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

SW Pipe, RR Montgomery, KP Pratt… - Blood, The Journal …, 2016 - ashpublications.org
SW Pipe, RR Montgomery, KP Pratt, PJ Lenting, D Lillicrap
Blood, The Journal of the American Society of Hematology, 2016ashpublications.org
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 …
Abstract
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.
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