Fibrinogen

Fibrinogen (factor I) is a glycoprotein that circulates in the blood of vertebrates. During tissue and vascular injury it is converted enzymatically by thrombin to fibrin and subsequently to a fibrin-based blood clot. Fibrinogen functions primarily to occlude blood vessels and thereby stop excessive bleeding. However, fibrinogen's product, fibrin, binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, serves to limit blood clotting. Loss or reduction in this antithrombin 1 activity due to mutations in fibrinogen genes or hypo-fibrinogen conditions can lead to excessive blood clotting and thrombosis. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby functions to promote tissue revascularization, wound healing, and tissue repair. Fibrinogen (factor I) is a glycoprotein that circulates in the blood of vertebrates. During tissue and vascular injury it is converted enzymatically by thrombin to fibrin and subsequently to a fibrin-based blood clot. Fibrinogen functions primarily to occlude blood vessels and thereby stop excessive bleeding. However, fibrinogen's product, fibrin, binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, serves to limit blood clotting. Loss or reduction in this antithrombin 1 activity due to mutations in fibrinogen genes or hypo-fibrinogen conditions can lead to excessive blood clotting and thrombosis. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby functions to promote tissue revascularization, wound healing, and tissue repair. Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human fibrinogen-related disorders. These disorders represent a clinically important group of rare conditions in which individuals may present with severe episodes of pathological bleeding and thrombosis; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively. Certain of these disorders may also be the cause of liver and kidney diseases. Fibrinogen is a 'positive' acute-phase protein, i.e. its blood levels rise in response to systemic inflammation, tissue injury, and certain other events. It is also elevated in various cancers. Elevated levels of fibrinogen in inflammation as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions. Fibrinogen is made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells are also reported to make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein. The final secreted, hepatocyte-derived glycoprotein is composed of two trimers with each trimer composed of three different polypeptide chains, the fibrinogen alpha chain (also termed the Aα or α chain) encoded by the FGA gene, the fibrinogen beta chain (also termed the Bβ or β chain) encoded by the FGB gene, and the fibrinogen gamma chain (also termed the γ chain) encoded by the FGG gene. All three genes are located on the long or 'p' arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively). Alternate splicing of the FGA gene produces a minor expanded isoform of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing of FGG produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen; FGA is not alternatively spliced. Hence, the final fibrinogen product is composed principally of Aα, Bβ, and γ chains with a small percentage of it containing AαE and/or γ' chains in place of Aα and/or γ chains, respectively. The three genes are transcribed and translated in co-ordination by a mechanism(s) which remains incompletely understood. The coordinated transcription of these three fibrinogen genes is rapidly and greatly increased by systemic conditions such as inflammation and tissue injury. Cytokines produced during these systemic conditions, such as interleukin 6 and interleukin 1β, appear responsible for up-regulating this transcription. The Aα, Bβ, and γ chains are transcribed and translated coordinately on the endoplasmic reticulum (ER) with their peptide chains being passed into the ER while their signal peptide portions are removed. Inside the ER, the three chains are assembled initially into Aαγ and Bβγ dimers, then to AαBβγ trimers, and finally to (AαBβγ)2 heximers, i.e. two AαBβγ trimers joined together by numerous disulfide bonds. The heximer is transferred to the Golgi where it is glycosylated, hydroxylated, sulfated, and phosphorylated to form the mature fibrinogen glycoprotein that is secreted into the blood. Mature fibrinogen is arranged as a long flexible protein array of three nodules held together by a very thin thread which is estimated to have a diameter between 8 and 15 Angstrom (Å). The two end nodules (termed D regions or domains) are alike in consisting of Bβ and γ chains while the center slightly smaller nodule (termed the E region or domain) consists of two intertwined Aα alpha chains. Measurements of shadow lengths indicate that nodule diameters are in the range 50 to 70 Å. The length of the dried molecule is 475 ± 25 Å. The fibrinogen molecule circulates as a soluble plasma glycoprotein with a typical molecular weight (depending on its content of Aα verses AαE and γ versus γ' chains) of ~340 kDa. It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and has a negative net charge at physiological pH ( its isoelectric point is pH 5.8). The normal concentration of fibrinogen in blood plasma is 150–400 mg/dL with levels appreciably below or above this range associated with pathological bleeding and/or thrombosis. Fibrinogen has a circulating half-life of ~4 days. During blood clotting, thrombin attacks the N-terminus of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two small polypeptides, fibrinopeptides a and b derived from these respective chains. The individual fibrin strands then polymerize and are cross-linked with other fibrin stands by blood factor XIIIa to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot. In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor. Fibrin participates in limiting blood clot formation and lysing formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites (two in fibrin's E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen. Second, fibrin's Aα chain accelerates by at least 100-fold the mount of plasmin activated by tissue plasminogen activator; plasmin breaks-down blood clots. Plasmin's attack on fibrin releases D-dimers (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis. Several disorders in the quantity and/or quality of fibrinogen cause pathological bleeding, pathological blood clotting, and/or the deposition of fibrinogen in the liver, kidneys, and other tissues. The following list of these disorders briefly describes and compares them and gives linkages to main article Wikipedia pages that offer more complete descriptions.