VWF is a large (∼250 kDa) protein containing multiple domains (multicolored cylinders), including the CTCK domain (thin, light-colored disk) at one end of the VWF monomer. The extreme stability of this dimer is the result of the highly unusual “triple reinforcement” architecture that includes the cysteine knot, intermolecular disulfide bridges, and intermolecular β-sheet formation (represented artistically by knotted strings, metal chains, and handcuffs). These features, together with favorable amino acid side-chain interactions and very high relative surface burial upon dimerization, allow the ultralarge VWF multimers to withstand the incredible shearing forces in the circulatory system.