TY - JOUR
T1 - Life in the shadow of a dominant partner
T2 - The FVIII-VWF association and its clinical implications for hemophilia A
AU - Pipe, Steven W.
AU - Montgomery, Robert R.
AU - Pratt, Kathleen P.
AU - Lenting, Peter J.
AU - Lillicrap, David
N1 - Funding Information:
D.L. is the recipient of research funding relating to FVIII and VWF from the Canadian Institutes of Health Research and holds a Canada Research Chair in Molecular Hemostasis. P.J.L. is a recipient of a grant from the Agence Nationale de la Recherche (ANR-13-BSV1-0014). K.P.P. acknowledges startup funding from Uniformed Services University of the Health Sciences. This review was initiated at a face-to-face meeting for which travel support was provided by CSL. CSL did not select the coauthor group and there was no commercial involvement in considering the content or in the writing of this review.
PY - 2016/10/20
Y1 - 2016/10/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84992390506&partnerID=8YFLogxK
U2 - 10.1182/blood-2016-04-713289
DO - 10.1182/blood-2016-04-713289
M3 - Review article
C2 - 27587878
AN - SCOPUS:84992390506
SN - 0006-4971
VL - 128
SP - 2007
EP - 2016
JO - Blood
JF - Blood
IS - 16
ER -