Fibrin Formation, Structure and Properties

Abstract

Fibrinogen and fibrin are essential for hemostasis and are major factors in thrombosis, wound healing, and several other biological functions and pathological conditions. The X-ray crystallographic structure of major parts of fibrin(ogen), together with computational reconstructions of missing portions and numerous biochemical and biophysical studies, have provided a wealth of data to interpret molecular mechanisms of fibrin formation, its organization, and properties. On cleavage of fibrinopeptides by thrombin, fibrinogen is converted to fibrin monomers, which interact via knobs exposed by fibrinopeptide removal in the central region, with holes always exposed at the ends of the molecules. The resulting half-staggered, double-stranded oligomers lengthen into protofibrils, which aggregate laterally to make fibers, which then branch to yield a three-dimensional network. Much is now known about the structural origins of clot mechanical properties, including changes in fiber orientation, stretching and buckling, and forced unfolding of molecular domains. Studies of congenital fibrinogen variants and post-translational modifications have increased our understanding of the structure and functions of fibrin(ogen). The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active proteolytic enzyme, plasmin, results in digestion of fibrin at specific lysine residues. In spite of a great increase in our knowledge of all these interconnected processes, much about the molecular mechanisms of the biological functions of fibrin(ogen) remains unknown, including some basic aspects of clotting, fibrinolysis, and molecular origins of fibrin mechanical properties. Even less is known concerning more complex (patho)physiological implications of fibrinogen and fibrin.

Loss of fibrinogen in zebrafish results in an asymptomatic embryonic hemostatic defect and synthetic lethality with thrombocytopenia

“…Fibrinogen is a liver‐derived hexameric glycoprotein encoded by paralogous genes FGA , FGB and FGG (coding for A α , B β and γ chains, respectively) on human chromosome 4 (4q31.3–4q32.1) . In the presence of thrombin, fibrinopeptides (A and B) are removed, leaving fibrin monomers, which are stabilized by FXIII cross‐linking , driving insoluble clot formation. Mutations in FGA , FGB or FGG can all affect the synthesis, assembly, intracellular processing, stability or secretion of fibrinogen.…”

Ca(2+)-dependent regulation of fibrinolytic system activation on fibrin(ogen) D-domains

“…Two sets of high-affinity binding sites for both tissue-type plasminogen activator and plasminogen, which play an important role in the initiation of fibrinolysis, are located on the αC-domain and the peripheral D-domain [2]. These sites are hidden in the intact fibrinogen and exposed in fibrin during polymerization.…”

“…Calcium binding sites are integral parts of the fibrinogen molecule. There are three high-affinity binding sites, two of which are associated with the D-domain and one located at the E-domain [2]. In the E-domain Ca 2+ -binding site is not clearly identified [4].…”

“…Covalent cross-linkage by factor XIIIa also needs calcium ions. During fibrin digestion, Ca 2+ limits the extent of plasmin and trypsin action [2].…”

The application of large amplitude oscillatory stress in a study of fully formed fibrin clots

“…1 The evolving fibrin network entraps cells such as red blood cells, white blood cells, and platelets and is reinforced by Factor XIII mediated covalent cross-linking to produce a more mechanically and chemically stable fully formed fibrin clot. [2][3][4] In disease, the undesirable formation of fibrin clots can block blood vessels, thus preventing blood supply to tissues. Blockages in the veins are termed a Venous Thromboembolism (VTE) and are responsible for a significant global disease burden.…”