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

Helen R Mcpherson,Lih T Cheah,Khalid M Naseem,Marco M Domingues,Simon Da Connell,Matthew S Hindle,Victoria C Ridger,Robert As Ariëns,Nathan L Asquith,Cedric Duval,Stephen R Baker,Ramzi A Ajjan,Helen Philippou

doi:10.7554/elife.68761

Abstract

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.

Highlights

Fibrinogen is a major component of the blood, normally circulating at concentrations between 1.5-4 mg/mL (Bridge et al, 2014)
Clots produced from α220 fibrinogen have stunted fibres and abnormal network structures that show drastically reduced mechanical and fibrinolytic resistance
These findings demonstrate a far greater role for the fibrinogen αC-region than hitherto thought, with it being critically important for normal fibrin fibre formation, growth and clot stability

Summary

Introduction

Fibrinogen is a major component of the blood, normally circulating at concentrations between 1.5-4 mg/mL (Bridge et al, 2014). The fibrinogen molecule is composed of two pairs of three chains each (Aα2Bβ2γ2). The E-region is connected to two distal D-regions by two coiled-coil regions comprised of all three chains. While the C-termini of the B - and γ-chains end in the D-region, the Aα-chains extend for a substantial length from the Dregion (Undas and Ariëns, 2011). This extension is known as the αC-region and is composed of two main subsections, a highly flexible αC-connector (α221-α391) and a globular domain known as the αC-domain (α392-α610)(Tsurupa et al, 2002)

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