ArticleBlood2021
Molecular determinants of the factor VIII/von Willebrand factor complex revealed by BIVV001 cryo-electron microscopy.
Article in Blood, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
- Decoding full-length factor VIII through the structural and functional lens of its B domain.Blood vessels, thrombosis & hemostasis · 2026Article
- Structural basis for membrane binding by coagulation factors V and VIII and their specificity for phosphatidylserine-containing membranes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Molecular mechanism of cleavage at R271 during prothrombin activation revealed by cryo-EM.Blood · 2026Article
- HMB-002: a monovalent antibody that elevates circulating VWF and FVIII levels for treatment of von Willebrand disease.Blood advances · 2026Article
- Estimate of Numbers of Disulfide-Bonded Protein States.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Individual Comparative PK Evaluation of Single-dose Octocog Alfa, Rurioctocog Alfa Pegol, and Efanesoctocog Alfa in Adults with Severe Hemophilia A.TH open : companion journal to thrombosis and haemostasis · 2026Article
- Regulation of immune responses to therapeutic factor VIII by transplacental delivery of Fc-fused immunodominant factor VIII domains or peptides.Haematologica · 2025Article
- Normalization in hemophilia: conceptual foundations and clinical implications.Research and practice in thrombosis and haemostasis · 2025Review
- Patient anti-FVIII drug antibodies bind preferentially to a subset of FVIII covalent states.Blood advances · 2025Article
- Analyzing 6211 unique variants in the upgraded interactive FVIII web database reveals novel insights into hemophilia A.Blood vessels, thrombosis & hemostasis · 2025Article
- Anchoring the Hemophilia Joint Health Score for Conventional Value Assessment in the Care of People Living with Severe Hemophilia A.PharmacoEconomics · 2025Article
- Article
- Atomistic Mechanism of Lipid Membrane Binding for Blood Coagulation Factor VIII with Molecular Dynamics Simulations on a Microsecond Time Scale.The journal of physical chemistry. B · 2025Article
- How Electricity Prevents Us from Bleeding to Death.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain.Journal of thrombosis and haemostasis : JTH · 2024Article
- Efanesoctocog alfa: the renaissance of Factor VIII replacement therapy.Haematologica · 2024Review
- The Prothrombin-Prothrombinase Interaction.Sub-cellular biochemistry · 2024Review
- Structure of coagulation factor VIII bound to a patient-derived anti-C1 domain antibody inhibitor.Blood · 2023Article
- Cryo-EM structure of coagulation factor V short.Blood · 2023Article
- Mechano-covalent protection of coagulation factor VIII by von Willebrand factor.Blood advances · 2023Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Interaction of factor VIII (FVIII) with von Willebrand factor (VWF) is mediated by the VWF D'D3 domains and thrombin-mediated release is essential for hemostasis after vascular injury. VWF-D'D3 mutations resulting in loss of FVIII binding are the underlying cause of von Willebrand disease (VWD) type 2N. Furthermore, the FVIII-VWF interaction has significant implications for the development of therapeutics for bleeding disorders, particularly hemophilia A, in which endogenous VWF clearance imposes a half-life ceiling on replacement FVIII therapy. To understand the structural basis of FVIII engagement by VWF, we solved the structure of BIVV001 by cryo-electron microscopy to 2.9 Å resolution. BIVV001 is a bioengineered clinical-stage FVIII molecule for the treatment of hemophilia A. In BIVV001, VWF-D'D3 is covalently linked to an Fc domain of a B domain-deleted recombinant FVIII (rFVIII) Fc fusion protein, resulting in a stabilized rFVIII/VWF-D'D3 complex. Our rFVIII/VWF structure resolves BIVV001 architecture and provides a detailed spatial understanding of previous biochemical and clinical observations related to FVIII-VWF engagement. Notably, the FVIII acidic a3 peptide region (FVIII-a3), established as a critical determinant of FVIII/VWF complex formation, inserts into a basic groove formed at the VWF-D'/rFVIII interface. Our structure shows direct interaction of sulfated Y1680 in FVIII-a3 and VWF-R816 that, when mutated, leads to severe hemophilia A or VWD type 2N, respectively. These results provide insight on this key coagulation complex, explain the structural basis of many hemophilia A and VWD type 2N mutations, and inform studies to further elucidate how VWF dissociates rapidly from FVIII upon activation.
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