Endogenous VWF binding to FVIII vs bioengineered BIVV001. (A) Endogenous VWF complexed with FVIII is cleared from plasma with a half-life of 12 to 14 hours. FVIII (blue) binds to VWF via the D′D3 domain (red). VWF multimers are linked by disulfide bonds at the N-terminal D′D3 as well as the C-terminal CK domain (gray). The VWF-A domains (green) bear binding sites for platelet GP Ibα (A1), ADAMTS13 cleavage site (A2), and collagen (A1 and A3). (B) Bioengineered recombinant FVIII (rFVIII)/VWF-D′D3 construct, namely BIVV001, has an extended half-life of 25 to 31 hours, which is a threefold to fourfold improvement compared with the endogenous FVIII/VWF complex. The modifications include single-chain reconstruction of the heterodimer of B domain–deleted rFVIII with VWF-D′D3, fusion of the Fc fragment of human immunoglobulin G1, and 2 XTEN polypeptides conjugation.