updated with growing knowledge on predictors of inhibitor development.
The immune response to FVIII is a highly complex and multifactorial process. Major progress has been made in the knowledge on non-genetic factors that modulate the risk of inhibitor development. However, more knowledge about the risk factors of inhibitor development is needed, for it is a condition for prediction and possibly even prevention of the development of inhibitors in patients with severe haemophilia A. If we are able to prevent inhibitor development, the morbidity of patients with haemophilia will be greatly improved. Moreover, inhibitors will then not hinder the cure of haemophilia by gene therapy. l
References 1. Srivastava A, Brewer AK, Mauser-Bunschoten EP et al. Guidelines for the management of hemophilia. Haemophilia 2013;19:e1–47.
2. Darby SC et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007;110:815–25.
3. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418–35.
4. Hay CR et al. Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom. Blood 2011;117:6367–70.
5. Gringeri A, Mantovani LG, Scalone L, Mannucci PM. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003;102:2358–63.
6. Wight J, Paisley S, Knight C. Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic review. Haemophilia 2003;9:436–63.
7. Eckhardt CL et al. Intensive peri-operative use of factor VIII and the Arg593->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A J Thromb Haemost 2009;7:930–7.
8. Gouw SC et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012;119:2922–34.
9. White GC et al. Cellular immune responses in hemophilia: why do inhibitors develop in some, but not all hemophiliacs? J Thromb Haemost 2005;3:1676–81.
10. Hay CR et al. HLA class II profile: A weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party. Thromb Haemost 1997;77:234–7.
11. Oldenburg J et al. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII. Thromb
12. Astermark J et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood 2006;108:3739–45.
13. Astermark J, Berntorp E, White GC, Kroner BL. The Malmo International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients. Haemophilia 2001;7:267–72.
14. Viel KR et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 2009;360:1618–27.
15. Schwarz J et al. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Haemophilia 2013;19:113–8.
16. Astermark J et al. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood 2006;107:3167–72.
17. Astermark J et al. Polymorphisms in the CTLA-4 gene and inhibitor development in patients with severe hemophilia A. J Thromb Haemost 2007;5:263–5.
18. Astermark J et al. The polygenic nature of inhibitors in hemophilia A: results from the
binding of factor VIII in different therapeutic concentrates. Br J Haematol 1999;107:323–9.
27. Franchini M, Tagliaferri A, Mengoli C, Cruciani M. Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: a critical systematic review. Crit Rev Oncol Hematol 2012;81:82–93.
28. Iorio A et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010;8:1256–65.
29. Mannucci PM, Gringeri A, Peyvandi F, Santagostino E. Factor VIII products and inhibitor development: the SIPPET study (survey of inhibitors in plasma-product exposed toddlers). Haemophilia 2007;13 Suppl 5:65–8.
30. Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Center Doctors’ Organisation (UKHCDO) guideline approved by the British Committee for Standards in Haematology. Haemophilia 2008;14:671–84.
“If we are able to prevent inhibitor development, the morbidity of patients with haemophilia will be greatly improved”
Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort. Blood 2013;121:1446–54.
19. Gouw SC, van der Bom JG, van den Berg HM. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007;109:4648–54.
20. Gouw SC et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood 2013
21. Maclean PS, Richards M, Williams M et al. Treatment related factors and inhibitor development in children with severe haemophilia A. Haemophilia 2011;17:282–7.
22. Santagostino E, Mancuso ME, Rocino A et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol 2005;130:422–7.
23. Matzinger P. Tolerance, danger, and the extended family. Annu.Rev.Im
24. Suzuki T et al. Factor VIII inhibitor antibodies with C2 domain specificity are less inhibitory to factor VIII complexed with von Willebrand factor. Thromb Haemost 1996;76:749–54.
25. Wadhwa M et al. Identification of transforming growth factor-beta as a contaminant in factor VIII concentrates: a possible link with immunosuppressive effects in hemophiliacs. Blood 1994;84:2021–30.
26. Raut S, Weller L, Barrowcliffe TW. Phospholipid
31. Peerlinck K et al. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemost 1993;69:115–8.
32. Rosendaal FR et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 1993;81:2180–6.
33. Gouw SC et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013;368:231–9.
34. Dhadwar SS, Kiernan J, Wen J, Hortelano G. Repeated oral administration of chitosan/DNA nanoparticles delivers functional FVIII with the absence of antibodies in hemophilia A mice. J Thromb Haemost 2010;8:2743–50.
35. Kitazawa T et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012;18:1570–4.
36. Welch EM et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007;447:87-91.
37. Nathwani AC et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011;365:2357–65.
38. Ter Avest PC et al. Risk stratification for inhibitor development at first treatment for severe haemophilia A: a tool for clinical practice. J Thromb Haemost 2008;6:2048–54.
| Page 2
| Page 3
| Page 4
| Page 5
| Page 6
| Page 7
| Page 8
| Page 9
| Page 10
| Page 11
| Page 12
| Page 13
| Page 14
| Page 15
| Page 16
| Page 17
| Page 18
| Page 19
| Page 20
| Page 21
| Page 22
| Page 23
| Page 24
| Page 25
| Page 26
| Page 27
| Page 28
| Page 29
| Page 30
| Page 31
| Page 32
| Page 33
| Page 34
| Page 35
| Page 36