Fig. 4

Molecular model of flow-induced VWF activation. a Schematic of extended VWF⁵ and platelet surface drawn to scale, including average spacing between GPIbα/GPIbβ 1:2 complexes and length of mucin-like regions shown as brush-like curves. “+” and “−” indicate net electrostatic charge at plasma pH; sialic acid makes mucins negatively charged. b Model of VWF activation under flow. VWF is tethered on a vessel wall. Three values of shear stress (σ) are shown that do not extend, extend but do not activate, or extend VWF and are above the threshold shear stress required for activation (σ ₅₀, a function of N _VWF). Tension is proportional to the number of VWF monomers downstream of the tether point. Activation of A1 is schematized as disruption by mechanical tension of hydrogen bonds involving residues external to the A1 disulfide, converting A1 from a low-affinity square shape to a high-affinity round shape. c, d Views of the GPIbα–A1 complex crystal structure⁵⁵ with similar orientations in the upper portion of each panel. c Ribbon cartoons of GPIbα in gray and A1 in rainbow from N (blue) to C-terminus (red). Spheres mark N and C-termini. The lower panel shows the force-bearing region at the N and C-termini near the long-range disulfide (gold stick). Hydrogen bonds involving residues external to the disulfide are shown as black dashes. d Electrostatic surface potentials colored according to the key. In the lower, open-book view, GPIbα and A1 are rotated 90° towards the viewer around the dashed axis to show their highly electrostatic interfaces. e Shear and elongational flows⁵. (Left) Shear flow can be represented as the combination of elongational flow and rotational flow. Arrows show flow streamlines and dots indicate no-flow regions. (Right) Effects of vasoconstriction and bleeding on flow. VWF concatemers (red) are more compact in shear flow, and as the elongational component of flow increases, they are more extended. When tethered to the vessel wall, as shown in the constriction site, VWF is more easily extended when tethered than when in free solution since tension exerted on it cannot be minimized by movement with the flow—rather, the tension in the molecule must resist the total drag force induced by the flow on the downstream portions of VWF