Fibrinogen


Fibrinogen is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.
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. These disorders may also be the cause of certain 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.

Genes

Fibrinogen is made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells are also reported to make 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 encoded by the FGA gene, the fibrinogen beta chain encoded by the FGB gene, and the fibrinogen gamma chain encoded by the FGG gene. All three genes are located on the long or "q" arm of human chromosome 4.
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; 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 are transcribed and translated in co-ordination by a mechanism 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.

Structure

The Aα, Bβ, and γ chains are transcribed and translated coordinately on the endoplasmic reticulum, 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 2 heximers, i.e. two AαBβγ trimers joined 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 angstroms. The two end nodules are alike in consisting of Bβ and γ chains, while the center slightly smaller nodule 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 of ~340 – ~420 kDa . It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and has a negative net charge at physiological pH. 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.

Blood clot formation

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 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. 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 degrading formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites for thrombin; this binding sequesters thrombin from attacking fibrinogen. Second, fibrin's Aα chain accelerates by at least 100-fold the amount of plasmin activated by tissue plasminogen activator; plasmin breaks-down blood clots. Plasmin's attack on fibrin releases D-dimers. The detection of these dimers in blood is used as a clinical test for fibrinolysis.

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

Congenital afibrinogenemia is a rare and generally autosomal recessive inherited disorder in which blood does not clot due to a lack of fibrinogen 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 the FGA, FGB, or FBG gene. The mutations have virtually complete genetic penetrance with essentially all 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.

Congenital hypofibrinogenemia

Congenital hypofibrinogenemia is a rare inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen. 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.

Fibrinogen 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 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.

Congenital 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 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.

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.

Acquired 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 liver disease including hepatoma, chronic active hepatitis, cirrhosis, and jaundice due to biliary tract obstruction. The diseased liver synthesizes a fibrinogen which has a normally functional amino acid sequence but is incorrectly glycosylated 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 are plasma cell dyscrasias and autoimmune disorders in which a circulating abnormal immunoglobulin or other protein interferes with fibrinogen function, and rare cases of cancer and medication toxicities.