The burden of inhibitors in haemophilia patients

Christopher E. Walsh; Victor Jiménez-Yuste; Guenter Auerswald; Salvador Grancha

doi:10.1160/TH16-01-0049

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(S 01): S10-S17
DOI: 10.1160/TH16-01-0049

5th International Coagulation Meeting 2015 – Barcelona, Spain

Schattauer GmbH

The burden of inhibitors in haemophilia patients

Christopher E. Walsh

¹Division of Hematology and Medical Oncology, Mount Sinai School of Medicine, New York, New York, USA

,

Victor Jiménez-Yuste

²Department of Haematology, Autónoma University Madrid and La Paz University Hospital, Madrid, Spain

,

Guenter Auerswald

³Senior Advisor, Comprehensive Care Centre for Haemophilia and Thrombosis, Professor Hess Children’s Hospital, Klinikum Bremen-Mitte, Bremen, Germany

,

Salvador Grancha

⁴Research and Development, Grifols S. A., Barcelona, Spain

› Author Affiliations

Abstract

Summary

The burden of disease in haemophilia patients has wide ranging implications for the family and to society. There is evidence that having a current inhibitor increases the risk of morbidity and mortality. Morbidity is increased by the inability to treat adequately and its consequent disabilities, which then equates to a poor quality of life compared with non-inhibitor patients. The societal cost of care, or `burden of inhibitors’, increases with the ongoing presence of an inhibitor. Therefore, it is clear that successful eradication of inhibitors by immune tolerance induction (ITI) is the single most important milestone one can achieve in an inhibitor patient. The type of factor VIII (FVIII) product used in ITI regimens varies worldwide. Despite ongoing debate, there is in vitro and retrospective clinical evidence to support the use of plasma-derived VWF-containing FVIII concentrates in ITI regimens in order to achieve early and high inhibitor eradication success rates.

Keywords

Haemophilia - FVIII - immune tolerance induction - inhibitor - von Willebrand factor

Full Text

References

References
1 Gringeri A, Mantovani LG, Scalone L. et al. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003; 102: 2358-2363.
2 Scalone L, Mantovani LG, Mannucci PM. et al. Quality of life is associated to the orthopaedic status in haemophilic patients with inhibitors. Haemophilia 2006; 12: 154-162.
3 Leissinger C, Gringeri A, Antmen B. et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011; 365: 1684-1692.
4 Antunes SV, Tangada S, Stasyshyn O. et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia 2014; 20: 65-72.
5 Darby SC, Keeling DM, Spooner RJ. et al. UK Haemophilia Centre Doctors’ Organisation. 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.
6 Walsh CE, Soucie JM, Miller CH. et al. Impact of inhibitors on hemophilia A mortality in the United States. Am J Hematol 2015; 90: 400-405.
7 Eckhardt CL, Loomans JI, van Velzen AS. et al. Inhibitor development and mortality in non-severe hemophilia A. J Thromb Haemost 2015; 13: 1217-1225.
8 Johnson KA, Zhou ZY. Costs of care in hemophilia and possible implications of health care reform. Hematology Am Soc Hematol Educ Program 2011; 2011: 413-418.
9 Di Minno G, Coppola A. A role for von Willebrand factor in immune tolerance induction in patients with haemophilia A and inhibitors?. Blood Transfus 2011; 09 (Suppl. 02) s14-20.
10 Oldenburg J, Lacroix-Desmazes S, Lillicrap D. Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity. Haematologica 2015; 100: 149-156.
11 Valentino LA, Kempton CL, Kruse-Jarres R. et al. US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. Haemophilia 2015; 21: 559-567.
12 Di Minno G, Coppola A. Management of patients with long-term inhibitors: is immune tolerance an underestimated life-long solution?. Haemophilia 2013; 19 (Suppl. 01) 18-23.
13 Mauser-Bunschoten EP, Nieuwenhuis HK, Roosendaal G. et al. Lowdose immune tolerance induction in haemophilia A patients with inhibitors. Blood 1995; 86: 983-988.
14 Kucharski W, Scharf R, Nowak T. Immune tolerance induction in haemophiliacs with inhibitor to FVIII: high- or low-dose programme. Haemophilia 1996; 02: 224-228.
15 Batlle J, Lopez MF, Brackmann HH. et al. Induction of immune tolerance with recombinant factor VIII in haemophilia A patients with inhibitors. Haemophilia 1999; 05: 431-435.
16 Unuvar A, Warrier I, Lusher JM. Immune tolerance induction in the treatment of paediatric haemophilia A patients with factor VIII inhibitors. Haemophilia 2000; 06: 150-157.
17 Rocino A, Santagostino E, Mancuso ME. et al. Immune tolerance induction with recombinant factor VIII in haemophilia A patients with high responding inhibitors. Haematologica 2006; 91: 558-561.
18 DiMichele DM, Kroner BL. North American Immune Tolerance Study Group. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002; 87: 52-57.
19 Mariani G, Kroner B. for the Immune Tolerance Study Group. Immune tolerance in hemophilia with inhibitors: predictors of success. Haematologica 2001; 86: 1186-1193.
20 Coppola A, Margaglione M, Santagostino E. et al. Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost 2009; 07: 1809-1815.
21 Antun A, Monahan PE, Manco-Johnson MJ. et al. Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study. J Thromb Haemost 2015; 13: 1980-1988.
22 Kurth M, Puetz J, Kouides P. et al. The use of a single von Willebrand factor-containing, plasma-derived FVIII product in hemophilia A immune tolerance induction: the US experience. J Thromb Haemost 2011; 09: 2229-2234.
23 Rangajaran S, Yee TT, Roy A. Immune tolerance induction in adult severe haemophilia A patients with a single FVIII/VWF product: the UK experience. J Thromb Haemost 2013; 11 (Suppl. 02) 1081.
24 Santagostino E. More than a decade of international experience with a pdFVIII/ VWF concentrate in immune tolerance. Haemophilia 2013; 19 (Suppl. 01) 8-11.
25 Oldenburg J, Jiménez-Yuste V, Peiró-Jordán R. et al. Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate. Haemophilia 2014; 20: 83-91.
26 Rangarajan S, Jiménez-Yuste V, Santagostino E. Adult haemophilia A patients with inhibitors: successful immune tolerance induction with a single FVIII/ VWF product. Haemophilia 2014; 20: e414-e417.
27 Jiménez-Yuste V, Oldenburg J, Rangarajan S, Peiró R, Santagostino E. Long-term follow-up of hemophilia a patients who previously showed complete or partial success in immune tolerance induction therapy with a single plasma-derived FVIII/VWF product: Long-term ITI study. Blood 2015; 126: 2282.
28 Blanchette VS, Key NS, Ljung LR. et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1935-1939.
29 Lentz SR, Ehrenforth S, Karim FA. et al. Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa. J Thromb Haemost 2014; 12: 1244-1253.
30 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-e47.
31 Hedner U, Lee CA. First 20 years with recombinant FVIIa (NovoSeven). Haemophilia 2011; 17: e172-182.
32 Astermark J, Donfield SM, DiMichele DM. et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA Novo-Seven Comparative (FENOC) Study. Blood 2007; 109: 546-551.
33 Morfini M, Haya S, Tagariello G. et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007; 13: 606-612.
34 Leissinger C, Wulff K, Abdou A. Inhibitor prevalence and association with morbidity in severe hemophilia A patients. Blood 2001; 98: 535a.
35 Triemstra M, Rosendaal FR, Smit C. et al. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med 1995; 123: 823-827.
36 Recht M, Neufeld EJ, Sharma VR. et al. Impact of acute bleeding on daily activities of patients with congenital hemophilia with inhibitors and their caregivers and families: observations from the Dosing Observational Study in Hemophilia (DOSE). Value Health 2014; 17: 744-748.
37 Auerswald G, Kurnik K, Aledort LM. et al. The EPIC study: a lesson to learn. Haemophilia 2015; 21: 622-628.
38 Auerswald G, von Depka MProndzinski, Ehlken B. et al. Treatment patterns and cost-of-illness of severe haemophilia in patients with inhibitors in Germany. Haemophilia 2004; 10: 499-508.
39 Goudemand J. Treatment of patients with inhibitors: cost issues. Haemophilia 1999; 05: 397-401.
40 Farrugia A, Cassar J, Kimber MC. et al. Treatment for life for severe haemophilia A-A cost-utility model for prophylaxis vs. on-demand treatment. Haemophilia 2013; 19: e228-e238.
41 Earnshaw SR, Graham CN, McDade CL. et al. Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment. Haemophilia 2015; 21: 310-319.
42 Hay CR, DiMichele DM. International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119: 1335-1344.
43 Ogden CL, Fryar CD, Carroll MD. et al. Mean body weight, height, and body mass index, United States 1960–2002. Adv Data 2004; 347: 1-17.
44 Federici AB. The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica. 2003 88. EREP02.
45 Delignat S, Repessé Y, Navarrete AM. et al. Immunoprotective effect of von Willebrand factor towards therapeutic factor VIII in experimental haemophilia A. Haemophilia 2012; 18: 248-254.
46 Gringeri A, Ofosu FA, Grancha S, Oldenburg J, Ewing NP, Federici AB. Understanding FVIII/VWF complex–report from a symposium of XXIX WFH meeting 2010. Haemophilia 2012; 18: 469-475.
47 van Velzen AS, Peters M, van der Bom JG. et al. Effect of von Willebrand factor on inhibitor eradication in patients with severe haemophilia A: a systematic review. Br J Haematol 2014; 166: 485-495.
48 Bravo MI, Da Rocha-Souto B, Grancha S. et al. Native plasma-derived FVIII/ VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors. Haemophilia 2014; 20: 905-911.
49 Bravo MI, Costa M, Grancha S. et al Beneficial effect of VWF in FVIII recovery of different FVIII concentrates in a mouse model of severe hemophilia with high inhibitor titers [PO207-WED]. J Thromb Haemost 2015; 13 (Suppl. 02) 826-827.