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Factor VIII products

diagnosed, even though a substantial number of these inhibitors was of low titer and disappeared spontaneously.8 The overall conclusion based on the current literature still is that recombinant FVIII products are more immunogenic than plasma-derived products.10


the outcomes of numerous studies and systematic reviews have been contradictory. Small and heterogeneous study populations often include patients of different severities of haemophilia A; inclusion of minimally treated patients and patients who are still at risk of subsequent inhibitor development leads to an underestimate of inhibitor incidence. Debate is also ongoing as to whether plasma products with a higher von Willebrand content have a lower chance of developing an inhibitor.11

The diagnosis of an inhibitor is mostly by the detection of inhibitory antibodies in the Bethesda assay. Patients with an inhibitor do not bleed more without trauma than do non-inhibitor patients. This makes the diagnosis of an inhibitor initially highly dependent on laboratory results. Several clinical studies have been published that diagnosed an inhibitor only on one positive laboratory sample without recovery. Recombinant products were mainly used for newly diagnosed children with haemophilia. The reason was to prevent transmittable disease in a new generation of haemophiliacs. As patients develop inhibitors in their first 50 exposure days, this could have led to a publication bias on the overall results. After alarming reports of a higher incidence on recombinant products, several haemophilia centres again introduced the use of plasma products for young children. Nowadays, plasma products have been shown to be as safe as recombinant products for known transmittable pathogens, and the prevention of an inhibitor has a higher priority. The first systematic review of the comparison of plasma versus recombinant products was performed in 1993 by Wight and Paisley.12

A large

variation in inhibitor incidence was found between plasma and recombinant products and it was concluded that single plasma products seem to have a lower incidence generation for inhibitor. However, in both the CANAL and the RODIN studies, in which non-selected cohorts of PUPs were analysed, no difference between the inhibitor incidence of plasma versus recombinant products was found.13,14

However, these studies, 4 which were concentrated in a 20-year

3. 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.

4. Santagostino E et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study. Br J Haematol. 2005;130:422–7.

5. Tiede A et al. Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with haemophilia A. J Thromb Haemost 2013 Apr;11(4):670–8.

period, did demonstrate significantly lower titer inhibitors in children born after 2000.14

centre developed a randomised study between class plasma products versus class recombinant products.15


intention is that the SIPPET study will be able at last to give a clear answer as to whether recombinant products are more immunogenic than plasma products, an

6. Chorba TL, Holman RC, Clarke MJ, Evatt BL. Effects of HIV infection on age and cause of death for persons with haemophilia A in the United States. Am J Hematol. 2001 Apr;66(4):229–40.

To end the debate, the Milan

7. Soucie JM et al. Haemophilia Surveillance System Project Investigators. Risk factors for infection with HBV and HCV in a largecohort of haemophiliac males. Transfusion 2001;41(3):338–43.

8. Lusher JM, Arkin S, Abildgaard CF, Schwartz RS and the Kogenate study group. N Eng Med 1993; 328:453–9.

9. Rosendaal FR et al. A sudden increase in factor VIII inhibitor development in multitransfused

“Between 20 and 30 percent of patients with severe haemophilia A develop inhibitory antibodies against infused FVIII products”

answer that is clearly needed now that recombinant products are changed to increase their half-life. Recently, in the largest PUP study so far, different risks were found between recombinant products.14

This has also been

demonstrated for single plasma products in the past.12

It is clear that these

observations can have an impact on the overall interpretation of the results of the SIPPET study.

In conclusion To date, a final answer as to whether recombinant products have a higher chance of success than plasma products is not available. It is clear that from the 1990s the higher awareness of inhibitors, combined with more frequent testing, has been part of the increased inhibitor incidence. l

References 1. Berntorp E et al. Modern treatment of haemophilia. Bull World Health Organ 1995;73(5):691–701.

2. Schwaab R et al. Haemophilia A: Mutation type determines risk of inhibitor formation. Thromb Haemost 1995;74:1402–6.

haemophilia A patients in The Netherlands. Dutch Haemophilia Study Group Blood 1993;81(8):2180–6.

10. Iorio A et al. Rate of inhibitor development in previously untreated haemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010;8:1256–65.

11. Franchini M, Lippi G. Von Willebrand factor- containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review. Thromb Haemost 2010;104(5):931–40.

12. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418–35.

13. Gouw SC et al. Recombinant versus plasma- derived factor VIII products and the development of inhibitors in previously untreated patients with severe haemophilia A: the CANAL cohort study. Blood 2007;109(11):4693–7.

14. Gouw SCet al. PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe haemophilia A. N Engl J Med 2013;368(3):231–9.

15. 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.

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