Life in the shadow of a dominant partner: The FVIII-VWF association and its clinical implications for hemophilia A

Steven W. Pipe, Robert R. Montgomery, Kathleen P. Pratt, Peter J. Lenting, David Lillicrap*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

151 Scopus citations

Abstract

A normal he most aticresponsetovascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulateasanon-covalent complex, and each has a critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaper-one for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) and reduce dosing frequency by utilizing bioengineering techniques including PEGylation, Fc fusion, and single-chain design. However, these approaches have achieved only moderate increases in halflife of 1.5- to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain isstill regulated to a large extent by interaction with VWF. Therefore, the half-life of VWF (∼15 hours) appears to be the limiting factor that has confounded attempts to extend the half-life of rFVIII. Agreaterun-derstanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival of VWF or limit VWF-mediated clearance of FVIII.

Original languageEnglish
Pages (from-to)2007-2016
Number of pages10
JournalBlood
Volume128
Issue number16
DOIs
StatePublished - 20 Oct 2016
Externally publishedYes

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