| Fibrinogen alpha/beta chain family | |||||||
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 crystal structure of native chicken fibrinogen with two different bound ligands | |||||||
| Identifiers | |||||||
| Symbol | Fib_alpha | ||||||
| Pfam | PF08702 | ||||||
| InterPro | IPR012290 | ||||||
| SCOP2 | 1m1j /SCOPe /SUPFAM | ||||||
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| Fibrinogen alpha C domain | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | Fibrinogen_aC | ||||||
| Pfam | PF12160 | ||||||
| InterPro | IPR021996 | ||||||
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| Identifiers | |||||||
|---|---|---|---|---|---|---|---|
| Symbol | Fibrinogen_C | ||||||
| Pfam | PF00147 | ||||||
| Pfam clan | CL0422 | ||||||
| InterPro | IPR002181 | ||||||
| PROSITE | PDOC00445 | ||||||
| SCOP2 | 1fza /SCOPe /SUPFAM | ||||||
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Fibrinogen (coagulation factor I) is aglycoproteincomplex, produced in the liver,[1] that circulates in the blood of allvertebrates.[2] During tissue and vascular injury, it is convertedenzymatically bythrombin tofibrin and then to a fibrin-basedblood clot. Fibrin clots function primarily to occlude blood vessels to stopbleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to asantithrombin I, limits clotting.[1] Fibrin also mediates bloodplatelet andendothelial cell spreading, tissuefibroblast proliferation,capillary tube formation, andangiogenesis and thereby promotesrevascularization andwound healing.[3]
Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired humanfibrinogen-related disorders. These disorders represent a group of rare conditions in which individuals may present with severe episodes of pathological bleeding andthrombosis; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively.[4][5] These disorders may also be the cause of certain liver and kidney diseases.[1]
Fibrinogen is a "positive"acute-phase protein, i.e. its blood levels rise in response tosystemic inflammation, tissue injury, and certain other events. It is also elevated in variouscancers. Elevated levels of fibrinogen ininflammation as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions.[6][7]
Fibrinogen is made and secreted into the blood primarily by liverhepatocyte cells.Endothelium cells are also reported to make small amounts of fibrinogen, but this fibrinogen has not been fully characterized; bloodplatelets and their precursors, bone marrowmegakaryocytes, while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein.[4][7] The final secreted, hepatocyte-derived glycoprotein is composed of twotrimers, with each trimer composed of three differentpolypeptide chains, thefibrinogen alpha chain (also termed the Aα or α chain) encoded by theFGA gene, thefibrinogen beta chain (also termed the Bβ or β chain) encoded by theFGB gene, and thefibrinogen gamma chain (also termed the γ chain) encoded by theFGG gene. All three genes are located on the long or "q" arm of human chromosome 4 (atpositions 4q31.3, 4q31.3, and 4q32.1, respectively).[1]
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Alternate splicing of theFGA gene produces a minor expandedisoform of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing ofFGG produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen;FGB 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 aretranscribed andtranslated in co-ordination by a mechanism(s) which remains incompletely understood.[8][9][10][11][12] 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 asinterleukin 6 andinterleukin 1β, appear responsible for up-regulating this transcription.[11]
The Aα, Bβ, and γ chains aretranscribed andtranslated coordinately on theendoplasmic reticulum (ER), with their peptide chains being passed into the ER while theirsignal 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 by numerousdisulfide bonds. The heximer is transferred to theGolgi where it isglycosylated,hydroxylated,sulfated, andphosphorylated to form the mature fibrinogen glycoprotein that is secreted into the blood.[10][12] 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 angstroms (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.[14]
The fibrinogen molecule circulates as a solubleplasmaglycoprotein with a typicalmolecular weight of ~340 – ~420 kDa (kilodaltons)[15] (depending on its content of Aα verses AαE, γ versus γ' chains, and carbohydrate [~4 – ~10%w/w]). It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and has a negative net charge at physiological pH (itsisoelectric point ~5.5 – ~6.5, e.g. pH 5.8[16][17]). The normal concentration of fibrinogen inblood plasma is 150–400 mg/dl, with levels appreciably below or above this range associated with pathological bleeding and/or thrombosis. Fibrinogen has a circulatinghalf-life of ~4 days.[12]
During blood clotting,thrombin attacks theN-terminus of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two smallpolypeptides,fibrinopeptides A andB derived from these respective chains. The individual fibrin strands then polymerize and arecrosslinked with other fibrin strands by bloodfactor XIIIa to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot.[3][7][18] In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, bloodplatelets through binding to theirGpIIb/IIIa surface membrane fibrinogen receptor.[18]
Fibrin participates in limiting blood clot formation and degrading 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.[18] Second, fibrin's Aα chain accelerates by at least 100-fold the amount ofplasmin activated bytissue plasminogen activator; plasmin breaks-down blood clots.[5][18][3][7] Plasmin's attack on fibrin releasesD-dimers (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis.[5]
Severaldisorders 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.
Congenital afibrinogenemia is a rare and generallyautosomal recessive inherited disorder in which blood does not clot due to a lack of fibrinogen (plasma fibrinogen levels typically) but sometimes detected at extremely low levels, e.g. <10 mg/dl. This severe disorder is usually caused by mutations in both the maternal and paternal copies of either theFGA, FGB, orFBG gene. The mutations have virtually complete geneticpenetrance with essentially allhomozygous bearers experiencing frequent and sometimes life-threatening episodes of bleeding and/or thrombosis. Pathological bleeding occurs early in life, for example often being seen at birth with excessive hemorrhage from thenavel.[4]
Congenital hypofibrinogenemia is a rare inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen (plasma fibrinogen typically <150 but >50 mg/dl). The disorder reflects a disruptive mutation in only one of the two parentalFGA, FGB, orFBG genes and has a low degree of genetic penetrance, i.e. only some family members with the defective gene ever exhibit symptoms. Symptoms of the disorder, which more often occurs in individuals with lower plasma fibrinogen levels, include episodic bleeding and thrombosis that typically begin in late childhood or adulthood.[4]
Fibringogen storage disease is an extremely rare disorder. It is a form of congenital hypofibrinogenemia in which certain specific hereditary mutations in one copy of theFGG gene causes its fibrinogen product to accumulate in, and damage, liver cells. The disorder has not reported withFGA orFGB mutations. Symptoms of theseFGG mutations have a low level of penetrance. The plasma fibrinogen levels (generally <150 but >50 mg/dl) detected in this disorder reflect the fibrinogen made by the normal gene. Fibrinogen storage disease may lead to abnormal bleeding and thrombosis but is distinguished by also sometimes leading to livercirrhosis.[19]
Congenital dysfibrinogenemia is a rareautosomal dominant inherited disorder in which plasma fibrinogen is composed of a dysfunctional fibrinogen made by a mutatedFGA, FGB, orFBG gene inherited from one parent plus a normal fibrinogen made by a normal gene inherited from the other parent. As a reflection of this duality, plasma fibrinogen levels measured by immunological methods are normal (>150 mg/dl) but are c. 50% lower when measured by clot formation methods. The disorder exhibitsreduced penetrance, with only some individuals with the abnormal gene showing symptoms of abnormal bleeding and thrombosis.[20]
Hereditary fibrinogen Aα-Chain amyloidosis is an autosomal dominant extremely rare inherited disorder caused by a mutation in one of the two copies of theFGA gene. It is a form of congenital dysfibrinogenemia in which certain mutations lead to the production of an abnormal fibrinogen that circulates in the blood while gradually accumulating in the kidney. This accumulation leads over time to one form offamilial renal amyloidosis. Plasma fibrinogen levels are similar to that seen in other forms of congenital dysfibrinogenemia. Fibrinogen Aα-Chain amyloidosis has not associated with abnormal bleeding or thrombosis.[21]
Acquired dysfibrinogenemia is a rare disorder in which circulating fibrinogen is composed at least in part of a dysfunctional fibrinogen due to various acquired diseases. One well-studied cause of the disorder is severeliver disease includinghepatoma, chronic activehepatitis,cirrhosis, andjaundice due tobiliary tract obstruction. The diseased liver synthesizes a fibrinogen which has a normally functionalamino acid sequence but is incorrectlyglycosylated (i.e. has a wrong amount of sugar residues) added to it during its passage through the Golgi. The incorrectly glycosalated fibrinogen is dysfunctional and may cause pathological episodes of bleeding and/or blood clotting. Other, less well understood, causes areplasma cell dyscrasias andautoimmune disorders in which a circulating abnormal immunoglobulin or other protein interferes with fibrinogen function, and rare cases of cancer and medication (isotretinoin,glucocorticoids, andantileukemic drugs) toxicities.[18]
Congenital hypodysfibrinogenemia is a rare inherited disorder in which low levels (i.e. <150 mg/dl) of immunologically detected plasma fibrinogen are composed at least in part of a dysfunctional fibrinogen. The disorder reflects mutations typically in both inherited fibrinogen genes, one of which produces a dysfunctional fibrinogen, while the other produces low amounts of fibrinogen. The disorder, while havingreduced penetrance, is usually more severe than congenital dysfibrinogenemia, but like the latter disorder, causes pathological episodes of bleeding and/or blood clotting.[22]
Cryofibrinogenemia is an acquired disorder in which fibrinogen precipitates at cold temperatures and may lead to the intravascular precipitation of fibrinogen,fibrin, and other circulating proteins, thereby causing theinfarction of various tissues and bodily extremities. Cryoglobulonemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulonemia. Secondary cryofibrinoenemia can develop in individuals with infection (c. 12% of cases),malignant orpremalignant disorders (21%),vasculitis (25%), andautoimmune diseases (42%). In these cases, cryofibinogenema may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenmia is unclear. Cryofibrinogenemia can also occur in association with the intake of certain drugs.[23][24][25][26]
Acquired hypofibrinogenemia is a deficiency in circulating fibrinogen due to excessive consumption that may occur as a result oftrauma, certain phases ofdisseminated intravascular coagulation, andsepsis. It may also occur as a result of hemodilution as a result of blood losses and/or transfusions withpacked red blood cells or other fibrinogen-poor whole blood replacements.[27]
Clinical analyses of the fibrinogen disorders typically measure blood clotting using the following successive steps:[28] Higher levels are, amongst others, associated withcardiovascular disease (>3.43 g/L).[clarification needed] It may be elevated in any form ofinflammation, as it is anacute-phase protein; for example, it is especially apparent in humangingival tissue during theinitial phase of periodontal disease.[29][30]
Levels of functionally normal fibrinogen increase inpregnancy to an average of 4.5 gram/liter (g/L) compared to an average of 3 g/L in non-pregnant people. They may also increase in various forms of cancer, particularlygastric,lung,prostate, andovarian cancers. In these cases, thehyperfibrinogenemia may contribute to the development of pathological thrombosis. A particular pattern of migratorysuperficial vein thrombosis, termedtrousseau's syndrome, occurs in, and may precede all other signs and symptoms of, these cancers.[7][32] Hyperfibrinogenemia has also been linked as a cause ofpersistent pulmonary hypertension of the newborn[33] and post-operative thrombosis.[34] High fibrinogen levels had been proposed as a predictor of hemorrhagic complications during catheter-directed thrombolysis for acute or subacute peripheral native artery and arterial bypass occlusions.[35] However, a systematic review of the available literature until January 2016 found that the predictive value of plasma fibrinogen level for predicting hemorrhagic complications after catheter-directed thrombolysis is unproven.[36]
Paul Morawitz in 1905 described fibrinogen.[37]
