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

Anormal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWFand 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 halflife of 1.5- to 2-fold compared withmarketed 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 extendthe half-lifeof rFVIII.Agreaterunderstanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival ofVWF or limit VWF-mediated clearance of FVIII. [ABSTRACT FROM AUTHOR]