Revised model for platelet adhesion to collagen. The initial contact (tethering) to the ECM is mediated predominantly by GPIbα-VWF and GPVI-collagen interactions. The GPIbα-VWF interaction is essential at high shear rates (> 500 s^–1) but may not be required at lower shear rates.³  In a second step, GPVI-collagen interactions initiate cellular activation followed by shifting of integrins to high-affinity state and the release of second-wave agonists, most importantly ADP and TxA₂. GPIb-mediated signaling may amplify GPVI-induced activation pathways. Cellular activation and up-regulation of integrin affinity is proposed to be a strict prerequisite for adhesion. Finally, firm adhesion of platelets to collagen through activated α₂β₁ (directly) and α_IIbβ₃ (indirectly via VWF or other ligands) results in sustained GPVI signaling, enhanced release, and procoagulant activity. In this process, α₂β₁ and α_IIbβ₃ have partially redundant roles. Released ADP and TxA₂ amplify integrin activation on adherent platelets and mediate thrombus growth by activating additional platelets. This scheme does not exclude the involvement of other receptor-ligand interactions.