#Fibrinogen

#Biology

#Advanced

Introduction

• Fibrinogen is a protein made in the liver that plays a critical role in the formation of blood clots, helping to stop bleeding and promote healing.

• It is a hexameric glycoprotein with a molecular weight of 340 kDa and serves as the main structural element in blood clots.

• Glycoproteins are proteins containing glycans attached to amino acid side chains.

• All fibrin sealants in use have two major ingredients, purified fibrinogen (a protein) and purified thrombin (an enzyme) derived from human or bovine (cattle) blood.

Structure

• Fibrinogen is a protein with an elongated structure that consists of three types of polypeptide chains and several disulfide bonds: 

  • Chains: Fibrinogen is made up of two Aα, two Bβ, and two γ chains. 

  • Domains: Fibrinogen has two outer D domains and a central E domain. The D domains are connected to the E domain by a coiled-coil segment. 

  • Disulfide bonds: Fibrinogen has five symmetrical disulfide bridges that join the chains together. 

  • N-termini: The N-termini are located in the central E region. 

  • C-termini: The C-termini radiate outwards. 

• Fibrinogen has many functions, including blood clotting, wound healing, and inflammatory response. Thrombin can convert fibrinogen to fibrin by removing fibrinopeptides from the N-termini of the Aα and Bβ chains. The new N-termini then engage with the C-terminal globular domains of the γ and β chains.

• The αC-region of the fibrinogen α-chain is made up of the αC-domain and αC-connector. The αC-subregions affect clot structure and stability, and are important for longitudinal fiber growth. For example, a variant of fibrinogen with a truncation before the αC-domain produces denser clots with thinner fibers, while a variant with a truncation at the start of the αC-connector produces porous clots with short, stunted fibers.

• Using a fibrinogen mutant (γ-3X) unable to generate γ-γ cross-links [35] and studying clot microrheology using magnetic tweezers, fibrin α-chain cross-linking was shown to significantly increase clot stiffness (storage modulus, G′) by 1.4-fold and significantly decrease clot deformation (loss modulus, G″) by 1.4-fold.

• The Bβ chain attaches to the other two chains to form fibrinogen, which is then used to stop excessive bleeding after an injury.

• Clots formed with γ′ fibrinogen have thinner fibers and smaller pores, and are less stiff and more resistant to lysis. 

• First, it possesses three low affinity binding sites (two in fibrin's E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen.

• Disulfide bonds are required for the formation of a robust fibrin matrix that can withstand the forces of flowing blood and resist premature fibrinolysis.