Thromb Haemost 1999; 82(02): 516-524
DOI: 10.1055/s-0037-1615874
Research Article
Schattauer GmbH

Recombinant Clotting Factors in the Treatment of Hemophilia

Christine Lee
1   Royal Free Hospital, Haemophilia Centre & Haemostasis Unit, London, ENGLAND
› Author Affiliations
Further Information

Publication History

Publication Date:
09 December 2017 (online)

Introduction

The field of hemophilia has always been one of rapid change with improvements in clinical practice rapidly following the advances in basic science and clinical research. The major achievements of the last decade have reflected the application of molecular biology, and this has been particularly true for the development of recombinant clotting factors. The interest in developing recombinant factors VIII and IX was driven by the desire for a “safe” clotting factor following the terrible epidemics of transfusion-transmitted disease in the 1970s and 1980s.

Although the goals for treatment for hemophilia, as stated by the World Federation of Hemophilia, are “to minimize disability and prolong life, to facilitate general social and physical wellbeing, and to help each patient achieve full potential, while causing no harm,”1 the cost of recombinant clotting factors are comparatively high. As a result, in many instances, the provision has been rationed, even though such therapy is considered state-of-the-art treatment for all patients requiring replacement therapy.

 
  • References

  • 1 Kasper CK, Graham JB, Kernoff PBA, Larrieu MJ, Rickard KA, Mannucci PM. Hemophilia: state of the art of hematologic care 1988. Vox Sang 1989; 56: 141-144.
  • 2 Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM. Characterization of the human factor VIII gene. Nature 1984; 312: 326-330.
  • 3 Toole JT, 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: 342-347.
  • 4 Vehar GA, Keyt B, Eaton D, Rodriguez H, O’Brien DP, Rotblat F, Oppermann H, Keck R, Wood WI, Harkins RN. et al. Structure of human factor VIII. Nature 1984; 312: 337-342.
  • 5 Wood WI, Capon DJ, Simonsen CC, Eaton DL, Gitschier J, Keyt B, Seeburg PH, Smith DH, Hollingshead P, Wion KL. et al. Expression of active human factor VIII from recombinant DNA clones. Nature 1984; 312: 330-337.
  • 6 Antonarakis SE, Kazazian HH, Tuddenham EGD. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat 1995; 5: 1-22.
  • 7 Schwartz RS, Abildgaard CF, Aledort LM, Arkin S, Bloom AL, Brackmann HH, Brettler DB, Fukui H, Hilgartner MW, Inwood MJ. et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 1990; 323: 1800-1805.
  • 8 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. N Engl J Med 1993; 328: 453-459.
  • 9 Lusher JM. Recombinant clotting factor concentrates. Baillieres Clin Haematol 1996; 9: 291-303.
  • 10 White GC, Courter S, Bray GL, Lee M, Gomperts ED. A multicenter study of recombinant factor VIII (RecombinateTM) in previously treated patients with hemophilia A. Thromb Haemost 1997; 77: 660-667.
  • 11 White GC, McMillan CW, Kingdon HS, Shoemaker CB. Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Engl J Med 1989; 320: 166-170.
  • 12 Bray GL, Gomperts ED, Courter S, Gruppo R, Gordon EM, Manco-Johnson M, Shapiro A, Scheibel E, White 3rd G, Lee M. A multicenter study of recombinant factor VIII (Recombinant): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 1994; 83: 2428-2435.
  • 13 Toole JT, Pittman DD, Orr EC, Murtha P, Wasley LC, kaufman RJ. A large region (=95kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci USA 1986; 83: 5939-5942.
  • 14 Kessler CM, Spira J, Magill M. Safety and efficacy of a second generation, B-domain deleted recombinant factor VIII 9r-VIII SQ) in previously treated patients (PTPs). A four year update. Blood 1998; 92 (10) (Suppl. 01) 555a.
  • 15 Lusher JM, Spira J, Magill M. A four-year update of safety and efficacy of a second generation B-domain deleted factor VIII (R-VIII SQ) in previously untreated hemophilia A patients. Blood 1998; 92 (10) (Suppl. 01) 555a.
  • 16 Mikaelsson M, Eriksson B, Lind P. et al. Manufacturing and characterization of a new B-domain deleted recombinant factor VIII, r-VIII SQ. Thromb Haemost 1995; 69: 1205.
  • 17 Addiego J, Kasper C, Abildgaard C, Hilgartner M, Lusher J, Glader B, Aledort L. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993; 342: 462-464.
  • 18 Schwaab R, Brackmann HH, Meyer C, Seehafer J, Kirchgesser M, Haack A, Olek K, Tuddenham EG, Oldenburg J. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74: 1402-1406.
  • 19 Ehrenforth S, Kreutz W, Scharrer I, Linde R, Funk M, Gungor T, Krackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598.
  • 20 Peerlinck K, Rosendaal FR, Vermylen J. Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate. Blood 1993; 81: 3332-3335
  • 21 Guerois C, Laurian Y, Rothschild C, Parquet-Gernez A, Duclos AM, Negrier C, Vicariot M, Fimbel B, Fressinaud E, Fiks-Sigaud M. et al. 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: 215-218.
  • 22 Yee TT, Williams MD, Hill FG, 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: 1027-1029.
  • 23 Vermylen J. How do some haemophiliacs develop inhibitors?. Haemophilia 1998; 4: 538-542.
  • 24 Baglin T, Beacham E. Is a change of factor VIII product a risk factor for the development of a factor VIII inhibitor?. Thromb Haemost 1998; 80: 1036-1037.
  • 25 Williams IJ, Peake IR, Goodeve AV. Recombinate PUP mutation study: relationship between factor VIII mutation and inhibitor development. Haemophilia 1998; 4: 228.
  • 26 Kurachi K, Davie EW. Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci USA 1982; 79: 6461-6464.
  • 27 Choo GH, Gould KG, Rees DJ, Brownlee GG. Molecular cloning of the gene for human anti-haemophilic factor IX. Nature 1982; 299: 178-180.
  • 28 Kaufman RJ, Wasley IC, Furie BC, Furie B, Shoemaker CB. Expression, purification, and characterization of recombinant gamma-carboxylated factor IX synthesized in Chinese hamster ovary cells. J Biol Chem 1986; 261: 9622-9628.
  • 29 White GC, Beebe A, Nielsen B. Recombinant factor IX. Thromb Haemost 1997; 78: 261-265.
  • 30 Kim HC, McMillan CW, White GC, Bergman GE, Horton MW, Saidi P. Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates. Blood 1992; 79: 568-575.
  • 31 Goldsmith JC, Kasper CK, Blatt PM, Gomperts ED, Kessler CM, Thompson AR, Herring SW, Novak PL. Coagulation factor IX: successful surgical experience with a purified factor IX concentrate. Am J Hematol 1992; 40: 210-215.
  • 32 Berntorp E, Bjorkman S, Carlsson M, Lethagen S, Nilsson IM. Biochemical and in vivo properties of high purity factor IX concentrates. Thromb Haemost 1993; 70: 768-773.
  • 33 Poon MC, Aledort LM, Anderle K, Kunschak M, Morfini M. Comparison of the recovery and half-life of a high purity factor IX concentrate with those of a factor IX complex concentrate. Transfusion 1995; 35: 319-323.
  • 34 Shapiro A, Abshire T, Gill J, Kisker T, Pasi J, Rodriguez D. et al. Recombinant factor IX (rFIX) in the treatment of previously untreated patients (PUPS) with severe or moderately severe hemophilia B. Blood 1998; 92 (10) (Suppl. 01) 356a.
  • 35 Lusher JM, Wiseman C, Simpson P, Hurst P. Plasma levels measured after infusion of recombinant FVIII vary significantly with different assay methods — will the real FVIII level please stand up!. Blood 1995; 86 (Suppl. 01) 192a
  • 36 Lusher JM, Hillman-Wiseman C, Hurst D. In vivo recovery with products of very high purity-assay discrepancies. Haemophilia 1998; 4: 641-645.
  • 37 Mikaelsson M, Oswakdssib U, Sandberg H. Influence of phospholipids on the assessment of factor VIII activity. Haemophilia 1998; 4: 646-650.
  • 38 Lee C, Owens D, Giangrande P, Collins P, Hay C, Bray G. et al. In vivo pharmacokinetics of recombinant factor VIII (Recombinate) using one-stage clotting and chromogenic factor VIII assay. Haemophilia 1998; 4: 192.
  • 39 Lee C, Owens D, Giangrande P, Collins P, Hay C, Bray G. et al. Assay discrepancies in recovery levels of rFVIII “Recombinate”. Blood 1998; 92 (10) (Suppl. 01) 354a.
  • 40 Hedner U, Glazer S. Management of hemophilia patients with inhibitors. Hematol Oncol Clin North Am 1992; 6: 1035-1036.
  • 41 Hagen FS, Gray CL, O’Hara P, Grant FJ, Saari GC, Woodbury RG, Hart CE, Insley M, Kisiel W, Kurachi K. et al. Characterization of a rDNA coding for human factor VII. Proc Natl Acad Sci USA 1986; 83: 2412.
  • 42 United Kingdom Haemophilia Centre Directors’ Organisation Executive Committee. Guidelines on therapeutic products to treat haemophilia and other hereditary coagulation disorders. Haemophilia 1997; 3: 63-77.
  • 43 Lee C. Funding rare and expensive treatments: the case of haemophilia. Introduction. Haemophilia 1998; 4 (Suppl. 01) iii.
  • 44 Savidge GF. Brave new world: recombinant factor VIII and the treatment of haemophilia A: prophylaxis versus purse strings: is safety an issue?. Haemophilia 1995; 1 (Suppl. 02) 24-25.