Systematic Review of the Role of FVIII Concentrates in Inhibitor Development in Previously Untreated Patients with Severe Hemophilia A: A 2013 Update

Massimo Franchini; Antonio Coppola; Angiola Rocino; Elena Santagostino; Annarita Tagliaferri; Ezio Zanon; Massimo Morfini; ; Italian Association of Hemophilia Centers (AICE) Working Group

doi:10.1055/s-0033-1356715

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2013; 39(07): 752-766
DOI: 10.1055/s-0033-1356715

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Systematic Review of the Role of FVIII Concentrates in Inhibitor Development in Previously Untreated Patients with Severe Hemophilia A: A 2013 Update

Massimo Franchini

¹Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy

,

Antonio Coppola

²Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Naples, Italy

,

Angiola Rocino

³Hemophilia and Thrombosis Center, San Giovanni Bosco Hospital, Naples, Italy

,

Elena Santagostino

⁴Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Cà Granda Foundation, Maggiore Hospital Policlinico, Milan, Italy

,

Annarita Tagliaferri

⁵Regional Reference Centre for Inherited Bleeding Disorders, University Hospital, Parma, Italy

,

Ezio Zanon

⁶Department of Cardiologic, Haemophilia Centre, Thoracic and Vascular Sciences, University of Padua Medical School, Padua, Italy

,

Massimo Morfini

⁷Department of Emergency & Reception, Agency for Haemophilia, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy

,

; Italian Association of Hemophilia Centers (AICE) Working Group

› Author Affiliations

Abstract

Nowadays, patients with hemophilia A receive a high standard of care; therefore, the most challenging complication of factor VIII (FVIII) replacement therapy has become the development of FVIII inhibitors, which render the concentrate infusion ineffective and expose patients to an increased risk of morbidity and mortality. Among environmental risk factors influencing inhibitor development, the type of FVIII products has always drawn the attention of investigators. Conflicting results are reported in the literature concerning rates of inhibitor development after either plasma-derived or recombinant FVIII concentrates. To help elucidate this controversial issue, we have performed a systematic review and meta-analysis of prospective studies evaluating the incidence of inhibitors in previously untreated patients with severe hemophilia A receiving plasma-derived or recombinant FVIII products. The quality of the studies was assessed using the Newcastle–Ottawa Scale (NOS), the STrenghtening the Reporting of OBservational studies in Epidemiology and an ad hoc quality score. Overall, 28 prospective studies, including 1,421 patients with hemophilia A, fulfilled our selection criteria and were included in the systematic review. No statistically significant differences were observed in the inhibitor incidence between plasma-derived and recombinant FVIII concentrates considering all (weighted means: 23%, 95% CI: 15–33% vs. 29%, 95% CI: 26–32%) and high titer (16%, 95% CI: 10–26% vs. 18%, 95% CI: 15–21%) inhibitors. Similarly, no significant differences were found in the inhibitor incidence among the different classes of recombinant products. In conclusion, the results of our meta-analysis show that the different types of FVIII products are not associated with different risks of inhibitor development.

Keywords

plasma derived - recombinant - FVIII concentrates - inhibitors - bleeding - therapy - systematic review

Full Text

References

References
1 Mannucci PM, Tuddenham EG. The hemophilias—from royal genes to gene therapy. N Engl J Med 2001; 344 (23) 1773-1779
2 Franchini M, Coppola A, Molinari AC , et al. Forum on: the role of recombinant factor VIII in children with severe haemophilia A. Haemophilia 2009; 15 (2) 578-586
3 Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis 2012; 7: 24
4 Coppola A, Franchini M, Tagliaferri A. Prophylaxis in people with haemophilia. Thromb Haemost 2009; 101 (4) 674-681
5 Gringeri A, Mantovani LG, Scalone L, Mannucci PM ; COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003; 102 (7) 2358-2363
6 Darby SC, Keeling DM, Spooner RJ , et al; UK Haemophilia Centre Doctors' Organisation. The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977-99. J Thromb Haemost 2004; 2 (7) 1047-1054
7 Schwaab R, Brackmann HH, Meyer C , et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74 (6) 1402-1406
8 Gouw SC, van den Berg HM, Oldenburg J , et al. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood 2012; 119 (12) 2922-2934
9 Astermark J, Oldenburg J, Escobar M, White II GC, Berntorp E ; Malmö International Brother Study study group. The Malmö International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica 2005; 90 (7) 924-931
10 Viel KR, Ameri A, Abshire TC , et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med 2009; 360 (16) 1618-1627
11 Astermark J, Oldenburg J, Pavlova A, Berntorp E, Lefvert AK ; MIBS Study Group. 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 (8) 3167-3172
12 Astermark J, Oldenburg J, Carlson J , et al. Polymorphisms in the TNFA gene and the risk of inhibitor development in patients with hemophilia A. Blood 2006; 108 (12) 3739-3745
13 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 (3) 422-427
14 Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109 (11) 4648-4654
15 Franchini M, Lippi G. Von Willebrand factor-containing factor VIII concentrates and inhibitors in hemophilia A: A critical literature review. Thromb Haemost 2010; 104 (5) 931-940
16 Chambost H. Assessing risk factors: prevention of inhibitors in haemophilia. Haemophilia 2010; 16 (Suppl. 02) 10-15
17 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9 (4) 418-435
18 Iorio A, Halimeh S, Holzhauer S , 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 (6) 1256-1265
19 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 (1) 82-93
20 European Medicines Agency. Report of expert meeting on FVIII products and inhibitor development. 28 February – 2 March 2006. Doc Ref. EMEA/CHMP/BPWP/12835/2006. London, 22 February 2007. Available at http://www.emea.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500015512.pdf Last accessed May 21, 2013.
21 White II GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J ; Factor VIII and Factor IX Subcommittee. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 85 (3) 560
22 Rothschild C, Gill J, Scharrer I, Bray G. Transient inhibitors in the Recombinate PUP study. Thromb Haemost 2000; 84 (1) 145-146
23 Brant R. Assessing proportionality in the proportional odds model for ordinal logistic regression. Biometrics 1990; 46 (4) 1171-1178
24 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP ; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370 (9596) 1453-1457
25 Wells GA, Shea B, O'Connell D , et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Available at http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm . (last visit 14–03–2013).
26 Lusher JM, Salzman PM ; The Monoclate Study Group. Viral safety and inhibitor development associated with factor VIIIC ultra-purified from plasma in hemophiliacs previously unexposed to factor VIIIC concentrates. Semin Hematol 1990; 27 (2) (Suppl. 02) 1-7
27 Lusher JM. Viral safety and inhibitor development associated with monoclonal antibody-purified F VIII C. Ann Hematol 1991; 63 (3) 138-141
28 Ehrenforth S, Kreuz W, Scharrer I , et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339 (8793) 594-598
29 Ljung R, Petrini P, Lindgren AC, Tengborn L, Nilsson IM. Factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339 (8808) 1550
30 Addiego Jr JE-J, Gomperts E, Liu SL , et al. Treatment of hemophilia A with a highly purified factor VIII concentrate prepared by anti-FVIIIc immunoaffinity chromatography. Thromb Haemost 1992; 67 (1) 19-27
31 de Biasi R, Rocino A, Papa ML, Salerno E, Mastrullo L, De Blasi D. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost 1994; 71 (5) 544-547
32 Yee TT, Williams MD, Hill FG, Lee CA, Pasi KJ. Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product. Thromb Haemost 1997; 78 (3) 1027-1029
33 ElAlfy MS, Tantawy AA, Ahmed MH, Abdin IA. Frequency of inhibitor development in severe haemophilia A children treated with cryoprecipitate and low-dose immune tolerance induction. Haemophilia 2000; 6 (6) 635-638
34 Klukowska A, Komrska V, Jansen M, Laguna P. Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study. Haemophilia 2011; 17 (3) 399-406
35 Mauser-Bunschoten EP, van der Bom JG, Bongers M , et al. Purity of factor VIII product and incidence of inhibitors in previously untreated patients with haemophilia A. Haemophilia 2001; 7 (4) 364-368
36 Kreuz W, Ettingshausen CE, Zyschka A , et al. Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products. Semin Thromb Hemost 2002; 28 (3) 285-290
37 Gouw SC, van der Bom JG, Ljung R , et al; PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368 (3) 231-239
38 Bray GL, Gomperts ED, Courter SG , et al; The Recombinate Study Group. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. Blood 1994; 83 (9) 2428-2435
39 Gruppo R, Chen H, Schroth P, Bray GL. Safety and immunogenicity of recombinant factor VIII (Recombinate) in previously untreated patients: a 7.3 year update. Haemophilia 1998; 4: 228 (abstract no. 291, XXIII Congress of the WFH, The Hague).
40 Goodeve AC, Williams I, Bray GL, Peake IR ; Recombinate PUP Study Group. Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (Recombinate). Thromb Haemost 2000; 83 (6) 844-848
41 Rothschild C, Laurian Y, Satre EP , et al. French previously untreated patients with severe hemophilia A after exposure to recombinant factor VIII : incidence of inhibitor and evaluation of immune tolerance. Thromb Haemost 1998; 80 (5) 779-783
42 Lusher JM, Arkin S, Abildgaard CF, Schwartz RS ; Kogenate Previously Untreated Patient Study Group. 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 (7) 453-459
43 Lusher J, Abildgaard C, Arkin S , et al. Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation. J Thromb Haemost 2004; 2 (4) 574-583
44 Yoshioka A, Fukutake K, Takamatsu J, Shirahata A ; Kogenate Post-Marketing Surveillance Study Group. Clinical evaluation of a recombinant factor VIII preparation (Kogenate) in previously untreated patients with hemophilia A. Int J Hematol 2003; 78 (5) 467-474
45 Giangrande PLF ; KOGENATE Bayer Study Group. Safety and efficacy of KOGENATE Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs). Haemophilia 2002; 8 (Suppl. 02) 19-22
46 Kreuz W, Gill JC, Rothschild C , et al; International Kogenate-FS Study Group. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of an international clinical investigation. Thromb Haemost 2005; 93 (3) 457-467
47 Oldenburg J, Ivaskevicius V, Schröder J, Müller CR, Ganguly A. Genetic background and inhibitors in previously untreated or minimally treated young patients with severe haemophilia A treated with sucrose-formulated recombinant factor VIII. Thromb Haemost 2006; 95 (5) 903-905
48 Musso R, Santagostino E, Faradji A , et al; KOGENATE Bayer European PMS Study Group. Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: experience in the standard clinical setting. Thromb Haemost 2008; 99 (1) 52-58
49 Lusher JM, Lee CA, Kessler CM, Bedrosian CL ; ReFacto Phase 3 Study Group. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 9 (1) 38-49
50 Lusher JM, Roth DA. The safety and efficacy of B-domain deleted recombinant factor VIII concentrates in patients with severe haemophilia A: an update. Haemophilia 2005; 11 (3) 292-293
51 Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Semin Hematol 2001; 38 (2) (Suppl. 04) 52-59
52 Pollmann H, Externest D, Ganser A , et al. Efficacy, safety and tolerability of recombinant factor VIII (REFACTO) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria. Haemophilia 2007; 13 (2) 131-143
53 Auerswald G, Thompson AA, Recht M , et al. Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A. Thromb Haemost 2012; 107 (6) 1072-1082
54 Schwarzinger I, Pabinger I, Korninger C , et al. Incidence of inhibitors in patients with severe and moderate hemophilia A treated with factor VIII concentrates. Am J Hematol 1987; 24 (3) 241-245
55 McMillan CW, Shapiro SS, Whitehurst D, Hoyer LW, Rao AV, Lazerson J. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988; 71 (2) 344-348
56 Schwartz RS, Abildgaard CF, Aledort LM , et al. Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. recombinant Factor VIII Study Group. N Engl J Med 1990; 323 (26) 1800-1805
57 Rasi V, Ikkala E. Haemophiliacs with factor VIII inhibitors in Finland: prevalence, incidence and outcome. Br J Haematol 1990; 76 (3) 369-371
58 Fukui H, Yoshioka A, Shima M , et al. Clinical evaluation of recombinant human factor VIII (BAY w 6240) in the treatment of hemophilia A. Int J Hematol 1991; 54 (5) 419-427
59 Fukui H, Mori K, Ishikawa M , et al. A long-term, multi-center clinical study of recombinant human factor VIII (BAY w 6240) in the treatment of hemophilia A. . [in Japanese] Nihon Yuketsu Gakkai Zasshi. 1991; 37: 593-604
60 Lorenzo JI, Garcia R, Molina R. Factor VIII and Factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 1550-1551
61 Addiego J, Kasper C, Abildgaard C , et al. Inhibitors in factor VIII deficient hemophilia: Comparison of frequency based upon treatment. Blood 1992; 80 (Suppl. 01) 231 (Abstract)
62 Sultan Y ; French Hemophilia Study Group. Prevalence of inhibitors in a population of 3435 hemophilia patients in France. Thromb Haemost 1992; 67 (6) 600-602
63 Rosendaal FR, Nieuwenhuis HK, van den Berg HM , et al; Dutch Hemophilia Study Group. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Blood 1993; 81 (8) 2180-2186
64 Peerlinck K, Rosendaal FR, Vermylen J. Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate. Blood 1993; 81 (12) 3332-3335
65 Addiego J, Kasper C, Abildgaard C , et al. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993; 342 (8869) 462-464
66 Peerlinck K, Arnout J, Gilles JG, Saint-Remy JM, Vermylen J. 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 (2) 115-118
67 Schimpf K, Schwarz P, Kunschak M. Zero incidence of inhibitors in previously untreated patients who received intermediate purity factor VIII concentrate or factor IX complex. Thromb Haemost 1995; 73 (3) 553-555
68 Guérois C, Laurian Y, Rothschild C , et al. Incidence of factor VIII inhibitor development in severe hemophilia A patients treated only with one brand of highly purified plasma-derived concentrate. Thromb Haemost 1995; 73 (2) 215-218
69 Kamiya T, Takahashi I, Saito H. Retrospective study of inhibitor formation in Japanese hemophiliacs. Int J Hematol 1995; 62 (3) 175-181
70 White II GCII, Courter S, Bray GL, Lee M, Gomperts ED ; The Recombinate Previously Treated Patient Study Group. A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A. Thromb Haemost 1997; 77 (4) 660-667
71 Muntean W, Male C, Streif W , et al. Low inhibitor incidence in children treated with pasteurised human factor VIII. Thromb Haemost 1997; (Suppl. 01) 647 (abstract)
72 Aygören-Pürsün E, Scharrer I ; German Kogenate Study Group. A multicenter pharmacosurveillance study for the evaluation of the efficacy and safety of recombinant factor VIII in the treatment of patients with hemophilia A. Thromb Haemost 1997; 78 (5) 1352-1356
73 Lusher J, Arkin S, Abildgaard C, Hurst D. Recombinant FVIII (Kogenate) treatment of previously untreated patients (PUPs) with hemophilia A—update of safety, efficacy and inhibitor development after 7 study years. Thromb Haemost 1997; 78 (Suppl. ): 162
74 Peerlinck K, Arnout J, Di Giambattista M , et al. Factor VIII inhibitors in previously treated haemophilia A patients with a double virus-inactivated plasma derived factor VIII concentrate. Thromb Haemost 1997; 77 (1) 80-86
75 Giles AR, Rivard GE, Teitel J, Walker I. Surveillance for factor VIII inhibitor development in the Canadian Hemophilia A population following the widespread introduction of recombinant factor VIII replacement therapy. Transfus Sci 1998; 19 (2) 139-148
76 Goudemand J, D'Oiron R, Rothschild C , et al. Incidence des inhibiteurs anti-F VIII chez des patients traits par facteur VIII–LFB. Sang Thromb Vaiss 1998; 10: 77-81
77 Baglin T, Beacham E. Is a change of factor VIII product a risk factor for the development of a factor VIII inhibitor?. Thromb Haemost 1998; 80 (6) 1036-1037
78 Seremetis S, Lusher JM, Abildgaard CF, Kasper CK, Allred R, Hurst D ; The KOGENATE Study Group. Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. Haemophilia 1999; 5 (1) 9-16
79 Lusher JM, Kreuz W, Gazengel C , et al. Inhibitor formation monitoring in pediatric patients with severe hemophilia A receiving a second-generation rFVIII concentrate formulated with sucrose. Blood 1999; 94 (Suppl. 01) 237 (Abstract)
80 Rokicka-Milewska R, Klukowska A, Dreger B, Beer HJ. Incidence of factor VIII inhibitor development in previously untreated haemophilia A patients after exposure to a double virus inactivated factor VIII concentrate. Ann Hematol 1999; 78 (Suppl. 01) A10 (abstract)
81 Yee TT, Pasi KJ, Lilley PA, Lee CA. Factor VIII inhibitors in haemophiliacs: a single-centre experience over 34 years, 1964-97. Br J Haematol 1999; 104 (4) 909-914
82 Abshire TC, Brackmann HH, Scharrer I , et al. Sucrose formulated recombinant human antihemophilic factor VIII is safer and efficacious for treatment of hemophilia A in home therapy. Thromb Haemost 2000; 83: 811-816
83 Shirahata A, Fukutake K, Takamatsu J, Shima M, Yoshioka A. Pharmacokinetics, prophylactic effects, and safety of a new recombinant FVIII formulated with sucrose (BAY 14-2222) in Japanese patients with hemophilia A. Int J Hematol 2000; 72 (1) 101-107
84 Yoshioka A, Shima M, Fukutake K, Takamatsu J, Shirahata A ; Coganate FS Study Group. Safety and efficacy of a new recombinant FVIII formulated with sucrose (rFVIII-FS) in patients with haemophilia A: a long-term, multicentre clinical study in Japan. Haemophilia 2001; 7 (3) 242-249
85 Lorenzo JI, López A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113 (3) 600-603
86 Rothschild C, Scharrer I, Brackmann HH , et al. European data of a clinical trial with a sucrose formulated recombinant factor VIII in previously treated haemophilia A patients. Haemophilia 2002; 8 (Suppl. 02) 10-14
87 van der Bom JG, Mauser-Bunschoten EP, Fischer K, van den Berg HM. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003; 89 (3) 475-479
88 Gringeri A, Tagliaferri A, Tagariello G, Morfini M, Santagostino E, Mannucci P ; ReFacto-AICE Study Group. Efficacy and inhibitor development in previously treated patients with haemophilia A switched to a B domain-deleted recombinant factor VIII. Br J Haematol 2004; 126 (3) 398-404
89 Ewenstein BM, Gomperts ED, Pearson S, O'Banion ME. Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study. Haemophilia 2004; 10 (5) 491-498
90 Tarantino MD, Collins PW, Hay CR , et al; RAHF-PFM Clinical Study Group. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004; 10 (5) 428-437
91 Morado M, Villar A, Jiménez Yuste V, Quintana M, Hernandez Navarro F. Prophylactic treatment effects on inhibitor risk: experience in one centre. Haemophilia 2005; 11 (2) 79-83
92 Smith MP, Giangrande P, Pollman H, Littlewood R, Kollmer C, Feingold J ; Refacto St Louis Study Group. A postmarketing surveillance study of the safety and efficacy of ReFacto (St Louis-derived active substance) in patients with haemophilia A. Haemophilia 2005; 11 (5) 444-451
93 Kreuz W, Auerswald G, Budde U, Lenk H. The GTH-PUP-Study Group. In: Scharrer I, Schramm W, , eds. Inhibitor Development in Previously Treated Patients (PUPs) with Haemophilia A and B. A Prospective Multicentre Study of the German, Swiss and Austrian Society of Thrombosis and Haemostasis Research (GTH). 35th Haemophilia Symposium, Hamburg 2004. Heidelberg, Germany: Springer Verlag; 2005: 34-37
94 Gringeri A, Monzini M, Tagariello G, Scaraggi FA, Mannucci PM ; Emoclot15 Study Members. Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposure to a plasma-derived solvent-detergent factor VIII concentrate. Haemophilia 2006; 12 (2) 128-132
95 Goudemand J, Rothschild C, Demiguel V , et al; FVIII-LFB and Recombinant FVIII study groups. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood 2006; 107 (1) 46-51
96 Kempton CL, Soucie JM, Abshire TC. Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentrates. J Thromb Haemost 2006; 4 (12) 2576-2581
97 Gouw SC, van den Berg HM, le Cessie S, van der Bom JG. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A. J Thromb Haemost 2007; 5 (7) 1383-1390
98 Shi J, Zhao Y, Wu J, Sun J, Wang L, Yang R. Safety and efficacy of a sucrose-formulated recombinant factor VIII product for the treatment of previously treated patients with haemophilia A in China. Haemophilia 2007; 13 (4) 351-356
99 Singleton E, Smith J, Kavanagh M, Nolan B, White B. Low risk of inhibitor formation in haemophilia patients after a change in treatment from Chinese hamster ovary cell-produced to baby hamster kidney cell-produced recombinant factor VIII. Thromb Haemost 2007; 98 (6) 1188-1192
100 Chalmers EA, Brown SA, Keeling D , et al; Paediatric Working Party of UKHCDO. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007; 13 (2) 149-155
101 Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård U, van den Berg HM. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109 (11) 4693-4697
102 Delumeau JC, Ikegawa C, Yokoyama C, Haupt V. An observational study of sucrose-formulated recombinant factor VIII for Japanese patients with haemophilia A. Thromb Haemost 2008; 100 (1) 32-37
103 Rubinger M, Lillicrap D, Rivard GE , et al; Association of Hemophilia Clinic Directors of Canada. A prospective surveillance study of factor VIII inhibitor development in the Canadian haemophilia A population following the switch to a recombinant factor VIII product formulated with sucrose. Haemophilia 2008; 14 (2) 281-286
104 Boekhorst J, Lari GR, D'Oiron R , et al. Factor VIII genotype and inhibitor development in patients with haemophilia A: highest risk in patients with splice site mutations. Haemophilia 2008; 14 (4) 729-735
105 Blanchette VS, Shapiro AD, Liesner RJ , et al; rAHF-PFM Clinical Study Group. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost 2008; 6 (8) 1319-1326
106 Strauss T, Ravid B, Martinowitz U, Bashari D, Kenet G. Early exposure to recombinant factor concentrates may increase inhibitor development: a single center cohort study. Haemophilia 2008; 14 (Suppl. 02) 52 (abstract)
107 Bajwa N, Enriquez MM, Gorina E, Lemm G. Cumulative analysis of inhibitor formation in patients with haemophilia A treated with sucrose-formulated recombinant factor VIII. Haemophilia 2009; 15 (2) 597-600
108 Young JH, Liu HC, Hsueh EJ , et al. Efficacy and safety evaluation of sucrose-formulated recombinant factor VIII for Taiwanese patients with haemophilia A. Haemophilia 2009; 15 (4) 968-970
109 Recht M, Nemes L, Matysiak M , et al. Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor VIII. Haemophilia 2009; 15 (4) 869-880
110 Bidlingmaier C, Manner D, Halimeh S , et al. Influence of factor VIII products, viral inactivation and dosage regimens on meaningful inhibitor development in children with severe hemophilia A: results of a non-concurrent cohort study. J Thromb Haemost 2009; 7 (Suppl. 02) 525 (abstract)
111 Den Uijl I, Mauser-Bunschoten EP, Roosendaal G, Schutgens R, Fischer K. Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment. Haemophilia 2009; 15 (6) 1215-1218
112 Collins P, Faradji A, Morfini M, Enriquez MM, Schwartz L. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. J Thromb Haemost 2010; 8 (1) 83-89
113 Oldenburg J, Goudemand J, Valentino L , et al. Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method] demonstrates efficacy, safety and low-risk for immunogenicity in routine clinical practice. Haemophilia 2010; 16 (6) 866-877
114 Vidovic N, Musso R, Klamroth R, Enriquez MM, Achilles K. Postmarketing surveillance study of KOGENATE Bayer with Bio-Set in patients with haemophilia A: evaluation of patients' satisfaction after switch to the new reconstitution system. Haemophilia 2010; 16 (1) 66-71
115 Bacon CL, Singleton E, Brady B , et al. Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®). Haemophilia 2011; 17 (3) 407-411
116 Dmoszynska A, Kuliczkowski K, Hellmann A , et al. Clinical assessment of Optivate®, a high-purity concentrate of factor VIII with von Willebrand factor, in the management of patients with haemophilia A. Haemophilia 2011; 17 (3) 456-462
117 Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM ; ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9 (4) 700-710
118 Matysiak M, Bobrowska H, Balwierz W , et al. Clinical experience with Optivate®, high-purity factor VIII (FVIII) product with von Willebrand factor (VWF) in young children with haemophilia A. Haemophilia 2011; 17 (5) 737-742
119 Klukowska A, Windyga J, Batorova A. Clinical efficacy of a novel VWF-containing FVIII concentrate, Wilate(®), in the prophylaxis and treatment of bleeding episodes in previously treated haemophilia A patients. Thromb Res 2011; 127 (3) 247-253
120 Zhang L, Zhao Y, Sun J, Wang X, Yu M, Yang R. Clinical observation on safety and efficacy of a plasma- and albumin-free recombinant factor VIII for on-demand treatment of Chinese patients with haemophilia A. Haemophilia 2011; 17 (2) 191-195
121 Maclean PS, Richards M, Williams M , et al; Paediatric Working Party of UKHCDO. Treatment related factors and inhibitor development in children with severe haemophilia A. Haemophilia 2011; 17 (2) 282-287
122 Strauss T, Lubetsky A, Ravid B , et al. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study. Haemophilia 2011; 17 (4) 625-629
123 Shirahata A, Fukutake K, Higasa S , et al; Study Group on Factors Involved in Formation of Inhibitors to Factor VIII and IX Preparations. An analysis of factors affecting the incidence of inhibitor formation in patients with congenital haemophilia in Japan. Haemophilia 2011; 17 (5) 771-776
124 Mancuso ME, Mannucci PM, Rocino A, Garagiola I, Tagliaferri A, Santagostino E. Source and purity of factor VIII products as risk factors for inhibitor development in patients with hemophilia A. J Thromb Haemost 2012; 10 (5) 781-790
125 Pollmann H, Klamroth R, Vidovic N , et al. Prophylaxis and quality of life in patients with hemophilia A during routine treatment with ADVATE [antihemophilic factor (recombinant), plasma/albumin-free method] in Germany: a subgroup analysis of the ADVATE PASS post-approval, non-interventional study. Ann Hematol 2013; 92 (5) 689-698
126 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. 05) 65-68

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