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DOI: 10.1055/s-0038-1660345
Moderne Therapieformen zur Behandlung von Hämophilie
Vom Dunkel ins LichtPublication History
Publication Date:
26 June 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034925/199402/lookinside/thumbnails/10-1055-s-0038-1660345-1.jpg)
Zusammenfassung
In den vergangenen Jahren konnten bedeutende Fortschritte im Bereich der Behandlung von Hämophilie verzeichnet werden, die zweifelsohne als eine Reaktion der Wissenschaft auf den Alptraum der AIDS-Epidemie gesehen werden können. Gerinnungsfaktorkonzentrate werden immer sicherer, und somit wird gleichzeitig das Übertragungsrisiko von hämatogenen Infektionen immer geringer. Das Risiko einer HIV-lnfektion kann, wenn man menschliches Versagen ausschließt, als unbedeutend betrachtet werden. Ein geringes Restrisiko einer Übertragung von Hepatitisviren besteht noch, diesem sollte jedoch mit verbesserten Methoden zur Virusinaktivierung begegnet werden. Auch die Reinheit plasmatischer Konzentrate wird ständig erhöht. Einige Untersuchungsergebnisse deuten darauf hin, daß ultrareine, monoklonal gereinigte Plasmaprodukte bei HlV-seropositiven Blutern zu einer Stabilisierung der CD4-Lymphozytenzahl führen. Faktor VIII, der mittels rekombinanter Gentechnologie hergestellt wurde, ist in einigen Ländern bereits lizensiert. Auf diesem Weg gewonnener Faktor VIII ist von hoher Wirksamkeit und -so bleibt zu hoffen - frei von jeglichem Risiko einer Virenübertragung. Über die Frage, ob diese Produkte das Risiko einer Hemmkörperbildung erhöhen, wird immer noch diskutiert. Abschließend wäre zu bemerken, daß die gegenwärtig explosionsartig fortschreitende Entwicklung der Molekularbiologie auf eine erfolgreiche Entwicklung einer Gentherapie zur Behandlung von Hämophilie noch in diesem Jahrzehnt hoffen läßt.
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LITERATUR
- 1 Berntrop E, Nilsson IM. Biochemical and in vivo properties of commercial virusinactivated factor VIII concentrates. Eur J Haematol 1988; 40: 205-10.
- 2 Morfini M, Rafanelli D, Filimberti E, Cinotti S, Piazza E, Longo G, Rossi RFerrini. Protein content and factor VIII complex in untreated, treated and monoclonal factor VIII concentrates. Thromb Res 1989; 56: 169-79.
- 3 Mannucci PM, Colombo M. Virucidal treatment of clotting factor concentrate. Lancet 1988; 02: 782-5.
- 4 Thomas DP. Reducing the risk of virus transmission by blood products. Br J Haematol 1988; 70: 393-5.
- 5 Epstein JS, Fricke WA. Current safety of clotting factor concentrates. Arch Pathol Lab Med 1990; 114: 335-40.
- 6 White GC, Matthews TJ, Weinhold KJ, Hugues BT, Cromartie HL, McMillan CW, Bolognesi DP. HTLV-III serconversion associated with heat-treated factor VIII concentrate. Lancet 1986; 01: 611-2 (lett).
- 7 van den Berg W, ten Cate JW, Breederveld G, Goudsmit J. Seroconversion to HTLVIII in a hemophiliac given heat-treated factor VIII concentrate. Lancet 1986; 01: 803-4.
- 8 Mariani G, Ghirardini A, Mandelli F, Verani P, Butto S, Rossi GB, Mannucci PM. Heated clotting factor and seroconversion for human immunodeficiency virus in three hemophilic patients. Ann Intern Med 1987; 107: 113 (lett).
- 9 Weisser J. Transmission of the human immunodeficiency virus by a dry heat-treated factor VIII concentrate. Klin Pediatr 1988; 200: 375-9.
- 10 Dietrich SL, Mosley JW, Lusher JM, Hilgartner MW, Operskalski EA, Habel L, Aledort LM, Gjerset GF, Koerper MA, Lewis BM, Pegelow CH. The Transfusion Safety Study Group: Transmission of human immunodeficiency virus type 1 by dry-heated clotting factor concentrates. Vox Sang 1990; 59: 129-35.
- 11 Remis RJ. O’Shaughnessy MV, Tsoukas C, Growe GH, Schechter MT, Palmer RWH, Lawrence DN : HIV transmission to patients with hemophilia by heat-treated, donorscreened factor concentrate. Can Med Assoc J 1990; 142: 1247-54.
- 12 Williams MD, Skidmore SJ, Hill FGH. HIV seroconversion in hemophilic boys receiving heat-treated factor VIII concentrate. Vox Sang 1990; 58: 135-6.
- 13 Klein JP, Bailly E, Schneweis KE, Brackmann HH, Hammerstein U, Haufland P, van de Loo B, Oldenburg J. Acute HIV-1 infection in patients with hemophilia B treated with beta-propiolactone UV-inactivated clotting factor. Thromb Haemostas 1990; 64: 336-7 (lett).
- 14 Mannucci PM, Zanetti AR, Colombo M. Prospective study of hepatitis after factor VIII concentrate exposed to hot vapour. Br J Haematol 1988; 68: 427-30.
- 15 Brackmann HH, Egli H. Acute hepatitis B infection after treatment with heat-inactivated factor VIII concentrate. Lancet 1988; 02: 967 (lett).
- 16 Mannucci PM, Zanetti AR, Colombo M, Chistolini A, De Biasi R, Musso R, Tamponi G. Antibody to hepatitis C virus after a vapourheated factor VIII concentrate. The Study Group of the Fondazione deU’Emotilia. Thromb Haemostas 1990; 64: 232-4.
- 17 Schulman S, Lindgren ACh, Petrini P, Allander T. Transmission of hepatitis C with pasteurized factor VIII. Lancet 1992; 340: 305-6 (lett).
- 18 Schimpf K, Mannucci PM, Kreuz W, Brackmann HH, Auerswald G, Ciavarella N, Moesseler J, De Rosa V, Kraus MD, Brueckman CH, Mancuso G, Mittler V, Haschke F, Morfini M. Absence of hepatitis after treatment with a pasteurized factor VIII. N Engl J Med 1987; 316: 918-22.
- 19 Study Group of the UK Hemophilia Center Directors. Effect of dryheating of coagulation factor concentrates at 80° C for 72 hours on transmission of non-A, non-B hepatitis. Lancet 1988; 02: 814-6.
- 20 Horowitz MS, Rooks C, Horowitz B, Hilgartner M. Virus safety of solvent-detergent treated antihemophilic factor concentrate. Lancet 1988; 02: 186-9.
- 21 Mannucci PM, Schimpf K, Brettler DB, Ciavarella N, Colombo M, Haschke F, Lechner K, Lusher JM, Weissbach G. the International Study Group. Low risk for hepatitis in hemophiliacs given a highpurity, pasteurized factor VIII concentrate. Ann Intern Med 1990; 113: 27-32.
- 22 Kreuz W, Auerswald G, Bruckmann C, Zieger B, Linde R, Funk M, Auberger K, Sutor AH, Rasshofer R, Roggendorf FM. Prevention of hepatitis C virus infection in children with hemophilia A and B and von Willebrand’s disease. Thromb Haemostas 1992; 67: 189.
- 23 Mannucci PM, Schimpf K, Abe T, Aledort LM, Anderle K, Brettler DB, Hilgartner MW, Kernoff PBA, Kunschak M, Me Millan CW, Preston FE, Rivard GE. the International Study Group. Low risk of viral infection after administration of vapour heated factor VIII concentrates. Transfusion 1992; 32: 134-8.
- 24 Williams MD, Cohen B, Beddal AC, Pasi K, Mortimer PP, Hill FGH. Transmission of parvovirus B19 by coagulation factor concentrates. Vox Sang 1990; 58: 177-81.
- 25 Azzi A, Ciappi S, Zakvrezeska K, Morfini M, Mariani G, Mannucci PM. Human parvovirus B19 infection in hemophiliacs first infused with two high-purity virally attenuated factor VIII concentrates. Am J Hematol 1992; 39: 228-30.
- 26 Mannucci PM. Outbreak of hepatitis A among Italian patients with hemophilia. Lancet 1992; 339: 819 (lett).
- 27 Gerritzen A, Scheneweis KE, Brackmann HH, Oldenburg J, Haufland P, Gerlich WH, Caspari G. Acute hepatitis A in hemophiliacs. Lancet 1992; 340: 1231-2 (lett).
- 28 Temperley IJ, Cotter KP, Walsh TJ, Power J, Hillary IB. Clotting factors and hepatitis A. Lancet 1992; 340: 1466 (lett).
- 29 Peerlinck K, Vermylen J. Acute hepatitis A in patients with hemophilia A. Lancet 1993; 341: 179 (lett).
- 30 Rubinstein AI, Rubinstein DB, Coughlin J. Combined solvent/detergent and 100° C (boiling) sterilizing dry-heat treatment of factor VIII concentrates to assure sterility. Vox Sang 1991; 60: 60 (lett).
- 31 Carr R, Veitch SE, Edmond E, Peutherer JF, Prescott RJ, Steel CM, Ludlam CA. Abnormalities of circulating lymphocyte subsets in hemophiliacs in an AIDS-free population. Lancet 1989; 334: 1431-4.
- 32 Madhok R, Gracie A, Lowe GDO, Burnett A, Froebel K, Follett E, Forbes CD. Impaired cell mediated immunity in the absence of infection with human immunodeficiency virus. Br Med J 1986; 293: 978-80.
- 33 Teitel JM, Freedman JJ, Garvey MB, Kardish M. Two-year evaluation of clinical and laboratory variables of immune function in 117 hemophiliacs seropositive or seronegative for HIV-1. Am J Hematol 1989; 32: 262-72.
- 34 Cuthbert RJG, Ludlam CA, Steel CM, Beatson D, Peutherer JF. Immunological studies in HIV seronegative hemophiliacs: relationship to blood product therapy. Br J Haematol 1992; 80: 364-9.
- 35 Sullivan JL, Brewster FE, Brettler DB, Forsberg AD, Cheeseman SH, Byron KS, Balcer SM, Willits DL, Lew RA, Levine PH. Hemophiliac immunodeficiency: influence of exposure to factor VIII concentrate, LAV/HTLV-III and herpes virus. J Pediatr 1986; 108: 504-10.
- 36 Horsburg CR, Davis KC, Hasiba U, Weiss SH, Goedert JJ, Jârin P, Kirkpatrick CH. Altered immunity in hemophilia is correlated with the presence of antibody to human T-cell lymphotropic virus type III (HTLVIII). J Clin Immunol 1986; 06: 37.
- 37 Eyster ME, Gail MH, Ballard JO, AlMondhiry H, Goedert JJ. Natural history of human immunodeficiency virus infections in hemophiliacs: effects of T-cell subsets, platelet counts and age. Ann Intern Med 1987; 107: 1-6.
- 38 Brettler DB, Forsberg AD, Brewster FE, Sullivan JL, Levine PH. Delayed cutaneous hypersensitivity reaction in hemophilic subjects treated with factor concentrate. Am J Med 1986; 81: 607-11.
- 39 Margolick JB, Volkman DJ, Folks TM. HTLV-III/LAV detection by antigen induced activation of T-cells and amplification of direct suppression by virus of lymphocyte blastogénie responses. J Immunol 1987; 138: 1719-28.
- 40 Lederman MM, Saunders C, Toossi Z, Lemon N, Everson B, Ratnoff OD. Antihemophilic factor (factor VIII) preparations inhibit lymphocyte proliferation and production of interleukin-2. J Lab Clin Med 1986; 107: 471-8.
- 41 Thorpe R, Dilger P, Dawson NJ, Barrowcliffe TW. Inhibition of interleukin-2 secretion by factor VIII concentrates: a possible cause of immunosuppression in hemophiliacs. Br J Haematol 1989; 71: 387-91.
- 42 Eibl MM, Ahamad R, Wolf VM, Linnau Y, Gotz E, Mannhalter JW. A component of factor VIII preparations which can be separated from factor VIII activity downmodulates human monocyte function. Blood 1987; 69: 1153-60.
- 43 Brettler DB, Forsberg AD, Levine PH, Petillo J, Lamon K, Sullivan JL. Factor VIII: C concentrate purified from using monoclonal antibodies: human studies. Blood 1989; 73: 1859-63.
- 44 De Biasi R, Rocino A, Miraglia E, Mastrullo R, Quirino A. The impact of a very high purity factor VIII concentrate on the immune system of human immunodeficiency virus-infected hemophiliacs: a randomized, prospective, two-year comparison with an intermediate purity concentrate. Blood 1992; 78: 1919-22.
- 45 Seremetis S, Aledort LM, Bona R, Bray G, Brettler DB, Eyster E, Kessler C, Lusher J, Rickies F, Sacks H. A three-year randomized prospective study of high or intermediate purity factor VIII concentrates in asymptomatic HIV + hemophiliacs: effects on immune function. Blood 1992; 80 (suppl 1): 366a.
- 46 Mannucci PM, Gringeri A, de Biasi R, Baudo F, Morfini M, Ciavarella N. Immune status of asymptomatic HIV-infected hemophiliacs: randomized, prospective two-year comparison of treatment with a high-purity or an intermediate purity factor VIII concentrate. Thromb Haemostas 1992; 67: 310-3.
- 47 Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker CB, Orr EC, Amphlett GW, Foster B, Coe ML, Knutson GJ, Fass DN, Hewick RM. Molecular cloning of a cDNA encoding human antihemophilic factor. Nature 1984; 312: 342-7.
- 48 Wood WI, Capon DJ, Simonsen CC, Eaton DL, Gitschier J, Keyt B, Seeburg PH, Smith DH, Hollingshead P, Wion K, Delwart E, Tudenham EGD, Vehar GA, Lawn RM. Expression of active human factor VIII from recombinant DNA clones. Nature 1984; 312: 330-7.
- 49 Kaufman RJ, Wasley LC, Dorner AJ. Synthesis, processing and secretion of recombinant human factor VIII expressed in mammalian cells. J Biol Chem 1988; 263: 6351-62.
- 50 Klein U. Production and characterization of recombinant factor VIII. Sem Hematol 1991; 28 (suppl 1): 17-21.
- 51 Fournel M. Preclinical and in vivo studies of rFVIII. Sem Hematol 1990; 28 (suppl 1): 22-6.
- 52 Giles AR, Tinlin S, Hoogendoorn H, Fournel MA, Ng P, Pancham N. In vivo characterization of recombinant factor VIII in a canine model of hemophilia A (factor VIII deficiency). Blood 1988; 72: 335-42.
- 53 White GC, Me Millan 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: 166-70.
- 54 Schwartz RS, Abildgaard C, Aledort LM, Arkin S, Bloom A, Brackmann H, Brettler D, Dietrich S, Egli J, Hilgartner M, Inwood M, Kasper C, Kernoff P, Levine P, Lusher JM, Mannucci PM, Rose E, Scharrer I. Human recombinant DNA derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 1990; 323: 1800-5.
- 55 Goldsmith JC. and the Recombinate Study Group. Clinical trial of Recombinate : safety and efficacy of a genetically engineered antihemophilic factor in previously treated patients. Blood 1991; 78 (suppl 1): 64a.
- 56 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS. the Kogenate Previously Untreated Patients Study Group. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy and development of inhibitors. N Engl J Med 1993; 328: 453-9.
- 57 Bray GL, Liu-Maruya S, Courter S, High K, Gomberts E. and the Recombinate Study Group: Experience with recombinant factor VIII (Recombinate) in previously untreated patients (PUPs) with severe hemophilia A. Blood 1992; 80 (suppl 1): 229a.
- 58 Lusher JM, Salzman PM. and the Monoclate Study Group. Viral safety and inhibitor development associated with factor VIII ultrapurified from plasma in hemophiliacs previously unexposed to factor VIIIC concentrates. Sem Hematol 1990; 27 (suppl 2): 1-8.
- 59 Addiego SE, 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 Haemostas 1992; 67: 19-27.
- 60 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T, Brackhardt B, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitor in hemophiliacs. Lancet 1992; 339: 594-8.
- 61 Kasper CK. Thromboembolic complications. Thromb Diath Haemorrh 1975; 33: 640-8.
- 62 Magner A, Aronson DL. Toxicity of factor concentrates in mice. Devel Biol Stand 1979; 44: 185-9.
- 63 Menache D, Behre HE, Orthner CL, Nunez H, Anderson HD, Triantaphyllopoulos DC, Kosow DP. Coagulation factor IX concenträte: method of preparation and assessment of potential in vivo thrombogenicity in animal models. Blood 1984; 64: 1220-7.
- 64 Burnouf T, Michalski C, Goudemand M, Huart JJ. Properties of highly purified human plasma factor IX: C therapeutic concentrate prepared by conventional chromatography. Vox Sang 1989; 57: 225-32.
- 65 Mannucci PM, Bauer KA, Gringeri A, Barzegar S, Bottasso B, Simoni L, Rosenberg RD. Thrombin is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate. Blood 1991; 76: 2540-5.
- 66 Mannucci PM, Bauer KA, Gringeri A, Barzegar S, Santagostino E, Tradati FC, Rosenberg RD. No activation of the common pathway of the coagulation cascade after a highly purified factor IX concentrate. Br J Haematol 1991; 79: 606-11.
- 67 Bardin JM, Sultan Y. Factor IX concentrate versus prothrombin complex concentrate for the treatment of hemophilia B during surgery. Transfusion 1990; 30: 441-3.
- 68 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: 210-7.
- 69 Kim HC, McMillan CW, White GC, Bergman GE, Saidi P. Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison with prothrombin complex concentrates. Blood 1992; 79: 568-72.