Fibrinogen

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Fibrinogen alpha/beta chain family
SCOP2
1m1j / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Fibrinogen alpha C domain
Identifiers
SymbolFibrinogen_aC
PfamPF12160
InterProIPR021996
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Identifiers
SymbolFibrinogen_C
SCOP2
1fza / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Fibrinogen (factor I) is a

endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.[3]

Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human fibrinogen-related disorders. These disorders represent a 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.[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 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.[6][7]

Genes

Fibrinogen is made and secreted into the blood primarily by liver

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 "q" arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively).[1]

Chr. 4 q28
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StructuresSwiss-model
DomainsInterPro
Chr. 4 q28
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StructuresSwiss-model
DomainsInterPro
Chr. 4 q28
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StructuresSwiss-model
DomainsInterPro

interleukin 1β, appear responsible for up-regulating this transcription.[11]

Structure

C-terminal. Bottom: variant containing the AαE isoforms in the place of more common Aα. This AαE/AαE combination has an extended C-terminals (αEC) and a mass of 420 kDa, which is heavier than typical fibrinogen.[13]
Click to see the extended description.
fibrinopeptides B
. αC: Aα chain C-terminal domain. D: D domain. E: E domain.
Disulfide bonds
are also shown (highlighted with yellow). Parts of the actual structure are unresolved: e.g., the C-terminals of Aα chains are too short.

The Aα, Bβ, and γ chains are

sulfated, and phosphorylated 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 soluble

molecular 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 (its isoelectric point ~5.5 – ~6.5, e.g. pH 5.8[16][17]). 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.[12]

Blood clot formation

Main article: Coagulation
Fibrinopeptides B (FpB) are cut off by thrombin a bit later. New N-terminals link to Bβ chains of D domains. αCs previously bound by FpBs are also released. αCs allow for bi- and equilateral branching (Bi, Eq).[13] # XIIIa crosslinks fibrins (dark blue lines). C-terminal γA-γA- and Aα-Aα-crosslinks form.[13]

During blood clotting,

crosslinked with other fibrin strands by blood factor 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, blood platelets through binding to their GpIIb/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.

tissue plasminogen activator; plasmin breaks-down blood clots.[5][18][3][7] 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.[5]

Fibrinogen disorders

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.

Congenital afibrinogenemia

Main article: Congenital afibrinogenemia

Congenital afibrinogenemia is a rare and generally

homozygous 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 the navel.[4]

Congenital hypofibrinogenemia

Main article: Congenital hypofibrinogenemia

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 parental FGA, FGB, or FBG 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]

Fibrinogen storage disease

Main article: Congenital hypofibrinogenemia § Fibringogen storage disease

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 the FGG gene causes its fibrinogen product to accumulate in, and damage, liver cells. The disorder has not reported with FGA or FGB mutations. Symptoms of these FGG 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 liver cirrhosis.[19]

Congenital dysfibrinogenemia

Main article: Dysfibrinogenemia

Congenital dysfibrinogenemia is a rare

autosomal dominant inherited disorder in which plasma fibrinogen is composed of a dysfunctional fibrinogen made by a mutated FGA, FGB, or FBG 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 exhibits reduced penetrance, with only some individuals with the abnormal gene showing symptoms of abnormal bleeding and thrombosis.[20]

Hereditary fibrinogen Aα-Chain amyloidosis

Main article: Dysfibrinogenemia § Hereditary fibrinogen Aα-Chain amyloidosis

Hereditary fibrinogen Aα-Chain amyloidosis is an autosomal dominant extremely rare inherited disorder caused by a mutation in one of the two copies of the FGA 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 of familial 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

Main article: Dysfibrinogenemia

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 severe

antileukemic drugs) toxicities.[18]

Congenital hypodysfibrinogenemia

Main article: Hypodysfibrinogenemia

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 having reduced penetrance, is usually more severe than congenital dysfibrinogenemia, but like the latter disorder, causes pathological episodes of bleeding and/or blood clotting.[22]

Cryofibrinogenemia

Main article: Cryofibrinogenemia

premalignant disorders (21%), vasculitis (25%), and autoimmune 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

Acquired hypofibrinogenemia is a deficiency in circulating fibrinogen due to excessive consumption that may occur as a result of

trauma, certain phases of disseminated intravascular coagulation, and sepsis. It may also occur as a result of hemodilution as a result of blood losses and/or transfusions with packed red blood cells or other fibrinogen-poor whole blood replacements.[27]

Laboratory tests

Clinical analyses of the fibrinogen disorders typically measure blood clotting using the following successive steps:

gingival tissue during the initial phase of periodontal disease.[29][30]

Hyperfibrinogenemia

Levels of functionally normal fibrinogen increase in

trousseau'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 of persistent 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]

History

Paul Morawitz in 1905 described fibrinogen.[37]

References

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External links

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