title: 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 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.
authors: Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI.
authors: Steven W
authors: SW
authors: Pipe
authors: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.
authors: Robert R
authors: RR
authors: Montgomery
authors: Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD.
authors: Kathleen P
authors: KP
authors: Pratt
authors: INSERM, Unité Mixte de Recherche en Santé 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France; and.
authors: Peter J
authors: PJ
authors: Lenting
authors: Department of Pathology and Molecular Medicine, Queens University, Kingston, ON, Canada.
authors: David
authors: D
authors: Lillicrap
mesh_terms: D005169:Factor VIII / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; D014841:von Willebrand Factor; C078147:F8 protein, human; D005169:Factor VIII