Development of inhibitors in haemophilia

Summary

A number of 513 consecutive patients (494-haemophilia A and 19-haemophilia B) from eight haemophilia treatment centers have been investigated with Bethesda assay for the presence of factor VIII or IX inhibitors. The overall prevalence of inhibitors was 15.20%, 18.48% in severe, 5.60% in moderate and 12.24% in mild forms. The prevalence was higher than reported in most of the western countries. The age at start of substitution (p = 0.9775), the frequent switching of factor concentrates (p = 0.8931) were not relevant factors for the development of inhibitors. It is worth to be mentioned the unexpectedly occurrence of inhibitors in prior inhibitor negative (6/72) patients (during surgical interventions) probably due to their previous scarce substitution, occurrence which seems not being connected with the continuous infusion modality of factor VIII administration (p = 0.8341). In controversial situations, in the field of low titer (≤1 BU/ml) inhibitors for a reliable interpretation of the results the performance of recovery index and half-life time assessment of FVIII/IX was undertaken.

Zusammenfassung

In acht Hämophilie-Zentren wurden insgesamt 513 konsekutive Patienten (494 mit Hämophilie A und 19 mit Hämophilie B) für Hemmköper gegen FVIII/FIX mit der Bethesda-Methode untersucht. Die allgemeine Prävalenz von Inhibitoren lag bei 15,2%: 18,48% in schwerer, 5,6% in mittelschwerer und 12,24% in leichter Hämophilie. Die Bildung von Antikörpern tritt in höherer Zahl als in den meisten west europäischen Ländern auf. Beginn der Substitution (p = 0,9778), Frequenz von Änderungen von einem Faktorkonzentrat zu anderem (p = 0,8931) waren für die Entwicklung von Inhibitoren nicht relevant. Es ist zu vermerken die unerwartete Erscheinung von Inhibitoren bei vorher negativen Patienten (6/72) in Falle von chirurgischen Eingriffen, möglicherweise durch arme vorherige Substitution und nicht durch kontinuierliche Infusion von Faktor VIII (p = 0,8341) bedingt sein kann. In kontroversen Situationen, im Bereich von niedrigen Titern (≤1 BU/ml) wurde für eine korrekte Interpretation der Ergebnisse Recovery-Index und Halbwertszeit der Faktoren VIII und IX bestimmt.

Keywords

Haemophilia - inhibitors

Schlüsselwörter

Hämophilie - Inhibitoren

• References

• 1 Astermark J. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia 2010; 16: 747-766.
• 2 Auerswald G, Spranger T, Brackmann HH. The role of plasma-derived factor VIII/ von Willebrand factor concentrates in the treatment of haemophilia A patients. Haematologica. 2003 88. EREP05..
• 3 Ehrenforth S, Kreuz W, Scharrer I. et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598.
• 4 Escuriola CEttingshausen, Kreuz W. Recombinant vs. plasma-derived products, especially those with impact VWF, regarding inhibitor development. Haemophilia 2006; 12 (Suppl. 06) 102-106.
• 5 Ghosh K, Shetty S, Kulkarni B. Development of inhibitors in patients with haemophilia from India. Haemophilia 2001; 07: 273-279.
• 6 Goudemand J, Rothschild C. Demiguel et al. Influence of the type of factor VIII concentrate of the incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A. Blood 2006; 107: 46-51.
• 7 Gouw SC, van den Berg HM, le Cessie S. et al. Treatment characteristics and the risk of inhibitor development a multicenter cohort study among previously untreated patients with severe haemophilia A. J Thromb Haemost 2007; 05: 1383-1390.
• 8 Hay CR. The epidemiology of factor VIII inhibitors. Haemophilia 2006; 12 (Suppl. 06) 23-29.
• 9 Iorio A, Halimeh S, Holzhauser S, Goldenberg N. Rate of inhibitor development in PUP treated with plasma derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost. 2010; 08: 1256-1265.
• 10 Kim SY. Comparative measurement of FVIII inhibitors in HA patients using Elisa and Bethesda assay. Korean J Lab Med 2010; 03: 260-263.
• 11 Kreuz W, Escuriola-Ettinghausen C, Martinez I. et al. Factor VIII inhibitor bypass activity (FEIBA) for prophylaxis during immune tolerance induction (ITI) in patients with high-responding inhibitors. Blood 2000; 96 266a 1140.
• 12 Lorenzo JI, Lopez A, Altisent C. Incidence of FVIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113: 600-603.
• 13 Lusher JM, Arkin S, Abilgaard CF, Schwartz RS. 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.
• 14 Lusher IM. Is the incidence and prevalence of inhibitors greater with recombinant products? No. J Thrombo Hämost 2004; 02: 863-865.
• 15 Lusher JM. False positive inhibitor screen tests in haemophilia. Haemophilia. 2002 08. 42.
• 16 Meijer P, Verbruggen B. The between laboratory variation of FVIII inhibitor testing, the experience of the external quality assessements program of the ECAT foundation. Semin Thromb Hemost 2009; 35: 786-793.
• 17 Mihailov D, Schramm K, Schramm W. et al. Inhibitors in haemophilia patients. Review of risk factors in a single center experience. Hämostaseologie. 2008; 28 Suppl S31-S32.
• 18 Peerlinck K, Jacquemin M. Mild haemophilia: a disease with many faces and many unexpected pitfalls. Haemophilia 2010; 16: 100-110.
• 19 Rodriguez-Merchan EC. Inhibitors in Patients with Haemophilia. Blackwell Science. 2008
• 20 Rothschild C, Laurian Y, Satre EP. et al. French previously untreated patients with severe haemophilia A after exposure to recombinant factor VIII: incidence of inhibitor and evaluation of immune tolerance. Thromb Haemost 1998; 80: 779-783.
• 21 Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients – a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Haemophilia 1999; 05: 145-154.
• 22 Scharrer I, Ehrlich HJ. Lack of evidence for increased inhibitor incidence in patients switched from plasma-derived to recombinant factor VIII. Haemophilia 2001; 07: 346-348.
• 23 Sharathkumar A, Lilicrap D, Blanchette VS. et al. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild haemophilia A. J Thromb Haemost 2003; 01: 1228-1236.
• 24 Sharifian R, Hoseini M, Safai R. et al. Prevalence of inhibitors in a population of 1280 hemophilia A patients in Iran. Acta Medica Iranica 2003; 41: 66-68.
• 25 Wang XF. The prevalence of FVIII inhibitor and genetic aspects of inhibitor development in Chinese patients with haemophilia A. Haemophilia 2010; 16: 632-639.
• 26 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 09: 418-435.