Fibrinogen and fibrin structure and functions

Summary.  Fibrinogen molecules are comprised of two sets of disulfide‐bridged A α ‐, B β ‐, and γ ‐chains. Each molecule contains two outer D domains connected to a central E domain by a coiled‐coil segment. Fibrin is formed after thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen A α ‐chains, thus initiating fibrin polymerization. Double‐stranded fibrils form through end‐to‐middle domain (D:E) associations, and concomitant lateral fibril associations and branching create a clot network. Fibrin assembly facilitates intermolecular antiparallel C‐terminal alignment of γ ‐chain pairs, which are then covalently ‘cross‐linked’ by factor XIII (‘plasma protransglutaminase’) or XIIIa to form ‘ γ ‐dimers’. In addition to its primary role of providing scaffolding for the intravascular thrombus and also accounting for important clot viscoelastic properties, fibrin(ogen) participates in other biologic functions involving unique binding sites, some of which become exposed as a consequence of fibrin formation. This review provides details about fibrinogen and fibrin structure, and correlates this information with biological functions that include: (i) suppression of plasma factor XIII‐mediated cross‐linking activity in blood by binding the factor XIII A 2 B 2 complex. (ii) Non‐substrate thrombin binding to fibrin, termed antithrombin I (AT‐I), which down‐regulates thrombin generation in clotting blood. (iii) Tissue‐type plasminogen activator (tPA)‐stimulated plasminogen activation by fibrin that results from formation of a ternary tPA‐plasminogen‐fibrin complex. Binding of inhibitors such as α 2 ‐antiplasmin, plasminogen activator inhibitor‐2, lipoprotein(a), or histidine‐rich glycoprotein, impairs plasminogen activation. (iv) Enhanced interactions with the extracellular matrix by binding of fibronectin to fibrin(ogen). (v) Molecular and cellular interactions of fibrin β 15–42. This sequence binds to heparin and mediates platelet and endothelial cell spreading, fibroblast proliferation, and capillary tube formation. Interactions between β 15–42 and vascular endothelial (VE)‐cadherin, an endothelial cell receptor, also promote capillary tube formation and angiogenesis. These activities are enhanced by binding of growth factors like fibroblast growth factor‐2 (FGF‐2) and vascular endothelial growth factor (VEGF), and cytokines like interleukin (IL)‐1. (vi) Fibrinogen binding to the platelet α IIb β 3 receptor, which is important for incorporating platelets into a developing thrombus. (vii) Leukocyte binding to fibrin(ogen) via integrin α M β 2 (Mac‐1), which is a high affinity receptor on stimulated monocytes and neutrophils.