Dynamic equilibrium between VWF and FVIII and details of the VWF-FVIII association under normal conditions of synthesis, secretion, and clearance. Whereas the vast majority of VWF circulates as an FVIII-free protein in the circulation, the opposite is true for FVIII with 95% to 98% being in complex with VWF.¹²⁸  Although of relatively high affinity (K_D, 0.2 nM), complex formation is characterized by a temperature-sensitive highly dynamic equilibrium, with rapid association and dissociation rate constants (2-4 × 10⁶ M⁻¹ s⁻¹ and 0.3-6 × 10⁻³ s⁻¹), respectively.¹²⁹  The influence of shear on the VWF-FVIII association and configuration is unresolved but may play a role in modulating clearance and immunogenicity.