Proposed model illustrating type 2B VWD mutational effect on AIM-A1 thermodynamic cycling. Under normal blood flow, AIM-A1 exists in the bloodstream in an autoinhibited state because of cooperative protection from the N-terminal AIM (blue) and C-terminal AIM (orange), where both the α3β4 and β3α2 loops (light gray) have enhanced protection. Shear forces of the blood or other endogenous or exogenous factors lead to activation of the A1 domain, which equilibrates between low- and high-affinity states, in which the structure of the AIM is likely more flexible but is yet to be determined. The low-affinity A1 domain may transiently interact with GPIbα LBD as platelets roll over VWF with a higher dissociation rate constant. Based on this study, a potential molecular signature of an activated A1 domain is enhanced solvent exposure of the α3β4 loop (dark gray). The high-affinity state of the A1 domain dissociates from the LBD more slowly and can more effectively capture platelets. In this state, the A1 domain has enhanced exposure of both the α3β4 and β3α2 loops (dark gray). Severity of type 2B VWD may correlate with relative abundance of these high-affinity molecules.