A computational approach involving mathematical modeling and in silico experiments was used to characterize the determinants of extent and duration of platelet cyclooxygenase (COX)-1 inhibition by aspirin and design precision dosing in patients with accelerated platelet turnover or reduced drug bioavailability. To this purpose, a recently developed physiologically-based pharmacokinetics (PK) and pharmacodynamics (PD) model of low-dose aspirin in regenerating platelets and megakaryocytes, was used to predict the main features and determinants of platelet COX-1 inhibition. The response to different aspirin regimens in healthy subjects and in pathological conditions associated with alterations in aspirin PK (i.e., severely obese subjects) or PD (i.e., essential thrombocytemya patients), were simulated. A model sensitivity analysis was performed to identify the main processes influencing COX-1 dynamics. In silico experiments and sensitivity analyses indicated a major role for megakaryocytes and platelet turnover in determining the extent and duration of COX-1 inhibition by once-daily, low-dose aspirin. They also showed the superiority of reducing the dosing interval vs increasing the once-daily dose in conditions of increased platelet turnover, while suggested specific dose adjustments in conditions of possible reduction in drug bioavailability. In conclusion, the consistency of our model-based findings with experimental data from studies in healthy subjects and patients with essential thrombocythemia supports the potential of our approach for describing the determinants of platelet inhibition by aspirin and informing precision dosing which may guide personalized antithrombotic therapy in different patient populations, especially in those under-represented in clinical trials or in those associated with poor feasibility.