Fibrinogen is a large, complex, fibrous glycoprotein that plays a key role in blood clotting. It is composed of three pairs of polypeptide chains linked together by disulfide bonds1.
The fibrinogen-like (FBG) domain, which consists of approximately 200 amino acid residues, has high sequence similarity to the C-terminal halves of fibrinogen ß and ? chains. Three distinct fibrinogen-related proteins (FREPs) have been identified in human: ficolin, tenascins, and micro fibril-associated protein (MAP). These FREPs all contain a common C-terminal FBG domain with high sequence identity to the C-terminal regions of fibrinogen ß and ? chains, but differ in their N-terminal regions. The FBG domain in ficolin can be brought together as clusters of three by collagen O-like triple helices, and is responsible for N-acetylglucosamine (GlcNAc) binding activity2.
Physiologist Johannes Müller (1801-1858) described fibrin, the substance of a thrombus. Its soluble precursor, fibrinogen, was thus named by Rudolf Virchow (1821-1902), and isolated chemically by Prosper Sylvain Denis (1799-1863). Alexander Schmidt suggested that the conversion from fibrinogen to fibrin is the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin".HYPERLINK \l "cite_note-Shapiro-4
Fibrinogen is a 340 kDa glycoprotein composed of two sets of three polypeptide chains termed A alpha, B beta and gamma that are joined by 29 disulfide bridging within the N-terminal E domain. The molecules are elongated 45-nm structures consisting of two outer D domains, each connected to a central E domain by a coiled-coil segment. These domains contain constitutive binding sites that participate in fibrinogen conversion to fibrin, fibrin assembly, cross linking, and platelet interactions (e.g., thrombin substrate, Da, Db, gamma XL, D:D, alpha C, gamma A chain platelet receptor) as well as sites that are available after fibrinopeptide cleavage (e.g., E domain low affinity non-substrate thrombin binding site); or that become exposed as a consequence of the polymerization process (e.g., tPA-dependent plasminogen activation). A constitutive plasma factor XIII binding site and a high affinity non-substrate thrombin binding site are located on variant g' chains that comprise a minor proportion of the gamma chain population3.
Mode of action
Initiation of fibrin assembly by thrombin-mediated cleavage of fibrinopeptide A from A alpha chains exposes two EA polymerization sites, and subsequent fibrinopeptide B cleavage exposes two EB polymerization sites that can also interact with platelets, fibroblasts, and endothelial cells. Fibrin generation leads to end-to-middle intermolecular Da to EA associations, resulting in linear double-stranded fibrils and equilaterally branched trimolecular fibril junctions. Side-to-side fibril convergence results in bilateral network branches and multistranded thick fiber cables. Concomitantly, factor XIII or thrombin-activated factor XIIIa introduce intermolecular covalent epsilon-(gamma glutamyl) lysine bonds into these polymers, first creating gamma dimers between properly aligned C-terminal gamma XL sites, which are positioned transversely between the two strands of each fibrin fibril. Later, crosslinks form mainly between complementary sites on alpha chains (forming alpha-polymers), and even more slowly among gamma dimers to create higher order crosslinked gamma trimers and tetramers, to complete the mature network structure3.
Fibrinogen and fibrin play important, overlapping roles in blood clotting, fibrinolysis, cellular and matrix interactions, inflammation, wound healing, and neoplasia3,4. Fibrinogen also specifically binds a variety of other proteins, including fibronectin, albumin, thrombospondin, von Willebrand factor, fibulin, fibroblast growth factor-2, vascular endothelial growth factor, and interleukin-1. Fibrinogen binds to activated alphaIIbbeta3 integrin on the platelet surface, forming bridges responsible for platelet aggregation in hemostasis, and also has important adhesive and inflammatory functions through specific interactions with other cells1.
1.Yee VC, Pratt KP, Côté HC, Trong IL, Chung DW, Davie EW, Stenkamp RE, Teller DC (1997). Crystal structure of a 30 kDa C-terminal fragment from the gamma chain of human fibrinogen. Structure, 15, 5(1), 125-38.
2.Wang X, Zhao Q, and Christensen BM (2005). Identification and characterization of the fibrinogen-like domain of fibrinogen-related proteins in the mosquito, Anopheles gambiae, and the fruitfly, Drosophila melanogaster, genomes. BMC Genomics, 6, 114.
3.Mosesson MW, Siebenlist KR, Meh DA (2001). The structure and biological features of fibrinogen and fibrin. Ann., 936, 11-30