Langzeitprophylaxe bei kongenitaler Hämophilie mit Hemmkörpern

Zusammenfassung

Ein Problem in der Therapie der Hämophilie ist die Entwicklung von Antikörpern gegen den zugeführten Faktor VIII. Patienten mit Antikörpern sind bei spontanen Blutungen, Operationen oder Traumata besonders gefährdet. Ist die Immuntoleranztherapie mit hohen i.v.-Dosen von Faktor VIII nicht erfolgreich, kommt eine Behandlung mit rekombinantem Faktor VIIa oder aktiviertem Prothrombinkomplex in Betracht. Dieser Artikel fasst die Daten dreier Patienten mit einer schweren Form der Hämophilie A und einer Intron- 22-Inversion im FVIII-Gen, die Antikörper gegen FVIII entwickelt haben, zusammen.

Die Gabe von rFVIIa erwies sich bei diesen Patienten nicht nur als effektiv, sondern auch als sicher. Darüber hinaus zeigte sich unter der prophylaktischen Therapie mit rFVIIa in individueller Dosierung von 180 bis 270 μg/kg Körpergewicht einmal pro Tag eine deutliche Reduktion der spontanen Blutungsereignisse (Target Joints, Muskulatur, andere Lokalisation). Die verminderte Blutungsfrequenz führte zum Rückgang der Gelenk-und Muskelschmerzen und verhalf den jungen Patienten zu größerer Mobilität und deutlich besserer Lebensqualität.

Summary

A major challenge in the treatment of haemophilia patients is the development of autoantibodies against factor VIII. These patients are at particular risk if spontaneous bleedings or traumata occur or if surgery is necessary. In case of an unsuccessful immune tolerance therapy with high i.v. doses of factor VIII, treatment with recombinant factor VIIa or activated prothrombin complex should be considered.

This article summarises data of three patients with severe haemophila A due to an inversion of intron 22 in the FVIII gen. All three patients had autoantibodies against FVIII. The therapy of these patients with rFVIIIa was safe and effective. Furthermore a prophylactic therapy with rFVIIa (at an individual dose of 180–270 μg/kg body weight) reduced the number of spontaneous bleedings in joints and muscles as well as in other locations significantly. The reduced rate of spontaneous bleedings improved the mobility and the quality of life in the young patients studied.

Schlüsselwörter

Rekombinanter Faktor VIIa - Hämophilie A - Autoantikörper gegen Faktor VIII - Prophylaxe

Keywords

Recombinant factor VIIa - haemophilia A - factor VIII inhibitor - prophylaxis

• Literatur

• 1 Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004; 2: 899-909.
• 2 Borel-Derlon A, Slaoui M, Gautier P. et al. Prophylactic use of rFVIIa in a young hemophiliaA patient with factor VIII inhibitor. Blood 2005; 106: 97-98.
• 3 Brackmann HH, Effenberger W, Hess L. et al. Immune tolerance induction: a role for recombinant activated factor VII (rFVIIa)?. Eur J Haematol 1998; 63 Suppl 18-23.
• 4 Cooper HA, Jones CP, Campion E. et al. Rationale for the use of high dose rFVIIa in a high-titre inhibitor patient with haemophilia B during major orthopaedic procedures. Haemophilia 2001; 7: 517-522.
• 5 Di Michele D. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia 2002; 8: 280-287.
• 6 Di Michele DM. Immune tolerance: a synopsis of the international experience. Haemophilia 1998; 4: 568-573.
• 7 Forbes CD, Aledort LM, Madhok R. (eds). Hemophilia. New York: Chapman & Hall; 1997
• 8 Hausl C, Ahmad RU, Sasgary M. et al. High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors. Blood 2005; 106: 3415-3422.
• 9 Hay CR. UK Haemophilia Centre Doctors’ Organisation.. 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 2004; 2: 1047-1054.
• 10 Hilgartner MW, Makipernaa A, Dimichele DM. Long-term FEIBA prophylaxis does not prevent progression of existing joint disease. Haemophilia 2003; 9: 261-268.
• 11 Kavakli K, Makris M, Zulfikar B. et al. NovoSeven trial (F7HAEM-1510) investigators. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multicentre, randomised, double-blind, cross-over trial. Thromb Haemost 2006; 95: 600-605.
• 12 Kenet G, Lubetsky J, Luboshitz J. et al. 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 2003; 1: 450-455.
• 13 Kessler CM. New perspectives in hemophilia treatment. Hematology Am Soc Hematol Educ Program 2005; 429-435.
• 14 Key NS, Aledort LM, Beardsley D. et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998; 80: 912-918.
• 15 Konkle BA, Ebbesen LS, Friedrich U. et al. Secondary prophylactic treatment with rFVIIa in patients with haemophilia A or B and inhibitors with high requirements for on-demand treatment: analysis of primary endpoint and safety. Presented at WFH-Congress 2006 Vancouver, Canada.:
• 16 Kreuz W, Ettingshausen CE, Auerswald G. et al. GTH PUP Study Group. Epidemiology of inhibitors and current treatment strategies. Haematologica 2003; 88: EREP04.
• 17 Parameswaran R, Shapiro AD, Gill JC. et al. Dose effect and efficacy of recombinant factor VIIa in the treatment of hemophilia patients with inhibitors: analysis from the Hemophilia Research Society registry. Blood 2002; 100 (Suppl. 01) 22a.
• 18 Saxon BR, Shanks D, Jory CB. et al. Effective prophylaxis with daily recombinant factor VIIa (rFVIIa-Novoseven) in a child with high titre inhibitors and a target joint. Thromb Haemost 2001; 86: 1126-1127.
• 19 Sultan Y, Kazatchkine MD, Maisonneuve P. et al. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high-dose intravenous gammaglobulin. Lancet 1984; 2 8406 765-768.
• 20 Villar A, Aronis S, Morfini M. et al. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven®) in children vs. adults with haemophilia A. Haemophilia 2004; 10: 352-359.
• 21 Wiehl M. Rekombinante Präparate erhöhen die Sicherheit – Kein Infektionsrisiko für Hämophiliepatienten. Klinikarzt 2006; 35: VI.
• 22 Young G, McDaniel M, Nugent DJ. Prophylactic recombinant factor VIIa in haemophilia patients with inhibitors. Haemophilia 2005; 11: 203-207.