The trigger model of GPIb-IX-mediated signaling that leads to platelet clearance. A soluble multimeric ligand, such as plasma VWF or anti-LBD antibodies, can bind to the LBD of GPIbα and crosslink platelets. Under physiological shear, the crosslinking can generate a pulling force on GPIbα and induce unfolding of the MSD therein. Consequently, it induces platelet signaling as illustrated, including desialylation (the exposure of β-gal), leading to rapid clearance of platelets. Adapted from Deng et al with permission.⁴⁶