Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood 2016 Oct 20;128(16):2007-2016
Date
09/03/2016Pubmed ID
27587878Pubmed Central ID
PMC5073181DOI
10.1182/blood-2016-04-713289Scopus ID
2-s2.0-84992390506 (requires institutional sign-in at Scopus site) 147 CitationsAbstract
A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent 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 chaperone 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 half-life of 1.5- to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain is still 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. A greater understanding 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.
Author List
Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap DAuthor
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Factor VIIIHalf-Life
Hemophilia A
Humans
Recombinant Fusion Proteins
von Willebrand Factor
