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

eLife

Victoria C Ridger¹  Stephen R Baker²  Lih T Cheah³  Helen R McPherson³  Helen Philippou³  Khalid M Naseem³  Cedric Duval³  Robert AS Ariëns³  Matthew S Hindle³  Ramzi A Ajjan³  Nathan L Asquith⁴  Marco M Domingues⁵  Simon DA Connell⁶ 

[1] Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom;Department of Physics, Wake Forest University, Winston Salem, United States;Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom;Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States;Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal;Molecular and Nanoscale Physics Group, University of Leeds, Leeds, United Kingdom;

关键词: blood coagulation;    fibrinogen;    bleeding;    thrombosis;    vascular biology;    Human;    Mouse;   

DOI  :  10.7554/eLife.68761

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-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 αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.

【 授权许可】

CC BY