Abstract

Platelets, non-nuclear cells critical for hemostasis, initiate activation upon vascular injury primarily through the glycoprotein VI (GPVI) receptor, which recognizes the extracellular matrix protein collagen. This activation process involves a complex tyrosine kinase signaling cascade, leading to the initiation of calcium signaling via phospholipase Cγ2 (PLCγ2) and phosphoinositide signaling via phosphoinositide-3-kinase (PI3K). However, previous studies have revealed a significant, up to twofold, variability in the calcium response to GPVI activation among healthy donors, a phenomenon that remains mechanistically unclear. To address this, we developed a computational model of GPVI-mediated platelet activation, formulated as a system of ordinary differential equations. The model, adapted from a previously published CLEC-2 receptor activation model, was used to theoretically explore the factors governing this observed variability. Our simulations predicted a monotonic dependence of the activation degree on the number of GPVI receptors on the platelet surface. Sensitivity analysis further indicated that the platelet response is critically determined by both the number of GPVI receptors and the catalytic parameters of associated tyrosine kinases. Crucially, the model demonstrated that a mere twofold variation in GPVI receptor count is sufficient to account for the full range of observed variability in the calcium response. These findings theoretically predict that the inter-individual variability in platelet activation through the GPVI receptor is primarily determined by the natural variation in GPVI receptor expression levels among healthy individuals.