https://orcid.org/0000-0003-3871-8619
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Abstract
Background
Recombinant von Willebrand factor (rVWF, vonicog alfa) is a purified VWF concentrate produced from Chinese hamster ovary cells. rVWF is not exposed to the VWF-cleaving protease ADAMTS13 and so is not subject to proteolytic degradation of large (L) and ultra-large (UL) VWF multimers by that enzyme.
Purpose
To compare the structure and function of rVWF with the human plasma-derived VWF [pdVWF] concentrates Haemate P®/Humate-P®, Voncento®, Wilate®/Eqwilate®, and Wilfactin®/Willfact®; to investigate the relationship between VWF multimeric pattern and VWF:ristocetin cofactor (VWF:RCo) activity through population pharmacokinetic (PK) modeling in patients with severe von Willebrand disease (VWD) treated with rVWF.
Methods
Analyses included VWF:RCo activity, VWF:collagen-binding activity, VWF:platelet glycoprotein Ib receptor binding, factor VIII (FVIII) binding capacity, and VWF-mediated platelet adhesion under flow conditions. VWF multimeric structure was determined by agarose gel electrophoresis. Population PK models describing the activity-time profile of small, medium, and L/UL multimers following intravenous administration of rVWF in patients with severe VWD were developed.
Results
Findings demonstrate that rVWF contains a non-degraded VWF multimer pattern including the UL multimers not present in pdVWF concentrates. rVWF displayed higher specific platelet-binding activity, and faster mediation of platelet adhesion to collagen under shear stress versus pdVWF concentrates. rVWF also demonstrated higher FVIII binding capacity than Haemate P®, Voncento® and Wilate®. Modeling provided evidence that VWF:RCo activity in patients with severe VWD treated with rVWF is associated with L/UL VWF multimers in the circulation.
Conclusions
Findings suggest that the L and UL multimers preserved in rVWF contribute to high biological activity and might be important for providing hemostatic efficacy.
Abbreviations
EC, endothelial cell; ELISA, enzyme-linked immunosorbent assay; FVIII, factor VIII; HRP, horseradish peroxidase; L, large; M, medium; NIBSC, National Institute for Biological Standards and Control; pdVWF, plasma-derived VWF; PK, pharmacokinetic; PopPK, population pharmacokinetic; rVWF, recombinant VWF; S, small; SDS, Sodium dodecyl sulfate; UL, ultra-large; VWD, von Willebrand disease; VWF, von Willebrand factor; VWF:Ag, VWF antigen; VWF:CB, VWF collagen binding; VWF:FVIIIB, FVIII binding capacity of VWF products; VWF:GPlbM, VWF platelet glycoprotein Ib mutant receptor binding; VWF:RCo, VWF ristocetin cofactor.
Data Sharing Statement
The datasets analyzed in this study are available upon reasonable request from the corresponding author.
Acknowledgments
The authors acknowledge Françoise Truong Berthoz, MD, from Baxalta GmbH, a Takeda company, Zurich, Switzerland, who provided medical insights at the early stage of this project. The authors also acknowledge Alexander Bauer, Martin Wolfsegger (Baxalta Innovations GmbH, a Takeda company, Vienna, Austria), and Giovanni Smania (Pharmetheus AB, Uppsala, Sweden) for contributing population pharmacokinetic analyses of small, medium, and large/ultra-large molecular weight multimers following administration of rVWF; Ann-Katrin Holik, Michaela Schädler, Sylvia Peyrer-Heimstätt, Jutta Schreiner, and Manfred Billwein for VWF analytics; and Bettina Ploder (Baxalta Innovations GmbH, a Takeda company, Vienna, Austria) for contributing to the collection of the data. Medical writing support was provided by Nasser Malik, PhD, employee of Excel Medical Affairs (Fairfield, CT, USA) and was funded by Takeda Development Center Americas Inc., Lexington, MA, USA. This paper was presented at the International Society on Thrombosis and Haemostasis (ISTH) Virtual Congress, July 12–14, 2020, as an abstract presentation with interim findings. The poster’s abstract was published in “Poster Abstracts” in Research and Practice in Thrombosis and Haemostasis (RPTH). 2020; 4: Suppl 1 (https://abstracts.isth.org/abstract/recombinant-human-von-willebrand-factor-rvwf-differs-in-structure-and-function-from-plasma-derived-concentrates/).
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
HG, GS, and NW are employees of Baxalta Innovations GmbH, a Takeda company, and hold Takeda stock or stock options. BM is an employee of Takeda Development Center Americas, Inc., and holds Takeda stock or stock options. BE was an employee of Takeda Development Center Americas, Inc., during the analysis and development of the manuscript, and holds Takeda stock. PLT is an employee of Baxalta Innovations GmbH, a Takeda company, and holds relevant Takeda patents and Takeda stock or stock options. The authors report no other conflicts of interest in this work.