Unraveling the molecular mechanism of in situ surface-initiated thrombogenesis

Thrombosis caused by contact of blood with surfaces is a serious complication in the incorporation of biomedical devices. Adsorption of fibrinogen to these commonly hydrophobic surfaces can lead to conformational changes in the molecule, which eventually leads to thrombogenesis. The origin of these thrombi and the underlying mechanism through which the surfaces contribute to the outcome remains undefined.

This study aimed to investigate and understand the interactions of fibrinogen with surfaces at the molecular level.

Visualization of fibrinogen interactions following adsorption to polystyrene surfaces was performed using atomic force microscopy, transmission electron microscopy, and fluorescence microscopy and further evaluated using various antibodies and platelet flow assays.

Surface adsorption led to a misfolding of fibrinogen molecules, namely untethering of αC-domains. Conformational changes resulted in the onset of intermolecular interactions and random linkages of neighboring molecules, mediated by the N-terminal subdomain of the αC-domain (Aα406-483). When concentration of fibrinogen solutions was increased to 20 to 500 μg/mL, structured monolayers that grew continuously into multilayers were observed but were self-limited due to the decrease in untethered αC-domains in subsequent fibrinogen bilayers. Soluble fibrin structure was determined to be a clustered complex of fibrinogen and fibrin with a protofibril core. These complexes adsorbed and aggregated onto multilayers through exposed αC-domains on both surfaces, leading to large fiber formations. Surface fibers promoted platelet adhesion and activation, implying exposure of binding domain γ400-411.

This comprehensive study models the precise molecular mechanism of surface-initiated thrombogenesis and may provide the foundation necessary to design effective inhibition techniques.