![]() ![]() In addition to fibrin clot formation, fibrinogen is also necessary for an earlier step in hemostasis (called “primary hemostasis”), the aggregation of platelets leading to formation of a platelet “plug” at the site of vessel wall injury. Thrombosis, often resulting from atherosclerosis or many other pathological processes, is the most common cause of myocardial infarction, ischemic stroke, deep vein thrombosis, and other cardiovascular diseases. Imbalance in one direction (prevalence of fibrinolysis) can lead to bleeding while the opposite imbalance (prevalence of clotting) can cause thrombosis, or formation of a clot that blocks the flow of blood through a vessel (called a thrombus). In vivo, there is a careful balance between clotting, the conversion of fibrinogen to fibrin, and fibrinolysis, the proteolytic dissolution of the clot ( Fig. There is a balance between clotting and fibrinolysis such that excess clotting can lead to thrombosis, while excess fibrinolysis can lead to bleeding Plasmin is formed on the fibrin surface from the zymogen plasminogen by plasminogen activators. The fibrin clot is dissolved through fibrinolysis or cleavage by the proteolytic enzyme plasmin, resulting in fibrin degradation products (FDPs). The clot is formed via a cascade of enzymatic reactions that activates prothrombin to the proteolytic enzyme thrombin, which converts soluble fibrinogen to make insoluble fibrin, the process referred to as blood clotting. Fibrin clots are dissolved by the fibrinolytic system, acting in a series of enzymatic reactions with positive and negative feedback.īasic scheme of fibrin clot formation and fibrinolysis and the balance between these processes. A mechanically stable clot is necessary to prevent blood loss (stopping bleeding is called hemostasis) and to promote wound healing. Fibrinogen is a soluble macromolecule, but forms an insoluble clot or gel on conversion to fibrin by the action of the serine protease thrombin, which is activated by a cascade of enzymatic reactions triggered by vessel wall injury, activated blood cells, or a foreign surface ( Fig. It is a 340-kDa glycoprotein, normally present in human blood plasma at a concentration of about 1.5–4 g/L, that is essential for hemostasis, wound healing, inflammation, angiogenesis, and several other biological functions. Even less is known concerning more complex (patho)physiological implications of fibrinogen and fibrin.įibrinogen was first classified as a fibrous protein with keratin, myosin and epidermin, based on its wide angle X-ray diffraction pattern arising from its α-helical coiled-coil structure ( Bailey et al. 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. 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. Studies of congenital fibrinogen variants and post-translational modifications have increased our understanding of the structure and functions of fibrin(ogen). 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. 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. 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 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. Fibrinogen and fibrin are essential for hemostasis and are major factors in thrombosis, wound healing, and several other biological functions and pathological conditions. ![]()
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