Thromb Haemost 2015; 114(01): 46-55
DOI: 10.1160/TH14-11-0940
Coagulation and Fibrinolysis
Schattauer GmbH

Inhibitors in nonsevere haemophilia A: outcome and eradication strategies

Alice S. van Velzen
1   Department of Pediatric Hematology, Emma Children’s Hospital, the Academic Medical Center, Amsterdam, the Netherlands
,
Corien L. Eckhardt
1   Department of Pediatric Hematology, Emma Children’s Hospital, the Academic Medical Center, Amsterdam, the Netherlands
2   Department of Vascular medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Daniel P. Hart
3   Royal London Hospital, Barts and The London School of Medicine and Dentistry, London, UK
,
Marjolein Peters
1   Department of Pediatric Hematology, Emma Children’s Hospital, the Academic Medical Center, Amsterdam, the Netherlands
,
Savita Rangarajan
4   St. Thomas Hospital, London, UK
,
Maria Elisa Mancuso
5   Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
,
Frans J. Smiers
6   Leiden University Medical Center, Leiden, the Netherlands
,
Kate Khair
7   Great Ormond Street Hospital, London, UK
,
Pia Petrini
8   Karolinska University Hospital, Stockholm, Sweden
,
Victor Jimenez-Yuste
9   University Hospital La Paz, Madrid, Spain
,
Charles R. M. Hay
10   Royal Infirmary Hospital, Manchester, UK
,
Johanna G. van der Bom
11   Center for Clinical Transfusion Research, Sanquin Research and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
,
Thynn T. Yee
1   Department of Pediatric Hematology, Emma Children’s Hospital, the Academic Medical Center, Amsterdam, the Netherlands
,
Karin Fijnvandraat
1   Department of Pediatric Hematology, Emma Children’s Hospital, the Academic Medical Center, Amsterdam, the Netherlands
,
for the INSIGHT study group › Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 13. November 2014

Accepted after minor revision: 13. Februar 2015

Publikationsdatum:
22. November 2017 (online)

Summary

In nonsevere haemophilia A (HA) patients the presence of an inhibitor may exacerbate the bleeding phenotype dramatically. There are very limited data on the optimal therapeutic approach to eradicate inhibitors in these patients. We aimed to describe inhibitor eradication treatment in a large cohort of unselected nonsevere HA patients with inhibitors. We included 101 inhibitor patients from a source population of 2,709 nonsevere HA patients (factor VIII 2–40 IU/dl), treated in Europe and Australia (median age 37 years, interquartile range (IQR) 15–60; median peak titre 7 BU/ml, IQR 2–30). In the majority of the patients (71 %; 72/101) the inhibitor disappeared; either spontaneously (70 %, 51/73) or after eradication treatment (75 %, 21/28). Eradication treatment strategies varied widely, including both immune tolerance induction and immunosuppression. Sustained success (no inhibitor after rechallenge with factor VIII concentrate after inhibitor disappearance) was achieved in 64 % (30/47) of those patients rechallenged with FVIII concentrate. In high-titre inhibitor patients sustained success was associated with eradication treatment (unadjusted relative risk 2.3, 95 % confidence interval 1.3–4.3), compared to no eradication treatment. In conclusion, in nonsevere HA patients most inhibitors disappear spontaneously. However, in 35 % (25/72) of these patients an anamnestic response still can occur when rechallenged, thus disappearance in these patients does not always equal sustained response. Treatment for those requiring eradication has to be decided case by case, as one single approach is unlikely to be appropriate for all.

Study was carried out in: Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands.

* A complete list of the members of the INSIGHT Study Group is found in the Appendix.


 
  • References

  • 1 Fijnvandraat K, Cnossen MH, Leebeek FW. et al. Diagnosis and management of haemophilia. Br Med J 2012; 344: e2707.
  • 2 Eckhardt CL, van Velzen AS, Peters M. et al. Factor VIII gene (F8) mutation and risk of inhibitor development in non-severe haemophilia A. Blood 2013; 122: 1954.
  • 3 Hay CR, Ludlam CA, Colvin BT. et al. Factor VIII inhibitors in mild and moderate-severity haemophilia A. UK Haemophilia Centre Directors Organisation. Thromb Haemost 1998; 79: 762-766.
  • 4 Peerlinck K, Jacquemin M. Mild haemophilia: a disease with many faces and many unexpected pitfalls. Haemophilia 2010; 16 (Suppl. 05) 100-106.
  • 5 Morfini M, Haya S, Tagariello G. et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007; 13: 606-612.
  • 6 Darby SC, Keeling DM, Spooner RJ. et al. The incidence of factor VIII and factor IX inhibitors in the haemophilia population of the UK and their effect on subsequent mortality, 1977–99. J Thromb Haemost 2004; 02: 1047-1054.
  • 7 Wight J, Paisley S, Knight C. Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic review. Haemophilia 2003; 09: 436-463.
  • 8 Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors--twenty years’ ’bonn protocol’. Vox Sang 1996; 70 (Suppl. 01) 30-35.
  • 9 Freiburghaus C, Berntorp E, Ekman M. et al. Tolerance induction using the Malmö treatment model 1982–1995. Haemophilia : the official journal of the World Federation of Haemophilia 1999; 05: 32-39.
  • 10 Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G. et al. Low-dose immune tolerance induction in haemophilia A patients with inhibitors. Blood 1995; 86: 983-988.
  • 11 Nilsson IM, Berntorp E, Zettervall O. Induction of immune tolerance in patients with haemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide, and factor VIII. N Engl J Med 1988; 318: 947-950.
  • 12 Oldenburg J, Schwaab R, Brackmann HH. Induction of immune tolerance in haemophilia A inhibitor patients by the ’Bonn Protocol’: predictive parameter for therapy duration and outcome. Vox Sang 1999; 77 (Suppl. 01) 49-54.
  • 13 Van Leeuwen EF, Mauser-Bunschoten EP, Van Dijken PJ. et al. Disappearance of factor VIII:C antibodies in patients with haemophilia A upon frequent administration of factor VIII in intermediate or low dose. Br J Haematol 1986; 64: 291-297.
  • 14 Hay CR, Dimichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119: 1335-1344.
  • 15 Collins PW. Novel therapies for immune tolerance in haemophilia A. Haemophilia 2006; 12: 94-101.
  • 16 Franchini M, Mengoli C, Lippi G. et al. Immune tolerance with rituximab in congenital haemophilia with inhibitors: a systematic literature review based on individual patients’ analysis. Haemophilia 2008; 14: 903-912.
  • 17 Di Michele DM. Immune tolerance induction in haemophilia: evidence and the way forward. J Thromb Haemost 2011; 09 (Suppl. 01) 216-225.
  • 18 Saint-Remy JM, Lacroix-Desmazes S, Oldenburg J. Inhibitors in haemophilia: pathophysiology. Haemophilia 2004; 10 (Suppl. 04) 146-151.
  • 19 Kasper CK, Aledort L, Aronson D. et al. Proceedings: A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 612.
  • 20 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
  • 21 Kempton CL, Allen G, Hord J. et al. Eradication of factor viii inhibitors in patients with mild and moderate haemophilia A. Am J Hematol 2012; 87: 933-936.
  • 22 Collins PW, Chalmers E, Hart DP. et al. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). UK Haemophilia Centre Doctors Organization. Br J Haematol 2013; 160: 153-170.