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

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 halflife 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. (Blood.

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

“…The coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII) circulate in the plasma as a noncovalent complex, with VWF serving as a carrier to protect FVIII from accelerated proteolysis and clearance (1). VWF regulates primary hemostasis by facilitating platelet-platelet and platelet-endothelial cell interactions, while FVIII is an essential coagulation cofactor in the extrinsic tenase complex, facilitating secondary hemostasis.…”

Extended Half-Life Factor VIII and Factor IX Preparations

“…Therefore, half-life of vWF (approximately 15 h, high variability between individuals) is the limiting factor to half-life extension of FVIII with techniques available today. All approaches described above achieve only moderate increases of half-lives (1.5-to 2-fold compared to unmodified FVIII) [23]. This is in contrast to FIX where it was possible to increase the mean half-life 4-to 6-fold by different forms of bioengineering [24][25][26].…”

Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches?

“…PEGylation protects FVIII from proteolytic degradation, while both Fc fragment and albumin conjugation use the recycling of the endocytosed fusion protein through the neonatal Fc receptor pathway 6. Although both immunoglobulins and albumin normally have very long half-lives, these approaches have only resulted in a modest increase in the half-life of FVIII, likely due to the dependence on VWF that stabilizes FVIII 5. Even with only a modest gain in half-life, the decrease in the frequency of infusions can significantly increase the quality of life for HA patients.…”

“…Conjugation with albumin takes advantage of the natural half-life of albumin, whereas PEGylation protects FVIII from proteolytic enzymes. Fc conjugation takes advantage of the existence of the neonatal Fc receptor that allows protection and recirculation of the FVIII via this receptor pathway 5,6. Recently, a novel single-chain recombinant FVIII (Afstyla ® ) has been approved by the US Food and Drug Administration (US FDA) in May 2016.…”