A revised model of platelet activation in response to low dose collagen. (1) A rise in [Ca²⁺]_i stimulates the CalDAG-GEFI–dependent first wave of Rap1 and integrin activation. Activated Rap1 also triggers ERK-dependent generation of TxA₂, which in turn provides critical feedback for the activation of PKC. (2) In a next step, PKC triggers the release of granule contents, including ADP. Released ADP signals through P2Y12/Gi to stimulate the second wave of Rap1/integrin activation and TxA₂ generation, which is required for the formation of stable platelet-platelet contacts. Higher concentrations of GPVI agonists lead to the concomitant activation of CalDAG-GEFI and PKC, facilitating integrin activation independent of feedback by endogenous TxA₂ (dashed line). AA indicates arachidonic acid; Gi, heterotrimeric G protein; P, residue phosphorylation; PL, phospholipids; and TPα/β, thromboxane receptors.