ADP simultaneously binds to 2 P2Y receptors, P2Y₁ and P2Y₁₂, leading to sustained activation of Rap1b and a conformation change of αIIbβ3 integrins from an inactive to an active form. Activated αIIbβ3 binds fibrinogen to form a platelet aggregate. Activation of the platelet also promotes degranulation, thereby releasing ATP and ADP to activate nearby platelets and amplify aggregation. (Inset) His187 in the P2Y₁₂ receptor is hydrogen bonded to the 2′-OH of 2MeSADP, which ultimately leads to activation of P2Y₁₂ receptor–mediated signaling pathways. The 2 brothers with a severe bleeding history detailed by Lecchi et al have a homologous His187Gln mutation that disrupts receptor activation. cAMP, cyclic adenosine 5′-monophosphate.