Intramolecular interaction(s) between A1 and A2 regulates VWF shear-dependent functions. The absence of the C1669–C1670 disulfide bond in the VWF A2 domain of a model polypeptide (A1A2A3) leads to greater deformations that promote intramolecular dissociation between the A1 and A2 domains. As a result, platelets translocate more slowly across immobilized A1A2A3^{C1669S/C1670S} than they do across A1A2A3^wt. Prolonged tension from bound platelets under flow and a more easily unfolded A2 should enhance VWF’s susceptibility to proteolysis by ADAMTS13. Professional illustration by Somersault18:24.