Fibrinogen is a hexameric glycoprotein composed of two α (FGA), two β (FGB), and two γ (FGG) polypeptide chains. Fibrinogen subunits are primarily produced and assembled in hepatocytes before being secreted into the bloodstream as a complete fibrinogen hexamer, which circulates in plasma at high concentrations (2- 4 g/l) (Tennent GA et al, 2007; reviewed by Redman CM & Xia H 2001; Lord ST 2007; Kattula S et al., 2017; Dobson DA et al., 2024). Fibrinogen subunits are held together by disulfide bonds to form an elongated structure with two outer D domains connected through a coiled-coil segment to the central E domain. The D domains are made of the C-terminal ends of β and γ chains, while the E domain is formed by the N-terminal regions of all six chains (Spraggon G et al., 1997; Yang Z et al., 2000; Mosesson MW 2005; Kollman JM et al., 2009; Medved L & Weisel JW 2009; Weisel JW & Litvinov RI 2017; Butera D & Hogg PJ 2020; Litvinov RI et al., 2021). During coagulation, thrombin (FIIa) cleaves the alpha and beta chains of fibrinogen at the E domain. This cleavage results in the release of fibrinopeptides A and B from the N-terminal regions of the α and β chains, respectively, leading to the formation of a soluble fibrin monomer (Ni et al. 1989; Pechik I et al., 2006; Riedel T et al., 2011). The cleavage unmasks four binding sites in the E domain allowing binding to the C-terminal region of the D domain from other fibrin monomers leading to formation of protofibrils (reviewed by Litvinov RI et al., 2021; Wolberg AS 2023).

This Reactome event shows thrombin-mediated proteolytic cleavage of fibrinogen to fibrin, releasing fibrinopeptides A and B.
Some direct oral anticoagulant (DOAC) drugs are potent, competitive direct thrombin inhibitors (DTIs). They reversibly and specifically bind both clot-bound and free thrombin (unlike warfarin or heparin), as well as inhibiting thrombin-induced platelet aggregation. These drugs can be synthetic organic compounds (dabigatran, argatroban) or recombinant peptides (lepirudin, bivalirudin, desirudin). Dabigatran (brand name Pradexa) is formulated as a lipophilic prodrug, dabigatran etexilate, to promote gastrointestinal absorption before it is metabolised to the active drug. The kidneys excrete the majority (80%) of unchanged drug (Stangier J et al. 2007). Argatroban is a synthetic inhibitor of thrombin derived from L-arginine, which has a relatively short period of binding only to thrombin’s active site (Hursting MJ et al. 1997). It is given intravenously and is metabolised in the liver. Because of its hepatic metabolism, it may be used in patients with renal dysfunction. Lepirudin (brand name Refludan) is a recombinant hirudin derived from yeast cells (Weitz JI et al. 1990). Hirudin is a naturally occurring anticoagulant produced by the salivary glands of medicinal leeches. Bivalirudin (brand name Angiomax, Angiox) is a synthetic analog of hirudin, with a shorter period of binding to thrombin (Gladwell TD 2002). Desirudin (brand name Iprivask) is another recombinant hirudin derivative that directly inhibits free and fibrin-bound thrombin (Graetz TJ et al. 2011). Melagatran is the active drug formed from the prodrug ximelagatran and is a competitive and rapid inhibitor of thrombin (Gustafsson D et al. 1998). DuP 714 is a potent and specific thrombin inhibitor (Chiu AT et al. 1991).