The increasing application of nanomedicine requires deeper understanding of the interaction of the carrier with the circulatory system, as this system often serves as the gateway for carrier distribution in the body. As foreign materials, nanoparticles can activate blood coagulation and inflammatory systems. However, whether these activation processes respond linearly to the particle count, the interface area with blood, or the total mass remains uncertain. This study incubated 115, 240 or 450 nm diameter silk nanoparticles in vitro in flowing whole human blood at concentrations matching the total mass, total surface area of ideal spherical particles, and particle count and then analyzed the activation of the coagulation cascade, blood platelets, complement cascade and granulocytes. The immunocell association of nanoparticles was highly modulated by plasma proteins, which had a passivating effect. The activation of the humoral cascades mainly depended on the applied mass concentration, whereas granulocyte activation tended to show linear dependence mainly on the particle count, suggesting a direct interaction effect. Additional factors, such as curvature and area restriction for the assembly of enzyme complexes, superposed these effects on basic geometric parameters. Thus, the design of silk nanoparticles for drug delivery has to prioritize either low cell activation or low activation of plasmatic pathways.