Integrin activation is bidirectional and reciprocal. The αIIbβ3 equilibrates between resting and activated states, the resting state predominating in unstimulated platelets and the activated state in stimulated platelets. Conversion from resting to activated does not imply a single, abrupt change but rather a series of coordinated and linked conformational transitions. (A) Inside-out signaling. Agonist-dependent intracellular signals stimulate the interaction of key regulatory ligands (such as talin) with integrin cytoplasmic tails (in this case the β3 tail). This leads to conformational changes in the extracellular domain that result in increased affinity for adhesive ligands such as fibrinogen, von Willebrand factor (VWF), and fibronectin. Affinity modulation can be monitored in living cells with engineered monovalent Fab fragments derived from ligand-mimetic monoclonal antibodies.^35,50,137  Plasma fibrinogen and VWF support platelet aggregation at low and high shear rates, respectively, by bridging αIIbβ3 receptors on adjacent platelets.³  Studies in mice deficient in fibrinogen and VWF indicate that plasma fibronectin can also promote thrombus initiation, growth, and stability at high shear rates.¹³⁸  (B) Outside-in signaling. Extracellular ligand binding, initially reversible, becomes progressively irreversible and promotes integrin clustering and further conformational changes that are transmitted to the cytoplasmic tails. This results in the recruitment and/or activation of enzymes, adaptors, and effectors to form integrin-based signaling complexes.