Structural Insights into Blood Coagulation Factor VIII: Procoagulant Complexes, Membrane Binding, and Antibody Inhibition

Authors: Childers, KC; Peters, SC; Clint Spiegel, P, JR

Affiliations: Chemistry Department, Western Washington University, Bellingham, WA, USA. Chemistry Department, Western Washington University, Bellingham, WA, USA.

Publication: Journal of thrombosis and haemostasis: JTH ; 2022

Abstract: Advances in structural studies of blood coagulation factor VIII (FVIII) have provided unique insight into FVIII biochemistry. Atomic detail models of the B domain-deleted FVIII structure alone and in complex with its circulatory partner, von Willebrand factor (VWF), provide a structure-based rationale for hemophilia A-associated mutations which impair FVIII stability and increase FVIII clearance rates. In this review, we discuss the findings from these studies and their implications toward the design of a recombinant FVIII with improved circulatory half-life. Additionally, we highlight recent structural studies of FVIII bound to inhibitory antibodies which have refined our understanding of FVIII binding to activated platelet membranes and formation of the intrinsic tenase complex. The combination of bioengineering and structural efforts to understand FVIII biochemistry will improve therapeutics for treating hemophilia A, either through FVIII replacement therapeutics, immune tolerance induction, or gene therapy approaches.