Reviews
Vol. 5 No. 1 (2026)
Bioequivalence of von Willebrand factor-containing concentrates: implications for the choice in patients with von Willebrand disease. A position paper from the Italian Association of Hemophilia Centers
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 26 January 2026
780
Views
225
Downloads
57
HTML
Authors
Von Willebrand disease (VWD) is a bleeding disorder caused by quantitative and/or qualitative defects of von Willebrand factor (VWF), a multimeric glycoprotein synthesized by endothelial cells and megakaryocytes. VWF plays a crucial role in hemostasis by mediating platelet adhesion to the sub-endothelium, platelet-platelet aggregation, and by acting as the carrier protein for circulating factor VIII (FVIII) in plasma, protecting it from early proteolytic degradation. The treatment and prevention of bleeding episodes in VWD patients requires the administration of either VWF/FVIII or purified VWF-containing concentrates when desmopressin (DDAVP) is contraindicated or ineffective. Many VWF/FVIII-containing concentrates, one purified plasma-derived VWF (pd-VWF) and one recombinant VWF (rVWF) product are available. These products are characterized by different manufacturing methods, variable VWF/FVIII ratio and multimers composition and content, which could influence their hemostatic efficacy. With this as background, the Italian Association of Hemophilia Centers (AICE) established a multidisciplinary expert panel to analyze the available literature evidences about the bioequivalence of the different licensed VWF-containing products. The data retrieved and their implications for therapeutic choices are discussed in this manuscript, which AICE endorsed as a position paper.
Downloads
Download data is not yet available.
Citations
1. Leebeek FWG, Eikenboom JCJ. Von Willebrand’s Disease. N Engl J Med 2016;375:2067-80. DOI: https://doi.org/10.1056/NEJMra1601561
2. Brehm MA. Von Willebrand factor processing. Hamostaseologie 2017;37:59-72. DOI: https://doi.org/10.5482/HAMO-16-06-0018
3. Lenting PJ, Christophe OD, Denis C V. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015;125:2019-28. DOI: https://doi.org/10.1182/blood-2014-06-528406
4. Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis 2014;25:206-16. DOI: https://doi.org/10.1097/MBC.0000000000000065
5. Federici AB, Elder JH, de Marco L, et al. Carbohydrate moiety of von Willebrand factor is not necessary for maintaining multimeric structure and ristocetin cofactor activity but protects from proteolytic degradation. J Clin Invest1984;74:2049-55. DOI: https://doi.org/10.1172/JCI111628
6. Federici AB, De Romeuf C, De Groot PG, et al. Adhesive properties of the carbohydrate-modified von Willebrand factor (CHO-vWF). Blood 1988;71:947-52. DOI: https://doi.org/10.1182/blood.V71.4.947.bloodjournal714947
7. De Groot R, Lane DA, Crawley JTB. The role of the ADAMTS13 cysteine-rich domain in VWF binding and proteolysis. Blood 2015;125:1968–75. DOI: https://doi.org/10.1182/blood-2014-08-594556
8. Federici AB, Bader R, Pagani S, et al. Binding of von Willebrand factor to glycoproteins Ib and IIb/IIIa complex: affinity is related to multimeric size. Br J Haematol 1989;73:93-9. DOI: https://doi.org/10.1111/j.1365-2141.1989.tb00226.x
9. Ruggeri ZM, Mannucci PM, Lombardi R, et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand’s disease subtypes. Blood 1982;59:1272-8. DOI: https://doi.org/10.1182/blood.V59.6.1272.bloodjournal5961272
10. Cattaneo M, Federici AB, Lecchi A, et al. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb Haemost 1999;82:35-9. DOI: https://doi.org/10.1055/s-0037-1614626
11. Batlle J, López-Fernández MF, Fraga EL, et al. Von Willebrand factor/factor VIII concentrates in the treatment of von Willebrand disease. Blood Coagul Fibrinolysis 2009;20:89-100. DOI: https://doi.org/10.1097/MBC.0b013e3283254570
12. Mannucci PM, Chediak J, Hanna W, et al. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood 2002;99:450-6. DOI: https://doi.org/10.1182/blood.V99.2.450
13. Bello IF, Yuste VJ, Molina MQ, Navarro FH. Fanhdi, efficacy and safety in von Willebrand’s disease: prospective international study results. Haemophilia 2007;13:S25-32. DOI: https://doi.org/10.1111/j.1365-2516.2007.01570.x
14. Gill JC, Ewenstein BM, Thompson AR, et al. Successful treatment of urgent bleeding in von Willebrand disease with factor VIII/VWF concentrate (Humate-P): use of the ristocetin cofactor assay (VWF:RCo) to measure potency and to guide therapy. Haemophilia 2003;9:688-95. DOI: https://doi.org/10.1046/j.1351-8216.2003.00816.x
15. Thompson AR, Gill JC, Ewenstein BM, et al. Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P). Haemophilia 2004;10:42-51. DOI: https://doi.org/10.1046/j.1351-8216.2003.00809.x
16. Lethagen S, Kyrle PA, Castaman G, et al. von Willebrand factor/factor VIII concentrate (Haemate P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery. J Thromb Haemost 2007;5:1420-30. DOI: https://doi.org/10.1111/j.1538-7836.2007.02588.x
17. Federici AB, Castaman G, Franchini M, et al. Clinical use of Haemate P in inherited von Willebrand’s disease: a cohort study on 100 Italian patients. Haematologica 2007;92:944-51. DOI: https://doi.org/10.3324/haematol.11124
18. Lillicrap D, Poon MC, Walker I, et al., Efficacy and safety of the factor VIII/von Willebrand factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease. Thromb Haemost 2002;87:224-30. DOI: https://doi.org/10.1055/s-0037-1612977
19. Rivard GE, Aledort L. Efficacy of factor VIII/von Willebrand factor concentrate Alphanate in preventing excessive bleeding during surgery in subjects with von Willebrand disease. Haemophilia 2008;14:271-5. DOI: https://doi.org/10.1111/j.1365-2516.2007.01616.x
20. Federici AB, Baudo F, Caracciolo C, et al. Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi) in the treatment of von Willebrand disease: a retrospective clinical study. Haemophilia 2002;8:761-7. DOI: https://doi.org/10.1046/j.1365-2516.2002.00688.x
21. Kessler CM, Friedman K, Schwartz BA, et al. The pharmacokinetic diversity of two von Willebrand factor (VWF)/ factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease. Results from a prospective, randomised crossover study. Thromb Haemost 2011;106:279-88. DOI: https://doi.org/10.1160/TH11-02-0057
22. Goudemand J, Scharrer I, Berntorp E, et al. Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods. J Thromb Haemost 2005;3:2219-27. DOI: https://doi.org/10.1111/j.1538-7836.2005.01435.x
23. Castaman G, Linari S. Vonicog alfa for the treatment of von Willebrand disease. Expert Opin Orphan Drugs 2016;4:549-54. DOI: https://doi.org/10.1517/21678707.2016.1171138
24. Mannucci PM, Kempton C, Millar C, et al; rVWF Ad Hoc Study Group. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood 2013;122:648-57. DOI: https://doi.org/10.1182/blood-2013-01-479527
25. Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015;126:2038-46. DOI: https://doi.org/10.1182/blood-2015-02-629873
26. Makris M, Colvin B, Gupta V, et al. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemost 2002;88:387-8. DOI: https://doi.org/10.1055/s-0037-1613227
27. Mannucci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002;88:378-9. DOI: https://doi.org/10.1055/s-0037-1613225
28. Hazendonk HCAM, Heijdra JM, de Jager NCB,et al. Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment. Haemophilia 2018;24:460-70. DOI: https://doi.org/10.1111/hae.13451
29. Kuppens GZL, Fischer K, van Galen KPM, et al. Efficacy of a 1:1 ratio VWF/FVIII concentrate in patients with von Willebrand disease. Haemophilia 2024;30:1148-54. DOI: https://doi.org/10.1111/hae.15079
30. O’Donnell JS, Lavin M. Perioperative management of patients with von Willebrand disease. Hematology Am Soc Hematol Educ Program 2019;2019:604-9. DOI: https://doi.org/10.1182/hematology.2019000065
31. Peyvandi F, Mamaev A, Wang JD, et al. Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. J Thromb Haemost 2019;17:52-62. DOI: https://doi.org/10.1111/jth.14313
32. Connell NT, Flood VH, Brignardello-Petersen R, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021;5:301-25. DOI: https://doi.org/10.1182/bloodadvances.2020003264
33. Leebeek FWG, Peyvandi F, Escobar M, et al. Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results. Blood 2022;140:89-98. DOI: https://doi.org/10.1182/blood.2021014810
34. Tosetto A, Castaman G, Coppola A, et al. Linee Guida – Terapia della malattia di Von Willebrand. Accessed: 2025 Apr 8. Istituto Superiore di Sanità, Rome; 2024 Available from: https://www.iss.it/documents/20126/9398524/LG-C0017-AICE-SISET_Terapia-vWD_v2.pdf/da617911-a3f4-1a89-4c50-2881dc9e61a5?t=1718356517693
CRediT authorship contribution
All authors made a substantive intellectual contribution, read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work
How to Cite
1.
Zanon E, Castaman G, Federici AB, Mancuso ME, Pasut G, Tosetto A, et al. Bioequivalence of von Willebrand factor-containing concentrates: implications for the choice in patients with von Willebrand disease. A position paper from the Italian Association of Hemophilia Centers. Bleeding Thromb Vasc Biol [Internet]. 2026 Jan. 26 [cited 2026 Mar. 28];5(1). Available from: https://www.btvb.org/btvb/article/view/415
Copyright (c) 2026 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Similar Articles
- PO12 | Characterisation and real word clinical data of HEM006, a newly formulated intranasal spray desmopressin (DDAVP) to address a global treatment gap , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- CO21 | Viscoelastic testing in inherited bleeding disorders: a cross-sectional comparison between viscoelastic coagulation monitoring and rotational thromboelastometry , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- PO78 | Acquired hemophilia A as a paraneoplastic syndrome: two cases report on a rare coexistence , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Juan Eirís, Marina Suárez-Terrón, Pablo Granados, David Martínez-Campuzano, Ana Rosa Cid, Saturnino Haya, Santiago Bonanad, Allopurinol-induced acquired von Willebrand syndrome , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 4 (2023)
- Stefano Lancellotti, Monica Sacco, Maira Tardugno, Antonietta Ferretti, Raimondo De Cristofaro, The von Willebrand factor-ADAMTS-13 axis: a two-faced Janus in bleeding and thrombosis , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 1 (2022)
- CO39 | Artificial intelligence in hemophilia management: challenging the need for experts , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- PO90 | Acquired hemophilia A with high-titer inhibitor in a patient with cardiovascular and metabolic comorbidities , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Tiziano Martini, Alessandra Valpreda, Marina Marchetti, Alberto Catalano, Laura Contino, Raimondo De Cristofaro, Augusto Bramante Federici, Ilaria Quaglia, Rossana Rossi, Rita Carlotta Santoro, Armando Tripodi, Angelo Claudio Molinari, Diagnostic challenges in current laboratory practice at Italian Hemophilia Centers: findings from a nationwide survey , Bleeding, Thrombosis and Vascular Biology: Vol. 5 No. 1 (2026)
- Luca Puccetti, Vincenzo Sammartano, Federico Caroni, Margherita Malchiodi, Paola Calzoni, Eleonora Franceschini, Lucrezia Galasso, Monica Bocchia, Safety of COVID-19 mRNA vaccination in patients with history of acquired hemophilia A: a case series , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 3 (2022)
- PO49 | Use of emicizumab in two patients with acquired hemophilia A: a new therapeutic approach , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
You may also start an advanced similarity search for this article.
