Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis

McPherson, H.; Duval, C.; Baker, S. R.; Hindle, M. S.; Cheah, L. T.; Asquith, N. L.; Domingues, M. M.; Ridger, V. C.; Connell, S. D. A.; Naseem, K.; Philippou, H.; Ajjan, R. A.; Ariens, R.

doi:10.1101/2021.05.07.443174

bioRxiv · 10.1101/2021.05.07.443174

Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis

McPherson, H.·Duval, C.·Baker, S. R.·Hindle, M. S.·Cheah, L. T.·Asquith, N. L.·Domingues, M. M.·Ridger, V. C.·Connell, S. D. A.·Naseem, K.·Philippou, H.·Ajjan, R. A.·Ariens, R.

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Abstract

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen -chain (C-region) is composed of an C-domain and C-connector. Two recombinant fibrinogen variants (390 and 220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The 390 variant, truncated before the C-domain, produced clots with a denser structure and thinner fibres. In contrast, the 220 variant, truncated at the start of the C-connector, produced clots that were porous with short stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the C-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the C-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the C-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.

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McPherson, H., Duval, C., Baker, S. R., Hindle, M. S., Cheah, L. T., Asquith, N. L., Domingues, M. M., Ridger, V. C., Connell, S. D. A., Naseem, K., Philippou, H., Ajjan, R. A., Ariens, R.. 2021-05-08. Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis. https://doi.org/10.1101/2021.05.07.443174

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