Multiscale model of combinatorial platelet activation and thrombus formation under flow. Platelet agonists (blue) used individually or in pairs to activate GPVI- or G-protein–coupled receptors (the thromboxane receptor TP, purinergic receptors P2Y₁ and P2Y₁₂, and the prostacyclin receptor, IP) result in modulation of intracellular calcium (green) from intracellular stores distal of phospholipase C (PLC) activation or from store operated calcium entry via Stim1-Orai1 activation. Inhibitors (red) such as acetylsalicylic acid (ASA) or indomethacin inhibit COX-1. Autocrine pathways include release of TXA₂ and ADP (A). A 2-layer, 8-node/4-node NN with feedback is trained with 74 measured calcium traces to predict [Ca]_i for each patient-specific platelet PAS (B). The multiscale simulation of platelet deposition under flow requires simultaneous solution of the instantaneous velocity field over a complex and evolving platelet boundary Ω(t) by LB, concentration fields of ADP and TXA₂ by FEM, individual intracellular platelet state ([Ca]_i) and release reactions (R) for ADP and TXA₂ by NN, and all platelet positions and adhesion/detachment by LKMC (C-D).