Fibrinogen (Factor I) has many functions in haemostasis, a process that stops bleeding from damaged tissue. Such functions include coagulation (the creation of blood clots), fibrinolysis (the breaking down of blood clots), wound healing, inflammation and cell–cell interactions.
Coagulation, or blood clotting, is a highly regulated process that can be separated into four distinct stages (Monroe and Hoffman et al., 2007) (Figure 1):
Fibrinogen plays an important structural role in both the propagation and stabilisation stages of coagulation, allowing for both clot formation and stability. An important feature of the coagulation process is its ability to trigger a fast response when tissue is damaged. As a result, fibrinogen is produced in an inactive state (like many other coagulation factors) by the liver and is secreted into blood to a normal variable range described as 2–4.5 g/L (Collins et al., 2014) or 1.5–3.5 g/L (Tennent et al., 2007; Neerman-Arbez & Casini, 2018).
In its inactive state, fibrinogen is a large, soluble, hexameric glycoprotein that is made up of two copies each of three peptides Aα, Bβ and γ that are held together by disulphide bonds (Figure 2).
Upon initiation and amplification of the coagulation cascade (Figure 1), thrombin interacts with fibrinogen and cleaves the end-terminal regions of the Aα and Bβ peptides to produce fibrinopeptides A and B, respectively. This converts fibrinogen into soluble fibrin monomers that rapidly aggregate to form an insoluble fibrin polymer mesh. At the same time, thrombin converts another procoagulant, Factor XIII, into its active form, Factor XIIIa, a transglutaminase that cross-links glutamine residues from one fibrin monomer to lysine residues of another fibrin monomer, allowing for structural stability (Monroe and Hoffman et al., 2007) (Figure 3).
Activated platelets aggregate on to the fibrin meshes through their surface glycoproteins IIb/IIIa and separately, bind to blood vessel walls to create a haemostatic plug (blood clot). Fibrin meshes also serve as a binding scaffold for other proteins involved in blood clotting (Laurens et al., 2006). This includes fibronectin (involved in cell adhesion), albumin (regulates fibrin ‘thickness’), thrombospondin (regulates the aggregation and binding of platelets to fibrin), Von Willebrand factor (involved in platelet adhesion) and fibrulin (promotes platelet adhesion to the extracellular matrix). Growth factors such as fibroblast growth factor-2 and vascular endothelial growth factor that encourage blood vessel repair also interact with fibrin meshes (Brown et al., 1996; Sahni et al., 1998). Finally, fibrin is involved in activating the immune response, the first line of defence upon tissue damage. This is achieved through fibrin binding and accumulating cells required for both an inflammatory response and for tissue repair (Esmon et al., 2012). Altogether, activated fibrinogen creates an adhesive and stable structure for building blood clots and promoting blood vessel repair.
Fibrin is involved in regulating fibrinolysis, a process whereby blood clots that are no longer needed are broken down. This action reduces circulating blood clots that have the potential to block vessels and cause further damage (Chapin & Hajjar, 2015).
Plasmin is a serine protease enzyme that inactivates various blood plasma proteins through enzymatic cleavage (proteolysis), including fibrin clots. Plasmin is produced and released from the liver as a zymogen called plasminogen and two circulating types exist based on the number of glycosylation moieties they possess (one versus two). Type I plasminogen, which contains two glycosylation moieties, is preferentially recruited to blood clots. Freely circulating plasminogen is normally inactive until it binds to an activator such as a blood clot. This allows for a conformational change that promotes plasminogen conversion to plasmin through enzymes such as tissue plasminogen activator (tPA) (Chapin & Hajjar, 2015) (Figure 4). Importantly, fibrin is a cofactor that allows tPA activity and therefore is involved in promoting plasmin formation (Hoylaerts et al., 1982; Horrevoets et al., 1997). If plasmin levels are too low, as occurs in the absence of fibrin, then blood clots may persist as they are not being efficiently broken down, thus increasing the risk of thrombosis. Indeed, roles for fibrinogen in both clot formation and breakdown is ‘paradoxical’ in nature, whereby a deficiency can lead to reduced blood clotting and excessive bleeding, but at the same time, increases the risk of thrombotic complications.
The structural role for fibrinogen in clot formation and the regulatory role of fibrin in fibrinolysis impacts greatly on haemostasis, particularly during trauma involving bleeding. This is highlighted in patients that have congenital deficiencies of fibrinogen who are prone to excessive bleeding. Furthermore, fibrinogen is the first coagulant to dramatically decrease as a result of fibrinogen consumption, dilution or bleeding during trauma, cardiac surgery and postpartum haemorrhage.
Alternatively login via
Back to epgonline.org