Interplay of fibrinogen αEC globular domains and factor XIIIa cross-linking dictates the extensibility and strain stiffening of fibrin networks
J. Thromb. Haemost. , Volume 21 - Issue 10
Background: Fibrinogen is a plasma protein forming the fibrin scaffold of blood clots. Its mechanical properties therefore affect the risk of bleeding as well as thrombosis. There has been much recent interest in the biophysical mechanisms controlling fibrin mechanics; however, the role of molecular heterogeneity of the circulating fibrinogen in determining clot mechanical function remains poorly characterized. Objectives: By comparing 2 fibrinogen variants where the only difference is the Aα-chain length, with one variant having a globular domain at its C-terminus, this study aimed to reveal how the molecular structure impacts the structure and mechanics of fibrin networks. Methods: We characterized the mechanical response to large shear for networks formed from 2 recombinant fibrinogen variants: the most prevalent variant in circulation with a molecular weight of 340 kDa (recombinant human fibrinogen [rFib] 340) and a minor variant with a molecular weight of 420 kDa (rFib420). Results: We show that the elastic properties of the 2 variants are identical when fibrin is cross-linked with factor XIIIa but differ strongly in its absence. Uncross-linked rFib420 networks are softer and up to 3-fold more extensible than rFib340 networks. Electron microscopy imaging showed that the 2 variants formed networks with a comparable structure, except at 4 mg/mL, where rFib420 formed denser networks. Conclusion: We propose that the αEC domains of rFib420 increase the extensibility of uncross-linked fibrin networks by promoting protofibril sliding, which is blocked by FXIIIa cross-linking. Our findings can help explain the functional role of different circulating fibrinogen variants in blood clot mechanics and tissue repair.
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|J. Thromb. Haemost.
|Biological Soft Matter-Former Group
Martinez-Torres, C., Grimbergen, J., Koopman, J., & Koenderink, G. (2023). Interplay of fibrinogen αEC globular domains and factor XIIIa cross-linking dictates the extensibility and strain stiffening of fibrin networks. J. Thromb. Haemost., 21(10). doi:10.1016/j.jtha.2023.10.025