Fibrinogen
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| fibrinogen alpha chain | |
|---|---|
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| Identifiers | |
| Symbol | FGA |
| Entrez | 2243 |
| HUGO | 3661 |
| OMIM | 134820 |
| RefSeq | NM_000508 |
| UniProt | P02671 |
| Other data | |
| Locus | Chr. 4 q28 |
| fibrinogen beta chain | |
|---|---|
| Identifiers | |
| Symbol | FGB |
| Entrez | 2244 |
| HUGO | 3662 |
| OMIM | 134830 |
| RefSeq | NM_005141 |
| UniProt | P02675 |
| Other data | |
| Locus | Chr. 4 q28 |
| Fibrinogen gamma chain | |
|---|---|
| Identifiers | |
| Symbol | FGG |
| Entrez | 2266 |
| HUGO | 3694 |
| OMIM | 134850 |
| RefSeq | NM_021870 |
| UniProt | P02679 |
| Other data | |
| Locus | Chr. 4 q28 |
| Fibrinogen alpha/beta chain family | |||||||||
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crystal structure of native chicken fibrinogen with two different bound ligands
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| Identifiers | |||||||||
| Symbol | Fib_alpha | ||||||||
| Pfam | PF08702 | ||||||||
| InterPro | IPR012290 | ||||||||
| SCOP | 1m1j | ||||||||
| SUPERFAMILY | 1m1j | ||||||||
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| Fibrinogen alpha C domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | Fibrinogen_aC | ||||||||
| Pfam | PF12160 | ||||||||
| InterPro | IPR021996 | ||||||||
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| Fibrinogen beta and gamma chains, C-terminal globular domain | |||||||||
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crystal structure of native chicken fibrinogen with two different bound ligands
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| Identifiers | |||||||||
| Symbol | Fibrinogen_C | ||||||||
| Pfam | PF00147 | ||||||||
| Pfam clan | CL0422 | ||||||||
| InterPro | IPR002181 | ||||||||
| PROSITE | PDOC00445 | ||||||||
| SCOP | 1fza | ||||||||
| SUPERFAMILY | 1fza | ||||||||
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Fibrinogen (factor I) is a glycoprotein in vertebrates that helps in the formation of blood clots. It consists of a linear 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 are alike but the center one is slightly smaller. 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.[2]
The fibrinogen molecule is a soluble, large, and complex 340 kDa plasma glycoprotein, that is converted by thrombin into fibrin during blood clot formation. It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and it shows a negative net charge at physiological pH (IP at pH 5.2).[3] Fibrinogen is synthesized in the liver by the hepatocytes.[3] The concentration of fibrinogen in the blood plasma is 200–400 mg/dL (normally measured using the Clauss method).
During normal blood coagulation, a coagulation cascade activates the zymogen prothrombin by converting it into the serine protease thrombin. Thrombin then converts the soluble fibrinogen into insoluble fibrin strands. These strands are then cross-linked by factor XIII to form a blood clot. FXIIIa stabilizes fibrin further by incorporation of the fibrinolysis inhibitors alpha-2-antiplasmin and TAFI (thrombin activatable fibrinolysis inhibitor, procarboxypeptidase B), and binding to several adhesive proteins of various cells.[4] Both the activation of factor XIII by thrombin and plasminogen activator (t-PA) are catalyzed by fibrin.[4] Fibrin specifically binds the activated coagulation factors factor Xa and thrombin and entraps them in the network of fibers, thus functioning as a temporary inhibitor of these enzymes, which stay active and can be released during fibrinolysis.[5] Research from 2011 has shown that fibrin plays a key role in the inflammatory response and development of rheumatoid arthritis.[6][citation needed]
Physiology[edit]
In its natural form, fibrinogen can form bridges between platelets, by binding to their GpIIb/IIIa surface membrane proteins; however, its major function is as the precursor to fibrin.
Fibrinogen, the principal protein of vertebrate blood clotting, is a hexamer, containing two sets of three different chains (α, β, and γ), linked to each other by disulfide bonds. The N-terminal sections of these three chains contain the cysteines that participate in the cross-linking of the chains. The C-terminal parts of the α, β and γ chains contain a domain of about 225 amino-acid residues, which can function as a molecular recognition unit. In fibrinogen as well as in angiopoietin, this domain is implicated in protein-protein interactions. In lectins, such as mammalian ficolins and invertebrate tachylectin 5A, the fibrinogen C-terminal domain binds carbohydrates. On the fibrinogen α and β chains, there is a small peptide sequence (called a fibrinopeptide). These small peptides are what prevent fibrinogen from spontaneously forming polymers with itself.[7]
The conversion of fibrinogen to fibrin occurs in several steps. First, thrombin cleaves fibrinopeptide A and B located on the N-terminus of the fibrinogen alpha and beta chains respectively.[8] The resulting fibrin monomers polymerize end to end to from protofibrils, which in turn associate laterally to form fibrin fibers.[9] In a final step, the fibrin fibers associate to form the fibrin gel.[10]
Fibrinogen deficiency[edit]
Congenital fibrinogen deficiency (afibrinogenemia) or disturbed function of fibrinogen has been described in a few cases.[11]
It can lead to either bleeding or thromboembolic complications, or is clinically without pathological findings. More common are acquired deficiency stages that can be detected by laboratory tests in blood plasma or in whole blood by means of thrombelastometry.[12] Acquired deficiency is found after hemodilution, blood losses and/or consumption such as in trauma patients, during some phases of disseminated intravascular coagulation (DIC), and also in sepsis. In patients with fibrinogen deficiency, the correction of bleeding is possible by infusion of fresh frozen plasma (FFP), cryoprecipitate (a fibrinogen-rich plasma fraction) or by fibrinogen concentrates. There is increasing evidence that correction of fibrinogen deficiency or fibrinogen polymerization disorders is very important in patients with bleeding.[13]
Diagnostic use[edit]
Fibrinogen levels can be measured in venous blood. Normal levels are about 1.5-3 g/L, depending on the method used. In typical circumstances, fibrinogen is measured in citrated plasma samples in the laboratory; however, the analysis of whole-blood samples by use of thromboelastometry (platelet function is inhibited with cytochalasin D) is also possible.[12] Higher levels are, amongst others, associated with cardiovascular disease (>3.43 g/L). It may be elevated in any form of inflammation, as it is an acute-phase protein; for example, it is especially apparent in human gingival tissue during the initial phase of periodontal disease.[14] Fibrinogen levels increase in pregnancy to an average of 4.5 g/l, compared to an average of 3 g/l in non-pregnant people.[15]
It is used in veterinary medicine as an inflammatory marker: In horses, a level above the normal range of 1.0-4.0 g/L suggests some degree of systemic inflammatory response.[citation needed]
Low levels of fibrinogen can indicate a systemic activation of the clotting system, with consumption of clotting factors faster than synthesis. This excessive clotting factor consumption condition is known as disseminated intravascular coagulation or "DIC." DIC can be difficult to diagnose, but a strong clue is low fibrinogen levels in the setting of prolonged clotting times (PT or aPTT), in the context of acute critical illness such as sepsis or trauma. Besides low fibrinogen level, fibrin polymerization disorders that can be induced by several factors, including plasma expanders, can also lead to severe bleeding problems.[12] Fibrin polymerization disorders can be detected by viscoelastic methods such as thrombelastometry.[12]
A fibrinogen uptake test or fibrinogen scan is a test that was formerly used to detect deep vein thrombosis. In this method, radioactively labeled fibrinogen, typically with radioiodine, is given which is incorporated in the thrombus. The thrombus can then be detected by scintigraphy.
References[edit]
- ^ PDB: 1FZC; Everse SJ, Spraggon G, Veerapandian L, Riley M, Doolittle RF (June 1998). "Crystal structure of fragment double-D from human fibrin with two different bound ligands". Biochemistry. 37 (24): 8637–42. doi:10.1021/bi9804129. PMID 9628725.
- ^ Hall, Ph.D., Cecil E.; HENRY S. SLAYTER (18 August 1958). "The Fibrinogen Molecule: Its Size, Shape, and Mode of Polymerization" (PDF). The Journal of Biophysical and Biochemical Cytology. Plate 1. Cambridge, M: e Department of Biology, Massachusetts Institute of Technology. 5 (1): 11–6. doi:10.1083/jcb.5.1.11. PMC 2224630
. PMID 13630928. Retrieved 24 May 2014. - ^ a b Marucco, Arianna; et al. (2013). "Interaction of fibrinogen and albumin with titanium dioxide nanoparticles of different crystalline phases" (PDF). Journal of Physics. Conference Series. 429 (1). Retrieved 24 May 2014.
- ^ a b Muszbek L, Bagoly Z, Bereczky Z, Katona E (July 2008). "The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis". Cardiovascular & Hematological Agents in Medicinal Chemistry. 6 (3): 190–205. doi:10.2174/187152508784871990. PMID 18673233.
- ^ Kaiser B (2003). "DX-9065a, a direct inhibitor of factor Xa". Cardiovascular Drug Reviews. 21 (2): 91–104. doi:10.1111/j.1527-3466.2003.tb00108.x. PMID 12847561.
- ^ Gilliam BE; Reed, Melinda R; Chauhan, Anil K; Dehlendorf, Amanda B; Moore, Terry L (2011). "Evidence of Fibrinogen as a Target of Citrullination in IgM Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis". Pediatric Rheumatology. 9 (8): xx–xx. doi:10.1186/1546-0096-9-8. ISSN 1546-0096. PMC 3071779. PMID 21439056.
- ^ PDOC00445 Fibrinogen C-terminal domain in PROSITE
- ^ Blombäck B, Hessel B, Hogg D, Therkildsen L (October 1978). "A two-step fibrinogen--fibrin transition in blood coagulation". Nature. 275 (5680): 501–5. doi:10.1038/275501a0. PMID 692730.
- ^ Hermans J, McDonagh J (January 1982). "Fibrin: structure and interactions". Semin. Thromb. Hemost. 8 (1): 11–24. doi:10.1055/s-2007-1005039. PMID 7036348.
- ^ Lorand L, Credo RB; John W. Fenton; Kenneth G. Mann (1977). "Thrombin and fibrin stabilization". In Mann KG; Lundblad RL; Fenton J. Chemistry and Biology of Thrombin. Ann Arbor, Mich: Ann Arbor Science Publishers. pp. 311–323. ISBN 0-250-40160-6.
- ^ Acharya SS, Dimichele DM (November 2008). "Rare inherited disorders of fibrinogen". Haemophilia. 14 (6): 1151–8. doi:10.1111/j.1365-2516.2008.01831.x. PMID 19141154.
- ^ a b c d Lang T, Johanning K, Metzler H, Piepenbrock S, Solomon C, Rahe-Meyer N, Tanaka KA (March 2009). "The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia". Anesthesia and Analgesia. 108 (3): 751–8. doi:10.1213/ane.0b013e3181966675. PMID 19224779.
- ^ Fries D, Innerhofer P, Schobersberger W (April 2009). "Time for changing coagulation management in trauma-related massive bleeding". Current Opinion in Anaesthesiology. 22 (2): 267–74. doi:10.1097/ACO.0b013e32832678d9. PMID 19390253.
- ^ Page RC, Schroeder HE (March 1976). "Pathogenesis of inflammatory periodontal disease. A summary of current work". Lab. Invest. 34 (3): 235–49. PMID 765622.
- ^ Salvi, Vinita (2003). Medical and Surgical Diagnostic Disorders in Pregnancy. Jaypee Brothers Publishers. p. 5. ISBN 978-81-8061-090-5.
External links[edit]
- Jennifer McDowall/Interpro: Protein Of The Month: Fibrinogen.
- D'Eustachio/reactome: fibrinogen → fibrin monomer + 2 fibrinopeptide A + 2 fibrinopeptide B
- Khan Academy Medicine (on YouTube): Clotting 1 - How do we make blood clots?
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Wikimedia Commons has media related to Fibrinogen. |
