The study presents a model of shear-stress-based platelet activation. Twenty-eight patients (22 free from anticoagulants and major antiplatelet agents, and six under the effects of P2Y12 platelet inhibitors) participated. The main purpose was to verify the hypothesis that a model of shear-dependent blood activation does not require artificial activators to trigger clot formation. Whole blood collected from the patients received platelet function tests [ADPtest and thrombin receptor-activating peptide (TRAP)test] and was tested with a cone-on-plate viscosimeter at a shear rate of 100 s−1. Changes in blood viscosity were characterized by a time-to-gel point (TGP), a maximum clot viscosity and a steady clot viscosity (SCV). In patients free from major antiplatelet effects, the TGP was 180 s (interquartile range 148–290 s), while in patients under double antiplatelet therapy the TGP was significantly (P = 0.039) longer (345 s, interquartile range 250–452 s). The SCV was 16 centipoise (cP) (interquartile range 11–47 cP) in the patients free from major antiplatelet agents, significantly (P = 0.012) higher than in patients under double antiplatelet therapy (10 cP, interquartile range 6–11 cP). There was a significant (P = 0.011) association between platelet function at the TRAPtest and the maximum clot viscosity, and between TRAPtest and the SCV (P = 0.021). A shear rate of 100 s−1 triggers clot formation through a primary role of platelet activation in this model of blood activation.