| Coagulation factor XII (Hageman factor) |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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4BDW, 4BDX, 4XDE, 4XE4
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| Identifiers |
| Symbols |
F12 ; HAE3; HAEX; HAF |
| External IDs |
OMIM: 610619 MGI: 1891012 HomoloGene: 425 ChEMBL: 2821 GeneCards: F12 Gene |
| EC number |
3.4.21.38 |
| Gene ontology |
| Molecular function |
• serine-type endopeptidase activity
• protein binding
• misfolded protein binding
• serine-type aminopeptidase activity
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| Cellular component |
• extracellular region
• extracellular space
• plasma membrane
• extracellular exosome
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| Biological process |
• plasma kallikrein-kinin cascade
• Factor XII activation
• blood coagulation
• blood coagulation, intrinsic pathway
• positive regulation of plasminogen activation
• protein processing
• protein autoprocessing
• positive regulation of blood coagulation
• zymogen activation
• fibrinolysis
• innate immune response
• response to misfolded protein
• positive regulation of fibrinolysis
|
| Sources: Amigo / QuickGO |
|
| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
2161 |
58992 |
| Ensembl |
ENSG00000131187 |
ENSMUSG00000021492 |
| UniProt |
P00748 |
Q80YC5 |
| RefSeq (mRNA) |
NM_000505 |
NM_021489 |
| RefSeq (protein) |
NP_000496 |
NP_067464 |
| Location (UCSC) |
Chr 5:
177.4 – 177.41 Mb |
Chr 13:
55.42 – 55.43 Mb |
| PubMed search |
[1] |
[2] |
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Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 3.4.21.38) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.[1]
Contents
- 1 Structure
- 2 Function
- 3 Genetics
- 4 Role in disease
- 5 History
- 6 References
- 7 Further reading
- 8 External links
Structure
Human Factor XII is 596 amino acids long and consists of two domains, the heavy chain (353 residues) and light chain (243 residues) held together by a disulfide bond. It is 80,000 daltons. Its heavy chain contains two fibronectin-type domains (type I and II), two epidermal growth factor-like domains, a kringle domain, and a proline-rich region, and its light chain contains the protease domain. Recently, the structure of the FnI-EGF-like tandem domain of coagulation factor XII was solved by x-ray crystallography.[2][3]
Function
Factor XII is part of the coagulation cascade and activates factor XI and prekallikrein in vitro. Factor XII itself is activated to factor XIIa by negatively charged surfaces, such as glass. This is the starting point of the intrinsic pathway.[citation needed] Factor XII can also be used to start coagulation cascades in laboratory studies.[4]
In vivo, factor XII is activated by contact to polyanions. Activated platelets secrete inorganic polymers, polyphosphates. Contact to polyphosphates activates factor XII and initiates fibrin formation by the intrinsic pathway of coagulation with critical importance for thrombus formation. Targeting polyphosphates with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of Hermansky-Pudlak syndrome patients, indicating that the inorganic polymer is the endogenous factor XII activator in vivo. Platelet polyphosphate-driven factor XII activation provides the link from primary hemostasis (formation of a platelet plug) to secondary hemostasis (fibrin meshwork formation).[5]
Genetics
The gene for factor XII is located on the tip of the long arm of the fifth chromosome (5q33-qter).[1]
Role in disease
Factor XII deficiency is a rare disorder that is inherited in an autosomal recessive manner.[6] Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding.[6] Mice lacking the gene for factor XII, however, are less susceptible to thrombosis. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall.[7]
Factor XII does play an important role in clot formation during in vitro measurements of the partial thromboplastin time, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor XI deficiency.[6] As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result.[6] All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen.[6]
Excess levels of factor XII can predispose individuals towards greater risk of venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of plasmin.[8]
Factor XII is also activated by endotoxins, especially lipid A.
History
Hageman factor was first discovered in 1955 when a routine preoperative blood sample of the 37-year-old railroad brakeman John Hageman (1918) was found to have prolonged clotting time in test tubes, even though he had no hemorrhagic symptoms. Hageman was then examined by Dr. Oscar Ratnoff, who found that Mr. Hageman lacked a previously unidentified clotting factor.[9] Dr. Ratnoff later found that the Hageman factor deficiency is an autosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically, pulmonary embolism contributed to Hageman's death after an occupational accident. Since then, case studies and clinical studies identified an association between thrombosis and Factor XII deficiency. Hepatocytes express blood coagulation factor XII.[10]
References
- ^ a b Cool DE, MacGillivray RT (Oct 1987). "Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region". The Journal of Biological Chemistry 262 (28): 13662–73. PMID 2888762.
- ^ Stavrou E, Schmaier AH (Mar 2010). "Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis". Thrombosis Research 125 (3): 210–5. doi:10.1016/j.thromres.2009.11.028. PMC 2851158. PMID 20022081.
- ^ Beringer DX, Kroon-Batenburg LM (Feb 2013). "The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS". Acta Crystallographica. Section F, Structural Biology and Crystallization Communications 69 (Pt 2): 94–102. doi:10.1107/S1744309113000286. PMID 23385745.
- ^ Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C (Nov 2012). "In vivo roles of factor XII". Blood 120 (22): 4296–303. doi:10.1182/blood-2012-07-292094. PMID 22993391.
- ^ Müller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM, Schmidbauer S, Gahl WA, Morrissey JH, Renné T (Dec 2009). "Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo". Cell 139 (6): 1143–56. doi:10.1016/j.cell.2009.11.001. PMC 2796262. PMID 20005807.
- ^ a b c d e Wagenman BL, Townsend KT, Mathew P, Crookston KP (Jun 2009). "The laboratory approach to inherited and acquired coagulation factor deficiencies". Clinics in Laboratory Medicine 29 (2): 229–52. doi:10.1016/j.cll.2009.04.002. PMID 19665676.
- ^ Renné T, Pozgajová M, Grüner S, Schuh K, Pauer HU, Burfeind P, Gailani D, Nieswandt B (Jul 2005). "Defective thrombus formation in mice lacking coagulation factor XII". The Journal of Experimental Medicine 202 (2): 271–81. doi:10.1084/jem.20050664. PMC 2213000. PMID 16009717.
- ^ Kroll, Michael H. (2001). Manual of Coagulation Disorders. Blackwell Science. pp. 3–4, 206–207. ISBN 0-86542-446-2.
- ^ Ratnoff OD, Margolius A (1955). "Hageman trait: an asymptomatic disorder of blood coagulation". Transactions of the Association of American Physicians 68: 149–54. PMID 13299324.
- ^ Gordon EM, Gallagher CA, Johnson TR, Blossey BK, Ilan J (Apr 1990). "Hepatocytes express blood coagulation factor XII (Hageman factor)". The Journal of Laboratory and Clinical Medicine 115 (4): 463–9. PMID 2324612.
Further reading
- Girolami A, Randi ML, Gavasso S, Lombardi AM, Spiezia F (Apr 2004). "The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature". Journal of Thrombosis and Thrombolysis 17 (2): 139–43. doi:10.1023/B:THRO.0000037670.42776.cd. PMID 15306750.
- Renné T, Gailani D (Jul 2007). "Role of Factor XII in hemostasis and thrombosis: clinical implications". Expert Review of Cardiovascular Therapy 5 (4): 733–41. doi:10.1586/14779072.5.4.733. PMID 17605651.
- Harris RJ, Ling VT, Spellman MW (Mar 1992). "O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C". The Journal of Biological Chemistry 267 (8): 5102–7. PMID 1544894.
- McMullen BA, Fujikawa K, Davie EW (Feb 1991). "Location of the disulfide bonds in human plasma prekallikrein: the presence of four novel apple domains in the amino-terminal portion of the molecule". Biochemistry 30 (8): 2050–6. doi:10.1021/bi00222a007. PMID 1998666.
- Miyata T, Kawabata S, Iwanaga S, Takahashi I, Alving B, Saito H (Nov 1989). "Coagulation factor XII (Hageman factor) Washington D.C.: inactive factor XIIa results from Cys-571----Ser substitution". Proceedings of the National Academy of Sciences of the United States of America 86 (21): 8319–22. doi:10.1073/pnas.86.21.8319. PMC 298272. PMID 2510163.
- Bernardi F, Marchetti G, Patracchini P, del Senno L, Tripodi M, Fantoni A, Bartolai S, Vannini F, Felloni L, Rossi L (May 1987). "Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme". Blood 69 (5): 1421–4. PMID 2882793.
- Cool DE, MacGillivray RT (Oct 1987). "Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region". The Journal of Biological Chemistry 262 (28): 13662–73. PMID 2888762.
- Que BG, Davie EW (Apr 1986). "Characterization of a cDNA coding for human factor XII (Hageman factor)". Biochemistry 25 (7): 1525–8. doi:10.1021/bi00355a009. PMID 3011063.
- Royle NJ, Nigli M, Cool D, MacGillivray RT, Hamerton JL (Mar 1988). "Structural gene encoding human factor XII is located at 5q33-qter". Somatic Cell and Molecular Genetics 14 (2): 217–21. doi:10.1007/BF01534407. PMID 3162339.
- Citarella F, Tripodi M, Fantoni A, Bernardi F, Romeo G, Rocchi M (Dec 1988). "Assignment of human coagulation factor XII (fXII) to chromosome 5 by cDNA hybridization to DNA from somatic cell hybrids". Human Genetics 80 (4): 397–8. doi:10.1007/BF00273661. PMID 3198120.
- Henry ML, Everson B, Ratnoff OD (May 1988). "Inhibition of the activation of Hageman factor (factor XII) by beta 2-glycoprotein I". The Journal of Laboratory and Clinical Medicine 111 (5): 519–23. PMID 3361230.
- Chung DW, Fujikawa K, McMullen BA, Davie EW (May 1986). "Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats". Biochemistry 25 (9): 2410–7. doi:10.1021/bi00357a017. PMID 3521732.
- Tripodi M, Citarella F, Guida S, Galeffi P, Fantoni A, Cortese R (Apr 1986). "cDNA sequence coding for human coagulation factor XII (Hageman)". Nucleic Acids Research 14 (7): 3146. doi:10.1093/nar/14.7.3146. PMC 339730. PMID 3754331.
- Cool DE, Edgell CJ, Louie GV, Zoller MJ, Brayer GD, MacGillivray RT (Nov 1985). "Characterization of human blood coagulation factor XII cDNA. Prediction of the primary structure of factor XII and the tertiary structure of beta-factor XIIa". The Journal of Biological Chemistry 260 (25): 13666–76. PMID 3877053.
- McMullen BA, Fujikawa K (May 1985). "Amino acid sequence of the heavy chain of human alpha-factor XIIa (activated Hageman factor)". The Journal of Biological Chemistry 260 (9): 5328–41. PMID 3886654.
- de Grouchy J, Turleau C (1975). "Tentative localization of a Hageman (Factor XII) locus on 7q, probably the 7q35 band". Humangenetik 24 (3): 197–200. doi:10.1007/bf00283584. PMID 4140832.
- Fujikawa K, McMullen BA (Sep 1983). "Amino acid sequence of human beta-factor XIIa". The Journal of Biological Chemistry 258 (18): 10924–33. PMID 6604055.
- Hovinga JK, Schaller J, Stricker H, Wuillemin WA, Furlan M, Lämmle B (Aug 1994). "Coagulation factor XII Locarno: the functional defect is caused by the amino acid substitution Arg 353-->Pro leading to loss of a kallikrein cleavage site". Blood 84 (4): 1173–81. PMID 8049433.
- Schloesser M, Hofferbert S, Bartz U, Lutze G, Lämmle B, Engel W (Jul 1995). "The novel acceptor splice site mutation 11396(G-->A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients". Human Molecular Genetics 4 (7): 1235–7. doi:10.1093/hmg/4.7.1235. PMID 8528215.
- Hofferbert S, Müller J, Köstering H, von Ohlen WD, Schloesser M (Jun 1996). "A novel 5'-upstream mutation in the factor XII gene is associated with a TaqI restriction site in an Alu repeat in factor XII-deficient patients". Human Genetics 97 (6): 838–41. doi:10.1007/BF02346200. PMID 8641707.
External links
- The MEROPS online database for peptidases and their inhibitors: S01.211
- Factor XII at the US National Library of Medicine Medical Subject Headings (MeSH)
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Proteins: coagulation
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| Coagulation factors |
| Primary hemostasis |
- vWF
- platelet membrane glycoproteins: Ib (A
- B
- IX)
- IIb/IIIa (IIb
- IIIa)
- VI
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| Intrinsic pathway |
- HMWK/Bradykinin
- Prekallikrein/Kallikrein
- XII "Hageman"
- XI
- IX
- VIII
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| Extrinsic pathway |
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| Common pathway |
- X
- V
- II "(Pro)thrombin"
- I "Fibrin"
- Fibrinogen (FGA, FGG)
- XIII
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| Coagulation inhibitors |
- Antithrombin (inhibits II, IX, X, XI, XII)
- Protein C (inhibits V, VIII)/Protein S (cofactor for protein C)
- Protein Z (inhibits X)
- ZPI (inhibits X, XI)
- TFPI (inhibits III)
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| Thrombolysis/fibrinolysis |
- Plasmin
- tPA/urokinase
- PAI-1/2
- α2-AP
- α2-macroglobulin
- TAFI
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Index of cells from bone marrow
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| Description |
- Immune system
- Cells
- Physiology
- coagulation
- proteins
- granule contents
- colony-stimulating
- heme and porphyrin
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| Disease |
- Red blood cell
- Monocyte and granulocyte
- Neoplasms and cancer
- Histiocytosis
- Symptoms and signs
- Blood tests
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| Treatment |
- Transfusion
- Drugs
- thrombosis
- bleeding
- other
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Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21)
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| Digestive enzymes |
- Enteropeptidase
- Trypsin
- Chymotrypsin
- Elastase
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| Coagulation |
- factors: Thrombin
- Factor VIIa
- Factor IXa
- Factor Xa
- Factor XIa
- Factor XIIa
- Kallikrein
- PSA
- KLK1
- KLK2
- KLK3
- KLK4
- KLK5
- KLK6
- KLK7
- KLK8
- KLK9
- KLK10
- KLK11
- KLK12
- KLK13
- KLK14
- KLK15
- fibrinolysis: Plasmin
- Plasminogen activator
- Tissue plasminogen activator
- Urinary plasminogen activator
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| Complement system |
- Factor B
- Factor D
- Factor I
- MASP
- C3-convertase
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| Other immune system |
- Chymase
- Granzyme
- Tryptase
- Proteinase 3/Myeloblastin
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| Venombin |
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| Other |
- Acrosin
- Prolyl endopeptidase
- Pronase
- Proprotein convertases
- Prostasin
- Reelin
- Subtilisin/Furin
- Streptokinase
- S1P
- Cathepsin
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- Biochemistry overview
- Enzymes overview
- By EC number: 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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