Abstract
Fibrinogen is one of the key molecular players in haemostasis. Thrombin-mediated release of fibrinopeptides from fibrinogen converts this soluble protein into a network of fibrin fibres that form a building block for blood clots. Thrombin-activated factor XIII further crosslinks the fibrin fibres and incorporates antifibrinolytic proteins into the network, thus stabilising the clot. The conversion of fibrinogen to fibrin also exposes binding sites for fibrinolytic proteins to limit clot formation and avoid unwanted extension of the fibrin fibres. Altered clot structure and/or incorporation of antifibrinolytic proteins into fibrin networks disturbs the delicate equilibrium between clot formation and lysis, resulting in either unstable clots (predisposing to bleeding events) or persistent clots that are resistant to lysis (increasing risk of thrombosis). In this review, we discuss the factors responsible for alterations in fibrin(ogen) that can modulate clot stability, in turn predisposing to abnormal haemostasis. We also explore the mechanistic pathways that may allow the use of fibrinogen as a potential therapeutic target to treat vascular thrombosis or bleeding disorders. Better understanding of fibrinogen function will help to devise future effective and safe therapies to modulate thrombosis and bleeding risk, while maintaining the fine balance between clot formation and lysis.
Highlights
Fibrinogen is one of the most abundant plasma proteins, circulating at 2–3 mg/mL concentrations, but levels can more than double in pathological states [1,2]
Alterations in fibrin clot structure may result in either hyperfibrinolysis or hypofibrinolysis, both implicated in a number of pathologies
Rather than using a “sledge hammer” approach for thrombotic vascular occlusion, which increases the risk of bleeding complications, it is perhaps safer to focus on specific molecules that interact with fibrinogen in order to facilitate clot breakdown while maintaining physiological haemostasis
Summary
Fibrinogen is one of the most abundant plasma proteins, circulating at 2–3 mg/mL concentrations, but levels can more than double in pathological states [1,2]. Soluble fibrinogen is converted into an insoluble fibrin network, which forms the backbone of the blood clot and has a critical role in haemostasis by limiting blood loss following vascular injury [3]. We describe the process of clot formation and lysis, discuss the factors responsible for stabilising the fibrin network and explore the potential role of the fibrinogen molecule as a therapeutic target. Structural studies have shown that fibrinogen (Aα, Bβ, γ) assembles such that the Aα, Bβ, γ subunits are antiparallel to each other with the N termini of the subunits interacting with each other via disulphide bonds that hold the two trimeric subunits together to form the hexamer [13,14,15,16,17] (Figure 1). The two phases are coordinated in a precise temporal and spatial manner to reinstate haemostasis, control inflammation and promote tissue repair [19]
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