardtsen, E., and Bjorn, S. E. 2001. Recombinant activated factor VII (rFVIIa): characterization, manufacturing, and clinical development. Semin. Thromb. Hemost. 27:373–384.

    Article  PubMed  CAS  Google Scholar 

  • Kasper, C. K., Aledort, L., Aronson, D., Counts, R., Edson, J. R., van Eys, J., Fratantoni, J., Green, D., Hampton, J., Hilgartner, M., Levine, P., Lazerson, J., McMillan, C., Penner, J., Shapiro, S, and Shulman, N. R. 1975. A more uniform measurement of factor VIII inhibitors. Proceedings: A more uniform measurement of factor VIII inhibitors. Thromb. Diath. Haemorrh. 34:612.

    CAS  Google Scholar 

  • Kaufman, R. J. and Pipe, S. W. 1999. Regulation of factor VIII expression and activity by von Willebrand factor. Thromb. Haemost. 82:201–208.

    PubMed  CAS  Google Scholar 

  • Kavakli, K., Makris, M., Zulfikar, B., Abrams, Z., and Kenet, G. 2006. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb. Haemost. 95:600–605.

    CAS  Google Scholar 

  • Kenet, G., Lubetsky, A., Luboshitz, J., and Martinowitz, U. 2003. A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven). J. Thromb. Haemost. 1:450–455.

    Article  PubMed  CAS  Google Scholar 

  • Kessler, C. M. 2005. New perspectives in hemophilia treatment. Hematology (Am. Soc. Hematol. Educ. Program) 1:429–435.

    Google Scholar 

  • Key, N. S. 2004. Inhibitors in congenital coagulation disorders. Br. J. Haematol. 127:379–391.

    Article  PubMed  CAS  Google Scholar 

  • Key, N. S., Aledort, L. M., Beardsley, D., Cooper, H. A., Davignon, G., Ewenstein, B. M., Gilchrist, G. S., Gill, J. C., Glader, B., Hoots, W. K., Kisker, C. T., Lusher, J. M., Rosenfield, C. G., Shapiro, A. D., Smith, H., and Taft, E. 1998. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (NovoSeven) in haemophiliacs with inhibitors. Thromb. Haemost. 80:912–918.

    PubMed  CAS  Google Scholar 

  • Konkle, B. A., Ebbesen, L. S., Auerswald, G. K. H., Friedrich, U., Ljung, R. C. R., Roberts, H. R., and Hoots, W. K. 2006a. Secondary prophylaxis with rFVIIa improves quality of life of hemophilia patients with inhibitors and frequent bleeds. Abstract presented during the 48th Annual Meeting and Exposition of the American Society of Hematology (ASH), Orlando, Florida, USA, 9–12 December 2006 (abstract no. 766).

    Google Scholar 

  • Konkle, B. A., Ebbesen, L. S., Friedrich, U., Bianco, R. P., Lissitchkov, T., Rusen, L., Serban, M. A. and the NovoSeven (F7Haem-1505) Investigators. 2006b. Randomized, prospective clinical trial of rFVIIa for secondary prophylaxis in hemophilia patients with inhibitors. Data presented during the 48th Annual Meeting and Exposition of the American Society of Hematology (ASH), Orlando, Florida, USA, 9–12 December 2006 (abstract no. 1028).

    Google Scholar 

  • Kreuz, W., Ettingshausen, C. E., Auerswald, G., Saguer, I. M., Becker, S., Funk, M., Heller, C., Klarmann, D., Klingebiel, T., and the GTH PUP Study Group. 2003. Epidemiology of inhibitors and current treatment strategies. Haematologica 88:EREP04.

    Google Scholar 

  • Kreuz, W., Auerswald, G., Budde, U., Lenk, H., and the GTH-PUP-Study Group. 2005a. In: I. Scharrer and W. Schramm, Editors, Inhibitor development in previously untreated patients (PUPs) with haemophilia A and B. A prospective multicentre study of the German, Swiss and Austrian Society of Thrombosis and Haemostasis Research (GTH). 35th Haemophilia Symposium, Springer Verlag, Hamburg 2004, 34–37.

    Google Scholar 

  • Kreuz, W., Gill, J. C., Rothschild, C., Manco-Johnson, M. J., Lusher, J. M., Kellermann, E., Gorina, E., Larson, P. J., and the International Kogenate-FS Study Group. 2005b. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A. Results of an international clinical investigation. Thromb. Haemost. 93:457–467.

    Google Scholar 

  • Leissinger, C. A. 2004. Prevention of bleeds in hemophilia patients with inhibitors: emerging data and clinical direction. Am. J. Hematol. 77:187–193.

    Article  PubMed  Google Scholar 

  • Lenting, P., Neels, J., van den Berg, B., Clijsters, P. P., Meijerman, D. W., Pannekoek, H., van Mourik, J. A., Mertens, K., and van Zonneveld, A. J. 1999. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J. Biol. Chem. 274:23734–23739.

    Article  PubMed  CAS  Google Scholar 

  • Levi, M., Peters, M., and Buller, H. R. 2005. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit. Care Med. 33:883–890.

    Article  PubMed  CAS  Google Scholar 

  • Lin, Y., Yang, X., Chevrier, M. C. Craven, S., Barrowcliffe, T. W., Lemieux, R., and Ofosu, F. A. 2004. Relationships between factor VIII:Ag and factor VIII in recombinant and plasma derived factor VIII concentrates. Haemophilia 10:459–469.

    Article  PubMed  CAS  Google Scholar 

  • Lollar, P. 1991. The association of factor VIII with von Willebrand factor. Mayo Clin. Proc. 66:524–534.

    PubMed  CAS  Google Scholar 

  • Lorenzo, J. I., Lopez, A., Altisent, C., and Aznar, J. A. 2001. Incidence of factor VIII inhibitors in severe haemophilia: the importance of age. Br. J. Haematol. 113:600–603.

    Article  PubMed  CAS  Google Scholar 

  • Lusher, J. M. 1991. Thrombogenicity associated with factor IX complex concentrates. Semin. Hematol. 28 (3 Suppl. 6):3–5.

    PubMed  CAS  Google Scholar 

  • Lusher, J. M. 1996. Recombinant factor VIIa (NovoSeven) in the treatment of internal bleeding in patients with factor VIII and IX inhibitors. Haemostasis 26:124–130.

    PubMed  CAS  Google Scholar 

  • Lusher, J. M. 2000. Acute hemarthroses: the benefits of early versus late treatment with recombinant activated factor VII. Blood Coagul. Fibrinolysis 11 (Suppl. 1): S45–S49.

    PubMed  CAS  Google Scholar 

  • Lusher, J. M. 2004. Is the incidence and prevalence of inhibitors greater with recombinant products? No. J. Thromb. Haemost. 2:863–865.

    Article  CAS  Google Scholar 

  • Lusher, J. M., Arkin, S., Abildgaard, C. F., and Schwartz, R. S. 1993. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A – safety, efficacy, and development of inhibitors. N. Engl. J. Med. 328:453–459.

    Article  PubMed  CAS  Google Scholar 

  • Lusher, J., Ingerslev, J., Roberts, H., and Hedner, U. 1998. Clinical experience with recombinant factor VIIa. Blood Coagul. Fibrinol. 9:119–128.

    Article  CAS  Google Scholar 

  • Lusher, J. M., Lee, C. A., Kessler, C. M., Bedrosian, C. L., and the ReFacto Phase 3 Study Group. 2003. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 9:38–49.

    Google Scholar 

  • Lusher, J. M., Roberts, H. R., Davignon, G., Joist, J. H., Smith, H., Shapiro, A., Laurian, Y., Kasper, C. K., and Mannucci, P. M. 1998. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia 4:790–798.

    Article  PubMed  CAS  Google Scholar 

  • Lusher, J. M. and Roth, D. A. 2005. The safety and efficacy of B-domain deleted recombinant factor VIII concentrates in patients with severe haemophilia A: an update. Haemophilia 11:292–293.

    Article  PubMed  CAS  Google Scholar 

  • Lusher, J. M., Shapiro, S. S., Palascak, J. E., Rao, A. V., Levine, P. H., and Blatt, P. M. 1980. Efficacy of prothrombin-complex concentrates in hemophiliacs with antibodies to factor VIII: a multicenter therapeutic trial. N. Engl. J. Med. 303: 421–425.

    Article  PubMed  CAS  Google Scholar 

  • Luu, H. and Ewenstein, B. 2004. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia 10 (Suppl. 2):10–16.

    Article  PubMed  CAS  Google Scholar 

  • Mann, K. G. 1999. Biochemistry and physiology of blood coagulation. Thromb. Haemost. 82:165–174.

    PubMed  CAS  Google Scholar 

  • Mariani, G. and Kroner, B. L. 1999. International Immunetolerance Registry 1997 update. Vox Sang. 77:25–27.

    Article  PubMed  CAS  Google Scholar 

  • MASAC Recommendation #177, revised October 2006. Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation. Recommendations concerning the treatment of hemophilia and other bleeding disorders (www.hemophilia.org).

    Google Scholar 

  • McMillan, C. W., Shapiro, S. S., Whitehurst, D., Hoyer, L. W., Rao, A. V., and Lazerson, J. 1988. 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 71:344–348.

    PubMed  CAS  Google Scholar 

  • Morado, M., Villar, A., Jimenez-Yuste, V., Quintana, M., and Hernandez Navarro, F. 2005. Prophylactic treatment effects on inhibitor risk: experience in one centre. Haemophilia 11:79–83.

    Article  PubMed  CAS  Google Scholar 

  • Morrison, A. E., Ludlam, C. A., and Kessler, C. 1993. Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 81:1513–1520.

    PubMed  CAS  Google Scholar 

  • Negrier, C., Goudemand, J., Sultan, Y., Bertrand, M., Rothschild, C., and Lauroua, P. 1997. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. factor eight bypassing activity. Thromb. Haemost. 77:1113–1119.

    CAS  Google Scholar 

  • Nicolaisen, E. M. 1996. Clinical experience with NovoSeven: lack of antigenicity after repeated treatment with NovoSeven. Haemostasis 26 (Suppl. 1):98–101.

    PubMed  CAS  Google Scholar 

  • O’Connell, N., Mc Mahon, C., Smith, J., Khair, K., Hann, I., Liesner, R., and Smith O. P. 2002. Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high responding inhibitors. Br. J. Haematol. 116:632–635.

    Article  PubMed  CAS  Google Scholar 

  • Oldenburg, J., El-Maarri, O., and Schwaab, R. 2002. Inhibitor development in correlation to factor VIII genotypes. Haemophilia, 8 (Suppl. 2):23–29.

    Article  PubMed  CAS  Google Scholar 

  • Oldenburg, J. and Pavlova, A. 2006. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia 12 (Suppl. 6):15–22.

    Article  PubMed  CAS  Google Scholar 

  • Oldenburg, J., Picard, J. K., Schwaab, R. Brackmann, H. H., Tuddenham, E. G., and Simpson, E. 1997. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII. Thromb. Haemost. 77:238–242.

    PubMed  CAS  Google Scholar 

  • Oldenburg, J., Schroder, J., Brackmann, H. H., Müller-Reible, C., Schwaab, R., Tuddenham, E. 2004. Environmental and genetic factors influencing inhibitor development. Semin. Hematol. 41 (Suppl. 1):82–88.

    Article  PubMed  CAS  Google Scholar 

  • Oldenburg, J., and Tuddenham, E. 2002. Genetic basis of inhibitor development in severe haemophilia A and B. In: E. C. Rodriguez-Merchan and C. A. Lee, Editors, Inhibitors in patients with haemophilia, Blackwell Publishing, Oxford, pp. 21–26.

    Chapter  Google Scholar 

  • Parameswaran, R., Shapiro, A. D., Gill, J. C., Kessler, C. M., and the HTRS Registry Investigators. 2005. Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry. Haemophilia 11:100–106.

    Article  PubMed  CAS  Google Scholar 

  • Peerlinck, K. and Hermans, C. 2006. Epidemiology of inhibitor formation with recombinant factor VIII replacement therapy. Haemophilia 12:579–590.

    Article  PubMed  CAS  Google Scholar 

  • Pittman, D. D., Alderman, E. M., Tomkinson, K. N., Wang, J. H., Giles, A. R., and Kaufman, R. J. 1993. Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII. Blood 81:2925–2935.

    PubMed  CAS  Google Scholar 

  • Quintana-Molina, M., Martinez-Bahamonde, F., Gonzalez, G., Romero-Garrido, J., Villar-Camacho, A., Jiménez-Yuste, V., Fernández-Bello, I., and Hernández-Navarro, F. 2004. Surgery in haemophilic patients with inhibitor: 20 years of experience. Haemophilia 10 (Suppl. 2): 30–40.

    Article  PubMed  Google Scholar 

  • Roberts, H. R., Monroe, D. M. III, and Hoffman, M. 2004. Safety profile of recombinant factor VIIa. Semin. Hematol. 41 (Suppl. 1):101–108.

    Google Scholar 

  • Rokicka-Milewska, R., Klukowska, A., Dreger, B., and Beer, H. J. 1999. Incidence of factor VIII inhibitor development in previously untreated hemophilia A patients after exposure to a double viral inactivated factor VIII concentrate. Ann. Hematol. 78 (Suppl. 1):1–7.

    Google Scholar 

  • Rothschild, C., Gill, J., Scharrer, I., and Bray, G. 2000. Transient inhibitors in the Recombinate PUP Study. Thromb. Haemost. 84:145–146.

    PubMed  CAS  Google Scholar 

  • Saenko, E. L, Ananyeva, N., Kouiavskaia, D., Schwinn, H., Josic, D., Shima, M., Hauser, C.A., and Pipe, S. 2002. Molecular defects in coagulation factor VIII and their impact on factor VIII function. Vox Sang. 83:89–96.

    Article  PubMed  CAS  Google Scholar 

  • Sandberg, H., Almstedt, A., Brandt, J., Gray, E., Holmquist, L., Oswaldsson, U., Sebring, S., and Mikaelsson, M. 2001. Structural and functional characteristics of the B-domain-deleted recombinant factor VIII protein, r-VIII SQ. Thromb. Haemost. 85:93–100.

    PubMed  CAS  Google Scholar 

  • Santagostino, E., Gringeri, A., and Mannucci, P. M. 1999. Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: the advantages of early intervention. Br. J. Haematol. 104:22–26.

    Article  PubMed  CAS  Google Scholar 

  • Santagostino, E., Mancuso, M. E., Rocino, A., Mancuso, G., Mazzucconi, M. G., Tagliaferri, A., Messina, M., and Mannucci, P. M. 2005. Environmental risk factors for inhibitor development in children with haemophilia A: a Case-Control Study. Br. J. Haematol. 130:422–427.

    Article  PubMed  CAS  Google Scholar 

  • Santagostino, E., Mancuso, M. E., Rocino, A., Mancuso, G., Scaragg, F., and Mannucci, P. M. 2006. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. J. Thromb. Haemost. 4:367–371.

    Article  PubMed  CAS  Google Scholar 

  • Santagostino, E. and Mannucci, P. M. 2006. Protective effect of prophylaxis on inhibitor development in children with haemophilia A: more convincing studies are required. Response to Calvez and Laurian. Br. J. Haematol. 132:800–801.

    Article  Google Scholar 

  • Santagostino, E., Morfini, M., Rocino, A., Baudo, F, Scaraggi, F. A., and Gringeri, A. 2001. Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors. Thromb. Haemost. 86:954–958.

    PubMed  CAS  Google Scholar 

  • Scharrer, I., Bray, G. L., and Neutzling, O. 1999. Incidence of inhibitors in haemophilia A patients – a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 5:145–154.

    Article  PubMed  CAS  Google Scholar 

  • Scharrer, I. and Ehrlich, H. J. 2004. Reported inhibitor incidence in FVIII PUP studies: comparing apples with oranges? Haemophilia 10:197–198.

    Article  PubMed  CAS  Google Scholar 

  • Schwaab, R., Brackmann, H. H., Meyer, C., Seehafer, J., Kirchgesser, M., Haack, A., Olek, K., Tuddenham, E. G., and Oldenburg, J. 1995. Haemophilia A: mutation type determinates risk of inhibitor formation. Thromb. Haemost. 74:1402–1406.

    PubMed  CAS  Google Scholar 

  • Schwartz, R. S., Abildgaard, C. F., Aledort, L. M., Arkin, S., Bloom, A. L., Brackmann, H. H., Brettler, D. B., Fukui, H., Hilgartner, M. W., Inwood, M. J., et al. 1990. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N. Engl. J. Med. 323:1800–1805.

    Article  PubMed  CAS  Google Scholar 

  • Schwartz, H. P., Lenting, P. J., Binder, B., Mihaly, J., Denis, C., Dorner, F., and Turecek, P. L. 2000. Involvement of low-density lipoprotein receptor-related protein (LRP) in the clearance of factor VIII in von Willebrand factor-deficient mice. Blood 95:1703–1708.

    Google Scholar 

  • Seremetis, S., Lusher, J. M., Abildgaard, C. F., Kasper, C. K., Allred, R., and Hurst, D. 1999. Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. Haemophilia 5:9–16.

    Article  PubMed  CAS  Google Scholar 

  • Shapiro, S. S. 1984. Genetic predisposition to inhibitor formation. Prog. Clin. Biol. Res. 150:45–55.

    PubMed  CAS  Google Scholar 

  • Shapiro, A. D., Gilchrist, G. S., Hoots, W. K., Cooper, H. A., and Gastineau, D. A. 1998. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thromb. Haemost. 80:773–778.

    PubMed  CAS  Google Scholar 

  • Sharathkumar, A., Lillicrap, D., Blanchette, V. S., Kern, M., Leggo, J., Stain, A. M., Brooker, L, and Carcao, M. D. 2003. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild haemophilia A. J. Thromb. Haemost. 1:1228–1236.

    Article  PubMed  CAS  Google Scholar 

  • Smith, O. P. 2002. Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high-responding inhibitors. Pathophysiol. Haemost. Thromb. 32 (Suppl. 1):22–25.

    Article  CAS  Google Scholar 

  • Smith, O. P. and Hann, I. M. 1996. RFVIIa therapy to secure haemostasis during central line insertion in children with high-responding FVIII inhibitors. Br. J. Haematol. 92:1002–1004.

    Article  PubMed  CAS  Google Scholar 

  • Sultan, Y. 1992. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. French Hemophilia Study Group. Thromb. Haemost. 67: 600–602.

    CAS  Google Scholar 

  • Syamsoedin, L. J., Heijnen, L., Mauser-Bunschoten, E. P. van Geijlswijk J. L., van Houwelingen, H., van Asten, P., and Sixma, J. J. 1981. The effect of activated prothrombin-complex concentrate (FEIBA) on joint and muscle bleeding in patients with hemophilia A and antibodies to factor VIII. A double-blind clinical trial. N. Engl. J. Med. 305:717–721.

    Google Scholar 

  • Tarantino, M. D., Collins, P. W., Hay, C. R., Shapiro, A. D., Gruppo, R. A., Berntorp, E., Bray, G. L., Tonetta, S. A., Schroth, P. C., Retzios, A. D., Rogy, S. S., Sensel, M. G., Ewenstein, B. M., and the RAHF-PFM Clinical Study Group. 2004. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 10:428–437.

    Google Scholar 

  • Toole, J. J., Pittman, D. D., Orr, E. C., Murtha, P., Wasley, L. C., and Kaufman, R. J. 1986. A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc. Natl. Acad. Sci. USA 83: 5939–5942.

    Article  PubMed  CAS  Google Scholar 

  • Triemstra, M., Rosendaal, F. R., Smit, C., van der Ploeg, H. M., and Briët, E. 1995. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann. Intern. Med. 123:823–827.

    CAS  Google Scholar 

  • Turecek, P. L., Varadi, K., Gritsch, H., and Schwarz, H. P. 2004. FEIBA: mode of action. Haemophilia 10 (Suppl. 2):3–9.

    Article  PubMed  CAS  Google Scholar 

  • UK Haemophilia Centre Doctors’ Organisation. 2004. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977–99. J. Thromb. Haemost. 2:1047–1054.

    Google Scholar 

  • Van der Bom, J. G., Mauser-Bunschoten, E. P., Fischer, K., and van den Berg, H. M. 2003. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb. Haemost. 89:475–479.

    PubMed  Google Scholar 

  • Vehar, G. A., Keyt, B., Eaton, D., Rodriguez, H., O’Brien, D. P., Rotblat, F., Oppermann, H., Keck, R., Wood, W. I., Harkins, R. N., Tuddenham, E. G. D., Lawn, R. M., and Capon, D. J. 1984. Structure of human factor VIII. Nature 312: 337–340.

    Article  PubMed  CAS  Google Scholar 

  • Vlot, A. J., Koppelman, S. J., Bouma, B. N., and Sixma, J. J. 1998. Factor VIII and von Willebrand factor. Thromb. Haemost. 79:456–465.

    PubMed  CAS  Google Scholar 

  • Von Auer, C., Oldenburg, J., Von Depka, M., Escuriola-Ettinghausen, C., Kurnik, K., Lenk, H., and Scharrer, I. 2005. Inhibitor development in patients with hemophilia A after continuous infusion of factor VIII concentrates. Ann. NY Acad. Sci. 1051: 498–505.

    Article  CAS  Google Scholar 

  • White, G. C. II, Courter, S., Bray, G. L., Lee, M., and Gomperts, E. D. 1997. A multicenter study of recombinant factor VIII (RecombinateTM) in previously treated patients with hemophilia A. Thromb. Haemost. 77:660–667.

    PubMed  CAS  Google Scholar 

  • White, G. C. II, Rosendaal, F. R., Aledort, L. M., Lusher, J. M., Rothschild, C., Ingerslev, J., and the Factor VIII and Factor IX Subcommittee. 2001. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the Scientific and Standardization Committee of the International Society on Thromb Haemostas. Thromb. Haemost. 85:560.

    Google Scholar 

  • Wight, J. and Paisley, S. 2003. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 9:418–435.vvsp-2

    Article  PubMed  CAS  Google Scholar 

  • Wight, J., Paisley, S., and Knight, C. 2003. Immune tolerance induction in patients with hemophilia A with inhibitors: a systematic review. Haemophilia 9:436–463.

    Article  PubMed  CAS  Google Scholar 

  • Yee, T. T., Williams, M. D., Hill, F. G., Lee, C. A., and Pasi, K. J. 1997. Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product. Thromb. Haemost. 78: 1027–1029.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. Silke Ehrenforth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephanie Seremetis
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Copenhagen, Copenhagen, Denmark

    Marco van de Weert

  2. University of Copenhagen, Copenhagen, Denmark

    Eva Horn Møller

Rights and permissions

Reprints and permissions

Copyright information

© 2008 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

Ehrenforth, S., Seremetis, S. (2008). Case Study: Immunogenicity of Factor VIII. In: Weert, M.v., Møller, E.H. (eds) Immunogenicity of Biopharmaceuticals. Biotechnology: Pharmaceutical Aspects, vol VIII. Springer, New York, NY. https://doi.org/10.1007/978-0-387-75841-1_9

Download citation

Publish with us

Policies and ethics

Societies and partnerships

Search

Navigation