Conceptual model of VWF self-association. The A2 domain of WT/native VWF is in a closed conformation. The unfolding of this domain is promoted by fluid shear, and enhanced upon depleting calcium and mutating A2 to prevent calcium binding. Such shear mediated A2-unfolding promotes VWF self-association on platelet GpIbα thus enhancing SIPAct. This also augments VWF binding to collagen, promoting thrombus growth. The introduction of a disulfide bond across A2 locks/seals the domain, preventing A2-unfolding and VWF self-association.