Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Aug 21;8(8):CD003429.
doi: 10.1002/14651858.CD003429.pub5.

Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously untreated or minimally treated children with hemophilia A or B

Elham Razmpoosh  1 , Omotola O Olasupo  1 , Mihir Bhatt  2 , Davide Matino  3 , Alfonso Iorio  1
Affiliations
Review

Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously untreated or minimally treated children with hemophilia A or B

Elham Razmpoosh et al. Cochrane Database Syst Rev. .

Abstract

Background: The hallmark of severe hemophilia is recurrent bleeding into joints and soft tissues with progressive joint damage. The effect of early adoption of prophylactic regimens in children with severe hemophilia, although a promising approach for preventing joint damage, is yet to be systematically reviewed. This review is an update of a previous review, which has now been split to focus on children before the onset of progressive joint damage.

Objectives: To assess the benefits and harms of clotting factor concentrate prophylaxis in the management of previously untreated or minimally treated children with hemophilia A or B with no proven joint damage.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, CENTRAL, MEDLINE, Embase, trial registries, and handsearched relevant journals and reference lists of relevant articles. The last search for the Group's Coagulopathies Trials Register was 20 November 2024.

Selection criteria: We included randomized controlled trials and quasi-randomized controlled trials evaluating prophylactic use of factor concentrates in children with severe hemophilia A or hemophilia B not yet exposed or minimally exposed to clotting factor concentrates with no proven joint damage. Trials were eligible if they included children aged from birth to six years, and children aged over six years to 10 years if they had not received factor VIII/factor IX or showed no clinical or radiologic signs of arthropathy or target joints.

Data collection and analysis: Two review authors independently assessed studies for eligibility, assessed risk of bias, and extracted data. The primary outcomes were annualized joint bleeding rates, joint function protection, and quality of life. The secondary outcomes included annualized overall bleeding rates, radiologic joint score, clotting factor usage, and adverse events. We used the Cochrane RoB 1 tool and a random-effects model in the meta-analyses, and assessed the certainty of the evidence using GRADE.

Main results: We included three studies with 126 assessed children with hemophilia A. The mean age at study entry ranged from 1.6 years to 7.9 years. Each study compared a clotting factor prophylaxis regimen with episodic treatment. No studies compared clotting factor concentrates with placebo or alternative prophylactic regimens. Clotting factor prophylaxis regimen compared to episodic treatment For the primary outcome of annualized joint bleeding rates, clotting factor prophylaxis may reduce joint bleeds compared to episodic treatment (mean difference (MD) -4.22, 95% confidence interval (CI) -5.26 to -3.17; 3 trials, 126 participants; low-certainty evidence). Pooled analysis including two trials during four to seven years of follow-up showed 85.7% of children not having joint damage in the prophylaxis group compared to 58.7% of children in the episodic group. Prophylaxis may not reduce the number of participants with joint damage compared to the episodic group (RR 1.70, 95% CI 0.57 to 5.09; P = 0.34; 2 trials, 95 participants; low-certainty evidence). Bleed prevention using clotting factor concentrates may not improve quality of life compared to episodic treatment measured using the Haemophilia Quality of Life (Haemo-QoL) over two to 163 months, but the evidence is very uncertain (MD 1.61, 95% CI -4.44 to 7.66; 2 trials, 105 participants; very low-certainty evidence). For the secondary outcome of annualized overall bleeding events, pooled effect estimates showed that the use of a clotting factor prophylaxis regimen may reduce the number of bleeds per year compared to episodic treatment (MD -9.55, 95% CI -14.92 to -4.17; 3 trials, 126 participants; low-certainty evidence). There is likely no evidence of a difference between the groups in radiologic joint score measured using the Pettersson scale over a two- to 163-month period (MD -0.48, 95% CI -1.43 to 0.47; 2 trials, 61 participants; moderate-certainty evidence). Clotting factor prophylaxis may increase the number of infusions per child compared to episodic treatment, but the evidence is very uncertain (MD 7.72 infusions/month, 95% CI 4.36 to 11.07; 2 trials, 86 participants; very low-certainty evidence). There may be no difference in adverse events, including the development of inhibitors and infections, as well as hospitalizations between groups. The overarching certainty of the evidence was moderate to very low due to inherent biases, resulting from lack of blinding of study participants, attrition, heterogeneity, and indirectness of population characteristics, which may change our conclusions.

Authors' conclusions: There is evidence from randomized controlled trials that prophylaxis confers some protection against joint bleeds and overall bleeds. More conclusive evidence from well-designed studies is needed on the effect of bleed prevention using clotting factors and newer therapies on joint function protection in children with no signs of an onset of joint damage.

PubMed Disclaimer

Conflict of interest statement

ER: none.

OO: none.

MB: none.

DM is a consultant and has held grants and contracts from the following organizations: Novo Nordisk (Independent Contractor – Consultant), Bayer (Independent Contractor – Consultant), PFIZER CANADA INC. (grant/contract), Bayer (grant/contract), Octapharma USA, Inc. (Independent Contractor – Consultant), Sanofi and Genzyme US Companies (Independent Contractor – Consultant), Spark Therapeutics, Inc. (grant/contract), Novo Nordisk (grant/contract), SANOFI US SERVICES INC. (grant/contract), PFIZER CANADA INC (Independent Contractor – Consultant).

AI is a Hematology Consultant, Hamilton Health Sciences/McMaster University and is/previously held a Cochrane editorial role for the Cystic Fibrosis and Genetic Disorders Review group and Prognosis Methods group, but had no role in the editorial processing of this review.

Update of

  • doi: 10.1002/14651858.CD003429.pub4

References

References to studies included in this review

Gringeri 2011 {published data only}
    1. Gringeri A, Lundin B, Mackensen S, Mantovani LG, Mannucci PM, The ESPRIT study group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). Journal of Thrombosis and Haemostasis: JTH 2011;9(4):700-10. [DOI: 10.1111/j.1538-7836.2011.04214.x] - DOI - PubMed
Manco‐Johnson 2007 {published data only}
    1. Hacker MR, Page JH, Shapiro AD, Rich-Edwards JW, Manco-Johnson MJ. Central venous access device infections in children with hemophilia: a comparison of prophylaxis and episodic therapy. Journal of Pediatric Hematology/Oncology 2007;29(7):458-64. [DOI: 10.1097/MPH.0b013e318068b1d6] - DOI - PubMed
    1. Manco-Johnson MJ, Abshire TC, Brown D, Buchanan GR, Cohen AR, DiMichele D, et al. Initial results of a randomized, prospective trial of prophylaxis to prevent joint disease in young children with factor VIII (FVIII) deficiency. Blood 2005;106(Suppl):Abstract 3.
    1. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. New England Journal of Medicine 2007;357(6):535-44. - PubMed
    1. Manco-Johnson MJ, Blanchette VS. North American prophylaxis studies for persons with severe haemophilia: background, rationale and design. Haemophilia 2003;9(Suppl 1):44-9. [DOI: 10.1046/j.1365-2516.9.s1.15.x] - DOI - PubMed
    1. Manco-Johnson MJ, Manco-Johnson ML, Blades TA, Funk S, Lane H, McRedmond K, et al. Long-term orthopedic effects of delaying prophylaxis in severe hemophilia A until age 6 years: results of the Joint Outcome Study Continuation (JOSc). Blood 2013;122(21):210. [DOI: 10.1182/blood.V122.21.210.210] - DOI
Verma 2016 {published data only}
    1. Verma S, Dutta T, Mahadevan S, Nalini P, Biswal N, Basu D, et al. Low-dose factor VIII prophylaxis in children with severe hemophilia. Haemophilia 2014;20:95. [DOI: 10.1111/hae.12400] - DOI - PubMed
    1. Verma SP, Dutta TK, Mahadevan S, Nalini P, Basu D, Biswal N, et al. A randomized study of very low-dose factor VIII prophylaxis in severe haemophilia – a success story from a resource limited country. Haemophilia 2016;22(3):342-8. [DOI: 10.1111/hae.12838] - DOI - PubMed
    1. Verma SP, Dutta TK, Mahavevan S, Nalini P, Biswal N, Basu D, et al. Low dose factor VIII prophylaxis in children with severe hemophilia. Indian Journal of Hematology & Blood Transfusion 2013;29(4):345. [DOI: 10.1007/s12288-013-0302-z] - DOI

References to studies excluded from this review

Aronstam 1976 {published data only}
    1. Aronstam A, Arblaster PG, Rainsford SG, Turk P, Slattery M, Alderson MR, et al. Prophylaxis in haemophilia: a double-blind controlled trial. British Journal of Haematology 1976;33(1):81-90. [DOI: 10.1111/j.1365-2141.1976.tb00973.x] - DOI - PubMed
Bertolet 2020 {published data only}
    1. Bertolet M, Brooks MM, Ragni MV. The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia. Blood Advances 2020;4(21):5433-41. [DOI: 10.1182/BLOODADVANCES.2020002789] - DOI - PMC - PubMed
Bray 1994 {published data only}
    1. Bray GL, Gomperts ED, Courter S, Gruppo R, Gordon EM, Manco-Johnson M, et al. A multicenter study of recombinant factor VIII (Recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 1994;83(9):2428-35. - PubMed
Carcao 2023 {published data only}
    1. Carcao M, Chan AK, Wheeler AP, Nielsen PH, Holst H. Neurocognitive and neurological outcomes in children with hemophilia B are unaffected by long-term exposure to nonacog beta pegol (N9-GP). American Journal of Hematology 2023;98(Suppl 1):E17-8. [DOI: 10.1002/ajh.26841] - DOI
CCTRI/2009/091/001059 {published data only}
    1. CCTRI/2009/091/001059. Research trial to study inhibitor development in previously untreated or minimally exposed children to two different commercially available types of factor VIII. https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2009/091/001059 (first approved 9 September 2009).
Chakraborty 2018 {published data only}
    1. Chakraborty J, Bhattacharyya M, Sankar RS. Effect of low dose prophylaxis versus episodic treatment on joint events in severe hemophilia A patients above 2 years: a randomized open label pilot study in Eastern India. Indian Journal of Hematology & Blood Transfusion 2018;34(1):68.
Chowdary 2013 {published data only}
    1. Chowdary P, Friedrich U, Lethagen S, Angchaisuksiri P. A new treatment concept for haemophilia: safety, pharmacokinetics and pharmacodynamics of single i.v. and s.c. doses of a monoclonal anti-TFPI antibody in healthy males and haemophilia subjects. Journal of Thrombosis and Haemostasis: JTH 2013;11(Suppl 2):460.
Chowdary 2015 {published data only}
    1. Chowdary P, Kearney S, Yee D, Meunier J, Slothuus U, Hoxer CS. Improved health-related quality of life (QoL) of haemophilia B patients treated with a weekly 40 IU kg-1 dose of a new long-acting recombinant factor IX (FIX) product, nonacog beta pegol. Journal of Thrombosis and Haemostasis: JTH 2015;13:229. [DOI: 10.1111/jth.12993] - DOI
Chozie 2018 {published data only}
    1. Chozie N, Primacakti F, Tulaar A, Setiabudy R, Prasetyo M, Gatot D. Low-dose prophylaxis versus on-demand treatment in Indonesian children with severe hemophilia A: an interim report. Haemophilia 2018;24:94. [DOI: 10.1111/hae.13478] - DOI - PubMed
Chozie 2019 {published data only}
    1. Chozie NA, Primacakti F, Gatot D, Setiabudhy RD, Tulaar AB, Prasetyo M. Comparison of the efficacy and safety of 12-month low-dose factor VIII tertiary prophylaxis vs on-demand treatment in severe haemophilia A children. Haemophilia 2019;25(4):633-9. [DOI: 10.1111/hae.13770] - DOI - PubMed
Courter 2001 {published data only}
    1. Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Seminars in Hematology 2001;38(2 Suppl 4):52-9. [DOI: 10.1016/s0037-1963(01)90109-x] - DOI - PubMed
CTRI/2014/12/005277 {published data only}
    1. CTRI/2014/12/005277. A study to assess whether factor VIII given once a week will prevent major bleeds in severe hemophilia A. https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2014/12/005277 (first approved 20 February 2014).
CTRI/2018/08/015235 {published data only}
    1. CTRI/2018/08/015235. Prophylactic therapy in hemophilia. https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2018/08/015235 (first approved 17 October 2016).
Djunic 2014 {published data only}
    1. Djunic I, Dopsaj V, Miljic P, Suvajdzic-Vukovic N, Virijevic M, Novkovic A, et al. Correlation between oxidative stress and biomarkers of joint damage in patients with severe haemophilia treated by different prophylaxis regimens. Haematologica 2014;99(Suppl 1):209.
Dzinaj 1996 {published data only}
    1. Dzinaj T, Funk M, Schmidt H, Böttger S, Gngör T, Klarmann D, et al. Radiological score in paediatric haemophilic patients with early and late onset of factor VIII – prophylaxis. Thrombosis and Haemostasis 1996;76(4):630-1. - PubMed
EUCTR2006‐005575‐17‐AT {published data only}
    1. EUCTR2006-005575-17-AT. A study to compare the difference in effect between treating bleeds after they occur or giving preventative treatment on an ongoing basis, also to determine levels of factor VIII in the blood following treatment in children with hemophilia A. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2006-005575-17-AT (first registered 11 June 2008).
Feldman 2006 {published data only}
    1. Feldman BM, Pai M, Rivard GE, Israels S, Poon MC, Demers C, et al. Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. Journal of Thrombosis and Haemostasis: JTH 2006;4(6):1228-36. [DOI: 10.1111/j.1538-7836.2006.01953.x] - DOI - PubMed
Gomber 2022 {published data only}
    1. Gomber S, Singhal G, Dewan P, Upreti L, Sikka M. Twice weekly vs. thrice weekly low-dose prophylactic factor VIII therapy in children with hemophilia A: an open label randomized trial. Journal of Tropical Pediatrics 2022;68(3):fmac039. [DOI: 10.1093/tropej/fmac039] - DOI - PubMed
Karimi 2015 {published data only}
    1. Karimi M, Eshghi P, Haghpanah S, Zahedi Z, Habibpanah B. Efficacy and safety of prophylaxis in previously untreated patients with severe hemophilia A in Iran. Haematologica 2015;100:409. - PubMed
Karimi 2018 {published data only}
    1. Karimi M, Eshghi P, Safarpour MM, Haghpanah S, Meshksar A, Zahedi Z, et al. Modified primary prophylaxis in previously untreated patients with severe hemophilia A in Iran. Journal of Pediatric Hematology/Oncology 2018;40(3):188-91. [DOI: 10.1097/MPH.0000000000001082] - DOI - PubMed
Kenet 2023 {published data only}
    1. Kenet G, Young G, Chuansumrit A, Matsushita T, Yadav V, Zak M, et al. The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results. Journal of Thrombosis and Haemostasis: JTH 2023;21(11):3109-16. [DOI: 10.1016/j.jtha.2023.07.030] - DOI - PubMed
Kisker 2003 {published data only}
    1. Kisker CT, Eisberg A, Schwartz B. Prophylaxis in factor IX deficiency product and patient variation. Haemophilia 2003;9(3):279-84. [DOI: 10.1046/j.1365-2516.2003.00751.x] - DOI - PubMed
Kreuz 1998 {published data only}
    1. Kreuz W, Escuriola-Ettingshausen C, Funk M, Schmidt H, Kornhuber B. When should prophylactic treatment in patients with haemophilia A and B start? The German experience. Haemophilia 1998;4:413-7. [DOI: 10.1046/j.1365-2516.1998.440413.x] - DOI - PubMed
Kreuz 2005 {published data only}
    1. Kreuz W, Gill JC, Rothschild C, Manco-Johnson MJ, Lusher JM, Kellermann E, et al. 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. Thrombosis and Haemostasis 2005;93(3):457-67. [DOI: 10.1160/th03-10-0643] - DOI - PubMed
Ledger 2016 {published data only}
    1. Ledger KS, Bensen-Kennedy D, Backman N, Veldman A. Clinical decision making is effective in reducing bleeding rates without the need to monitor FVIII trough levels to patients with severe hemophilia A receiving prophylaxis with rVIII-single chain. 62nd Annual Meeting of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis; 2016 May 25-28; Montpellier, France. [DOI: 10.1111/jth.13325] - DOI
Lemons 2022 {published data only}
    1. Lemons R, Wang M, Curtin J, Huth-Kuehne A, Lepatan L, Male C, et al. Safety and efficacy of recombinant factor IX fusion protein (rIX-FP) in previously untreated patients with hemophilia B. Research and Practice in Thrombosis and Haemostasis 2022;6. [DOI: 10.1002/rth2.12787] - DOI - PMC - PubMed
Liesner 2016 {published data only}
    1. Liesner R, Abashidze M, Aleinikova O, Altisent C, Belletrutti MJ, Borel-Derlon A, et al. Inhibitor development in previously untreated patients with severe hemophilia A treated with Nuwiq, a new generation recombinant FVIII of human origin. Blood 2016;128:22.
Lundin 2015 {published data only}
    1. Lundin B, Hong W, Raunig D, Engelen S, Peterfy C, Werk M, et al. 3-year analyses from spinart: patient-and joint-level changes in magnetic resonance imaging scores with Bayer's sucrose-formulated recombinant factor VIII (RFVIIIFS) in adolescents and adults previously treated on demand. Haemophilia 2015;21(Suppl 2):40-1. [DOI: 10.1111/hae.12625] - DOI
Mahlangu 2021 {published data only}
    1. Mahlangu J, Levy H, Lee M, Del Greco F. Efficacy and safety of subcutaneous prophylaxis with dalcinonacog alfa in adults with haemophilia B. Haemophilia 2021;27(4):574-80. [DOI: 10.1111/hae.14315] - DOI - PMC - PubMed
Male 2023 {published data only}
    1. Male C, Konigs C, Dey S, Matsushita T, Millner AH, Zak M, et al. The safety and efficacy of N8-GP (Turoctocog alfa pegol) in previously untreated pediatric patients with hemophilia A. Blood Advances 2023;7(4):620-9. [DOI: 10.1182/bloodadvances.2022007529] - DOI - PMC - PubMed
Martinowitz 2011 {published data only}
    1. Martinowitz U, Bjerre J, Brand B, Klamroth R, Misgav M, Morfini M, et al. Bioequivalence between two serum-free recombinant factor VIII preparations (N8 and ADVATE) – an open-label, sequential dosing pharmacokinetic study in patients with severe haemophilia A. Haemophilia 2011;17(6):854-9. - PubMed
Morfini 1976 {published data only}
    1. Morfini M, Mannucci PM, Mariani G, Panicucci F, Petrucci F, Baicchi U, et al. Evaluation of prophylactic replacement therapy in haemophilia B. Scandinavian Journal of Haematology 1976;16(1):41-7. [DOI: 10.1111/j.1600-0609.1976.tb01115.x] - DOI - PubMed
Mullins 2019 {published data only}
    1. Mullins E, Kefurt C, Engl W, Tangada S. Design of a phase 3, prospective, multicenter, open-label study of safety and hemostatic efficacy of rurioctocog alfa pegol in previously untreated patients <6 years of age with severe hemophilia A. Haemophilia 2019;25(Suppl 1):83. [DOI: 10.1111/hae.13666] - DOI
Nolan 2020 {published data only}
    1. Nolan B, Klukowska A, Shapiro A, Rauch A, Recht M, Ragni M, et al. Final results of pups B-long study: evaluating safety and efficacy of rFIXFc in previously untreated patients with haemophilia B. Research and Practice in Thrombosis and Haemostasis 2020;4(Suppl 1):479. [DOI: 10.1002/rth2.12393] - DOI - PMC - PubMed
Peyvandi 2016 {published data only}
    1. Elalfy MS, Elbarbary NS, Andrawes NG, Abd El-Ghany S. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. QJM: Monthly Journal of the Association of Physicians 2018;111:i63.
    1. Peyvandi F, Mannucci PM, Garagiola I, The SIPPET Study C. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. New England Journal of Medicine 2016;374(21):2054-64. [DOI: 10.1056/NEJMoa1516437] - DOI - PubMed
Pocoski 2014 {published data only}
    1. Pocoski J, Kim B, Humphries TJ, Hong W. Regional differences in patient-reported outcomes in a study of adult prophylaxis versus on-demand treatment with Bayer's sucrose-formulated recombinant factor VIII: 3-year data from Spinart. Blood 2014;124:21.
Pompa 2015 {published data only}
    1. Pompa MT, Iosava G, Khayat C, Romashevskaya I, Aleinikova O, Stasyshyn O, et al. A phase III, open-label, multicentre study to evaluate efficacy and safety of a plasma-derived von Willebrand factor/factor VIII concentrate in pediatric subjects with hemophilia A (Swiftly-HA study). Journal of Thrombosis and Haemostasis: JTH 2015;13:841. [DOI: 10.1111/jth.12993] - DOI
Powell 2013 {published data only}
    1. Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. New England Journal of Medicine 2013;369(24):2313-23. [DOI: 10.1056/NEJMoa1305074] - DOI - PubMed
Ragni 2011 {published data only}
    1. Ragni M, Kessler C, Fogarty P, Josephson N, Neff A, Raffini L. Phase III randomized, controlled trial of pre-emptive vs. standard prophylaxis to prevent inhibitor formation in children with severe hemophilia A: the INHIBIT study. Haemophilia 2011;17(3):563. [DOI: 10.1111/j.1365-2516.2011.02550.x] - DOI
Reding 2015 {published data only}
    1. Reding MT, Kempton CL, Funk S, Engelen S, Walker D, Hong W. Spinart trial 3-year results with Bayer's sucrose formulated recombinant factor VIII: relationship between bleeding frequency and joint health in adults with severe hemophilia A using prophylaxis. Journal of Thrombosis and Haemostasis: JTH 2015;13(Suppl 2):132. [DOI: 10.1111/jth.12993] - DOI
Rendo 2012 {published data only}
    1. Rendo P, Barrette-Grischow MK, Smith L, Korth-Bradley JM, Charnigo R, Shafer FE. Evaluation of two secondary prophylaxis regimens of recombinant factor ix(r-ix) in moderately severe to severe (fix <=2%) hemophilia B patients. Blood 2012;120(21):4628.
Rusen 2018 {published data only}
    1. Rusen L, Kavakli K, Korth-Bradley J, Huard F, Rendo P, Fuiman J, et al. Clinical experience with moroctocog alfa (AF-CC) in younger paediatric patients with severe haemophilia A: two open-label studies. Haemophilia 2018;24(4):604-10. [DOI: 10.1111/hae.13466] - DOI - PubMed
Schimpf 1977 {published data only}
    1. Schimpf K, Fischer B, Rothmann P. Hemophilia A prophylaxis with factor VIII concentrate in a home-treatment program: a controlled study. Scandinavian Journal of Haematology. Supplementum 1977;30:79-80. [DOI: 10.1111/j.1600-0609.1977.tb01528.x] - DOI - PubMed
Schobess 2008 {published data only}
    1. Schobess R, Kurnik K, Friedrichs F, Halimeh S, Krümpel A, Bidlingmaier C, et al. Effects of primary and secondary prophylaxis on the clinical expression of joint damage in children with severe haemophilia A. Results of a multicenter non-concurrent cohort study. Thrombosis and Haemostasis 2008;99(1):71-6. [DOI: 10.1160/th07-06-0417] - DOI - PubMed
Shafer 2014 {published data only}
    1. Shafer F, Smith L, Vendetti N, Rendo P, Carr M. Lack of seasonal variation in bleeding and patient-assessed pain patterns in patients with haemophilia B receiving on-demand therapy. Haemophilia 2014;20(3):349-53. [DOI: 10.1111/hae.12305] - DOI - PMC - PubMed
Shapiro 2005 {published data only}
    1. Shapiro AD, Di Paola J, Cohen A, Pasi KJ, Heisel MA, Blanchette VS, et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B. Blood 2005;105(2):518-25. [DOI: 10.1182/blood-2004-06-2283] - DOI - PubMed
Sidonio 2021a {published data only}
    1. Sidonio RF, Knoll C, Peyvandi F, Stasyshyn O, Antmen AB, Yeoh SL, et al. Immunogenicity, efficacy and safety of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from an open-label multicenter clinical trial. Blood 2021;138(Suppl 1):3184. [DOI: 10.1182/blood-2021-146126] - DOI
Sidonio 2021b {published data only}
    1. Sidonio RF, Thompson AA, Peyvandi F, Albayrak C, Leng Yeoh S, Lam J, et al. Rurioctocog alfa pegol use in immune tolerance induction: interim results from an open-label multicenter clinical trial in previously untreated patients with severe hemophilia A. Blood 2021;138(Suppl 1):3185. [DOI: 10.1182/blood-2021-146143] - DOI
Sidonio 2023 {published data only}
    1. Sidonio RF, Thompson AA, Peyvandi F, Stasyshyn O, Yeoh SL, Sosothikul D, et al. Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study. Expert Review of Hematology 2023;16(10):793-801. [DOI: 10.1080/17474086.2023.2247160] - DOI - PubMed
Skotnicki 2016 {published data only}
    1. Skotnicki A, Lissitchkov TJ, Mamonov V, Buevich E, Kuliczkowski K, Goranov S, et al. Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO) in subjects with haemophilia A (SWIFT-HA study). Thrombosis Research 2016;137:119-25. [DOI: 10.1016/j.thromres.2015.10.014] - DOI - PubMed
Stasyshyn 2017 {published data only}
    1. Stasyshyn O, Djambas KC, Iosava G, Ong J, Abdul Karim F, Fischer K, et al. Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial. Journal of Thrombosis and Haemostasis: JTH 2017;15(4):636-44. [DOI: 10.1111/jth.13647] - DOI - PubMed
Tagliaferri 2015 {published data only}
    1. Tagliaferri A, Feola G, Molinari AC, Santoro C, Rivolta GF, Cultrera DB, et al. Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study. Thrombosis and Haemostasis 2015;114(1):35-45. [DOI: 10.1160/TH14-05-0407] - DOI - PubMed
Taki 2019 {published data only}
    1. Taki M, Fukutake K, Matsushita T, Nogami K, Shima M, Yoshioka A, et al. Inhibitor development, safety, and efficacy of Advate(®) in previously untreated patients with hemophilia A in a postmarketing surveillance in Japan. International Journal of Hematology 2019;109(1):70-8. [DOI: 10.1007/s12185-018-2499-y] - DOI - PubMed
Tehrani 2012 {published data only}
    1. Tehrani TS, Faranoush M, Ravanbod R, Ala F. Tailored primary prophylaxis with dose-escalation in Iranian hemophilia A. Haemophilia 2012;18:164. [DOI: 10.1111/j.1365-2516.2012.02820.x] - DOI
Valentino 2011 {published data only}
    1. Valentino LA, Plushch O, Rusen L, Andreeva T, Elezovic I, Charnigo R, et al. A multicenter, open-label study to compare on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in subjects with hemophilia B. Journal of Thrombosis and Haemostasis: JTH 2011;9(Suppl 2):357. [DOI: 10.1111/j.1538-7836.2011.04380_2.x] - DOI
Valentino 2014 {published data only}
    1. Valentino LA, Rusen L, Elezovic I, Smith LM, Korth-Bradley JM, Rendo P. Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects. Haemophilia 2014;20(3):398-406. [DOI: 10.1111/hae.12344] - DOI - PubMed
van den Berg 2001 {published data only}
    1. den Berg HM, Fischer K, Mauser-Bunschoten EP, Beek FJ, Roosendaal G, Bom JG, et al. Long-term outcome of individualized prophylactic treatment of children with severe haemophilia. British Journal of Haematology 2001;112(3):561-5. [DOI: 10.1046/j.1365-2141.2001.02580.x] - DOI - PubMed
Vdouin 2011 {published data only}
    1. Vdouin VV, Andreeva TA, Chernoua TA, Perina FG, Shiller EE, Svirin PV, et al. Prophylaxis with once, twice or three-times weekly dosing of rFVIII-FS prevents joint bleeds in a previously treated pediatric population with moderate/severe hemophilia A. Journal of Coagulation Disorders 2011;3(1):1-8.
Walter 2013 {published data only}
    1. Walter O, Liesner R, Jansen M, Knaub S. Clinical study to investigate the immunogenicity, efficacy and safety of treatment with human-cl rhFVIII in previously untreated patients with severe haemophilia A. Haemophilia 2013;19:75. [DOI: 10.1111/hae.12083] - DOI
Wu 2014 {published data only}
    1. Wu R, Sun J, Xiao J, Zhao Y, Yang R, Hu Y, et al. A quality of life study (CHO-KLAT) of boys with severe hemophilia A in China: a comparison of on-demand to short-term prophylaxis. Haemophilia 2014;20(Suppl 3):97. [DOI: 10.1111/hae.12400] - DOI
Wu 2020 {published data only}
    1. Wu R, Sun J, Xu W, Hu Q, Li W, Xiao J, et al. Safety and efficacy of Turoctocog alfa in the prevention and treatment of bleeding episodes in previously treated patients from China with severe hemophilia A: results from the guardian 7 trial. Therapeutics and Clinical Risk Management 2020;16:567-78. [DOI: 10.2147/TCRM.S243146] - DOI - PMC - PubMed
Xi 2022 {published data only}
    1. Xi Y, Jin C, Liu W, Zhou H, Wang Z, Zhou R, et al. Efficacy, safety and bioequivalence of the human-derived B-domain-deleted recombinant factor VIII TQG202 for prophylaxis in severe haemophilia A patients. Haemophilia 2022;28(6):e219-27. [DOI: 10.1111/hae.14652] - DOI - PMC - PubMed
Yaish 2020 {published data only}
    1. Yaish H, Matsushita T, Belhani M, Jimenez-Yuste V, Kavakli K, Korsholm L, et al. Safety and efficacy of Turoctocog alfa in the prevention and treatment of bleeds in previously untreated paediatric patients with severe haemophilia A: results from the guardian 4 multinational clinical trial. Haemophilia 2020;26(1):64-72. [DOI: 10.1111/hae.13883] - DOI - PMC - PubMed
Zanon 2020 {published data only}
    1. Zanon E, Tagliaferri A, Pasca S, Ettorre CP, Notarangelo LD, Biasioli C, et al. Physical activity improved by adherence to prophylaxis in an Italian population of children, adolescents and adults with severe haemophilia A: the SHAPE study. Blood Transfusion 2020;18(2):152-8. [DOI: 10.2450/2019.0040-19] - DOI - PMC - PubMed
Zhao 2014 {published data only}
    1. Zhao Y, Xiao J, Yang R, Wu R, Hu Y, Beckmann H, et al. Standard prophylaxis vs on-demand treatment for children with severe hemophilia A: comparison of bleeding events in Chinese patients with hemophilia. Haemophilia 2014;20(Suppl 3):95. [DOI: 10.1111/hae.12400] - DOI
Zhao 2017 {published data only}
    1. Zhao Y, Xiao J, Yang R, Wu R, Hu Y, Beckmann H, et al. Efficacy of standard prophylaxis versus on-demand treatment with Bayer's sucrose-formulated recombinant FVIII (rFVIII-FS) in Chinese children with severe hemophilia A. Pediatric Hematology and Oncology 2017;34(3):138-48. [DOI: 10.1080/08880018.2017.1313921] - DOI - PubMed

Additional references

Aronstam 1976
    1. Aronstam A, Arblaster PG, Rainsford SG, Turk P, Slattery M, Alderson MR, et al. Prophylaxis in haemophilia: a double blind controlled trial. British Journal of Haematology 1976;33(1):81-90. [PMID: ] - PubMed
Aronstam 1977
    1. Aronstam A, Kirk PJ, McHardy J, Culver-James JW, McLellan DS, Turk P, et al. Twice weekly prophylactic therapy in haemophilia A. Journal of Clinical Pathology 1977;30(1):65-7. - PMC - PubMed
Arruda 2018
    1. Arruda VR, Doshi BS, Samelson-Jones BJ. Emerging therapies for hemophilia: controversies and unanswered questions. F1000 Research 2018;7:489. [DOI: 10.12688/f1000research.12491.1] - DOI - PMC - PubMed
Blanchette 2014
    1. Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, den Berg HM, Srivastava A, Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. Journal of Thrombosis and Haemostasis: JTH 2014;12(11):1935-9. [DOI: 10.1111/jth.12672] [PMID: ] - DOI - PubMed
Carlsson 1996
    1. Carlsson M, Berntorp E, Bjorkman S, Lethagen S, Lindvall K, Ljung R. Clinical experience of pharmacokinetic dosing of factor VIII for prophylaxis. Haemophilia 1996;2(Suppl 1):16.
Chen 2023
    1. Chen Y, Cheng SJ, Thornhill T, Solari P, Sullivan SD. Health care costs and resource use of managing hemophilia A: a targeted literature review. Journal of Managed Care & Specialty Pharmacy 2023;29(6):647-58. [DOI: 10.18553/jmcp.2023.29.6.647] - DOI - PMC - PubMed
Cortesi 2018
    1. Cortesi PA, D'Angiolella LS, Lafranconi A, Micale M, Cesana G, Mantovani LG. Modern treatments of haemophilia: review of cost-effectiveness analyses and future directions. PharmacoEconomics 2018;36(3):263-84. - PubMed
GRADEpro GDT [Computer program]
    1. GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), 2023. Available at https://www.gradepro.org.
Grazzi 2023
    1. Grazzi F, Sun SX, Burke T, O'Hara J. The impact of pharmacokinetic-guided prophylaxis on clinical outcomes and healthcare resource utilization in hemophilia A patients: real-world evidence from the CHESS II study. Journal of Blood Medicine 2023;13:505-16. - PMC - PubMed
Higgins 2017
    1. Higgins JP, Altman DG. Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Churchill R, Chandler J, Cumpston MS, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.2.0 (updated June 2017), Cochrane, 2017. Available from https://www.cochrane.org/authors/handbooks-and-manuals/handbook/archive/....
Higgins 2020a
    1. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.1 (updated September 2020). Cochrane, 2020. Available from https://www.cochrane.org/authors/handbooks-and-manuals/handbook/archive/.... - PMC - PubMed
Higgins 2020b
    1. Higgins JP, Li T, Deeks JJ. Chapter 6: choosing effect measures and computing estimates of effect. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.1 (updated September 2020). Cochrane, 2020. Available from https://www.cochrane.org/authors/handbooks-and-manuals/handbook/archive/....
Higgins 2021
    1. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from https://www.cochrane.org/authors/handbooks-and-manuals/handbook/archive/.... - PMC - PubMed
Huwaldt 2020 [Computer program]
    1. Plot Digitizer 2.6.9. Huwaldt JA, Steinhorst S. Source Forge, 2020. https://plotdigitizer.sourceforge.net/.
Lim 2021
    1. Lim CY, In J. Considerations for crossover design in clinical study. Korean Journal of Anesthesiology 2021;74(4):293-9. [DOI: 10.4097/kja.21165] [PMID: PMCID: PMC8342834] - DOI - PMC - PubMed
Mahlangu 2022
    1. Mahlangu J, Bassa F, Bassingthwaighte M, Cruickshank AL, Du Plessis J, Goga Y, et al. Prophylaxis is the new standard of care in patients with haemophilia. South African Medical Journal 2022;112(6):405-8. [PMID: ] - PubMed
Mehta 2024
    1. Mehta P, Reddivari AK. Hemophilia. StatPearls 2024;(Internet):http://www.ncbi.nlm.nih.gov/books/NBK551607/. [PMID: ]
Miners 2004
    1. Miners A, Lee CA. Setting research priorities to improve cost-effectiveness estimations of primary prophylaxis with clotting factor for people with severe haemophilia A. Haemophilia 2004;10(Suppl 1):58-62. - PubMed
Miners 2009
    1. Miners A. Revisiting the cost-effectiveness of primary prophylaxis with clotting factor for the treatment of severe haemophilia A. Haemophilia 2009;15(4):881-7. - PubMed
Morfini 1976
    1. Morfini M, Mannucci PM, Mariani G, Panicucci F, Petrucci F, Baicchi U, et al. Evaluation of prophylactic replacement therapy in haemophilia B. Scandinavian Journal of Haematology 1976;16(1):41-7. - PubMed
Munawar Ali 2023
    1. Munawar Ali R, Abid M, Zafar S, Ali MS, Nadeem R, Ahmed R, et al. Management of severe hemophilia A: low-dose prophylaxis vs. on-demand treatment. Cureus 2023;5(15):e41410. - PMC - PubMed
Nugent 2018
    1. Nugent D, O'Mahony B, Dolan G. Value of prophylaxis vs on-demand treatment: application of a value framework in hemophilia. Haemophilia 2018;24(5):755-65. - PubMed
Olasupo 2021b
    1. Olasupo OO, Noronha N, Lowe MS, Ansel D, Bhatt M, Matino D. Non-clotting factor therapies for preventing bleeds in people with hemophilia. Cochrane Database of Systematic Reviews 2021, Issue 8. Art. No: CD014544. [DOI: 10.1002/14651858.CD014544] [PMID: ] - DOI - PMC - PubMed
Olasupo 2024
    1. Olasupo OO, Noronha N, Lowe MS, Ansel D, Bhatt M, Matino D. Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B. Cochrane Database of Systematic Reviews 2024, Issue 2. Art. No: CD014544. [DOI: 10.1002/14651858.CD014544.pub2] - DOI - PMC - PubMed
Pettersson 1993
    1. Pettersson H. Radiographic scores and implications. Seminars in Hematology 1993;30(3 Suppl 2):7-9. - PubMed
Pollak 2006
    1. Pollak E, Mühlan H, Mackensen S, Bullinger M, Haemo-QoL Group. The Haemo-QoL Index: developing a short measure for health-related quality of life assessment in children and adolescents with haemophilia. Haemophilia 2006;12(4):384-92. - PubMed
Sarmiento Doncel 2023
    1. Sarmiento Doncel S, Díaz Mosquera GA, Cortes JM, Agudelo Rico C, Meza Cadavid FJ, Peláez RG. Haemophilia A: a review of clinical manifestations, treatment, mutations, and the development of inhibitors. Hematology Reports 2023;15(1):130-50. - PMC - PubMed
Schep 2019
    1. Schep SJ, Boes M, Schutgens RE, Vulpen LF. An update on the 'danger theory' in inhibitor development in hemophilia A. Expert Review of Hematology 2019;12(5):335-44. - PubMed
Srivastava 2020
    1. Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia 2020;Suppl 6:1-158. [DOI: 10.1111/hae.14046] - DOI - PubMed
Sun 2014
    1. Sun J, Hilliard PE, Feldman BM, Zourikian N, Chen L, Blanchette VS, et al. Chinese Hemophilia Joint Health Score 2.1 reliability study. Haemophilia 2014;20(3):435-40. - PubMed
Thorat 2018
    1. Thorat T, Neumann PJ, Chambers JD. Hemophilia burden of disease: a systematic review of the cost-utility literature for hemophilia. Journal of Managed Care & Specialty Pharmacy 2018;24(7):632-42. - PMC - PubMed
Wan 2014
    1. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology 2014;14:135. - PMC - PubMed

References to other published versions of this review

Iorio 2011
    1. Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No: CD003429. [DOI: 10.1002/14651858.CD003429.pub4] - DOI - PubMed
Olasupo 2021a
    1. Olasupo OO, Lowe MS, Krishan A, Collins P, Iorio A, Matino D. Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B. Cochrane Database of Systematic Reviews 2021, Issue 8. Art. No: CD014201. [DOI: 10.1002/14651858.CD014201] - DOI - PMC - PubMed
Stobart 2002
    1. Stobart K, Wu JK. Clotting factor concentrates given to prevent bleeding and bleeding related complications in people with hemophilia A and B. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No: CD003429. [DOI: 10.1002/14651858.CD003429] - DOI - PubMed
Stobart 2005
    1. Stobart K, Iorio A, Wu JK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No: CD003429. [DOI: 10.1002/14651858.CD003429.pub2] - DOI - PubMed
Stobart 2006
    1. Stobart K, Iorio A, Wu JK. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No: CD003429. [DOI: 10.1002/14651858.CD003429.pub3] - DOI - PubMed

LinkOut - more resources