Shear-dependent platelet aggregation by ChAdOx1 nCoV-19 vaccine: a novel biophysical mechanism for arterial thrombosis Available to Purchase

• ChAdOx1 induces platelet aggregation under shear via biomechanically activated integrin α_IIbβ₃, bypassing GPIb-dependent platelet adhesion pathway.

• This thrombotic pathway, distinct from VITT, may explain rare postvaccination arterial thromboses, with implications for safer vaccine design.

Rare thrombotic events associated with ChAdOx1 nCoV-19 (ChAdOx1) vaccination have raised concerns; however, the underlying mechanisms remain elusive. Here, we report a novel biophysical mechanism by which ChAdOx1 directly interacts with platelets under arterial shear conditions, potentially contributing to postvaccination arterial thrombosis. Using microfluidic post assays, we demonstrate that ChAdOx1 induces shear-dependent platelet aggregation, distinct from conventional von Willebrand factor–mediated adhesion. This interaction is mediated by platelet integrin α_IIbβ₃ and requires biomechanical activation, explaining the absence of significant binding under static conditions. Molecular dynamics simulations and docking studies reveal preferential binding of ChAdOx1's penton arginine-glycine-aspartic acid (RGD) motif to the activated conformation of α_IIbβ₃. Inhibiting integrin α_IIbβ₃ completely abolishes ChAdOx1-induced platelet aggregation, whereas blocking glycoprotein (GP) Ib has minimal effect, confirming a mechanism that bypasses the conventional GPIb-dependent platelet adhesion pathway. Mutagenesis of the RGD motif to AAA eliminates platelet binding, verifying the specificity of this interaction. These findings provide a potential explanation for the association between ChAdOx1 vaccination and arterial thrombotic events, distinct from vaccine-induced immune thrombotic thrombocytopenia. Our results highlight the importance of considering biomechanical factors in vaccine-related thrombotic complications and suggest that shear-dependent integrin activation may be another determinant in the pathogenesis of these rare adverse events.