|Coagulation factor XII (Hageman factor)|
|Symbols||; HAE3; HAEX; HAF|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 22.214.171.124) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.
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.
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, which is now regarded as an obsolete term, because of the fact that there is no intrinsic pathway in vivo. Factor XII is only used to start coagulation cascades in laboratory studies and is considered to have little to no effect on coagulation in vivo.
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).
Role in disease
Factor XII deficiency is a rare disorder that is inherited in an autosomal recessive manner. Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding. 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.
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. 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. All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen.
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.
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. 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.
- Cool DE, MacGillivray RT (October 1987). "Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region". J. Biol. Chem. 262 (28): 13662–73. PMID 2888762.
- Stavrou E, Schmaier AH (March 2010). "Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis". Thromb. Res. 125 (3): 210–5. doi:10.1016/j.thromres.2009.11.028. PMC 2851158. PMID 20022081.
- Beringer DX, Kroon-Batenburg LM (February 2013). "The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 69 (Pt 2): 94–102. doi:10.1107/S1744309113000286. PMID 23385745.
- Renné T, Schmaler AH, Nickel KF, Blombäck M, Maas C (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.
- Wagenman, BL; Townsend, KT, Mathew, P, Crookston, KP (June 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 H-U, 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". Trans. Assoc. Am. Physicians 68: 149–54. PMID 13299324.
- Gordon EM, Gallagher CA, Johnson TR, Blossey BK, Ilan J (April 1990). "Hepatocytes express blood coagulation factor XII (Hageman factor)". J. Lab. Clin. Med. 115 (4): 463–9. PMID 2324612.
- Girolami A, Randi ML, Gavasso S, et al. (2005). "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". J. Thromb. Thrombolysis 17 (2): 139–43. doi:10.1023/B:THRO.0000037670.42776.cd. PMID 15306750.
- Renné T, Gailani D (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 (1992). "O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C". J. Biol. Chem. 267 (8): 5102–7. PMID 1544894.
- McMullen BA, Fujikawa K, Davie EW (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, et al. (1989). "Coagulation factor XII (Hageman factor) Washington D.C.: inactive factor XIIa results from Cys-571----Ser substitution". Proc. Natl. Acad. Sci. U.S.A. 86 (21): 8319–22. doi:10.1073/pnas.86.21.8319. PMC 298272. PMID 2510163.
- Bernardi F, Marchetti G, Patracchini P, et al. (1987). "Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme". Blood 69 (5): 1421–4. PMID 2882793.
- Cool DE, MacGillivray RT (1987). "Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region". J. Biol. Chem. 262 (28): 13662–73. PMID 2888762.
- Que BG, Davie EW (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, et al. (1988). "Structural gene encoding human factor XII is located at 5q33-qter". Somat. Cell Mol. Genet. 14 (2): 217–21. doi:10.1007/BF01534407. PMID 3162339.
- Citarella F, Tripodi M, Fantoni A, et al. (1989). "Assignment of human coagulation factor XII (fXII) to chromosome 5 by cDNA hybridization to DNA from somatic cell hybrids". Hum. Genet. 80 (4): 397–8. doi:10.1007/BF00273661. PMID 3198120.
- Henry ML, Everson B, Ratnoff OD (1988). "Inhibition of the activation of Hageman factor (factor XII) by beta 2-glycoprotein I". J. Lab. Clin. Med. 111 (5): 519–23. PMID 3361230.
- Chung DW, Fujikawa K, McMullen BA, Davie EW (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, et al. (1986). "cDNA sequence coding for human coagulation factor XII (Hageman)". Nucleic Acids Res. 14 (7): 3146. doi:10.1093/nar/14.7.3146. PMC 339730. PMID 3754331.
- Cool DE, Edgell CJ, Louie GV, et al. (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". J. Biol. Chem. 260 (25): 13666–76. PMID 3877053.
- McMullen BA, Fujikawa K (1985). "Amino acid sequence of the heavy chain of human alpha-factor XIIa (activated Hageman factor)". J. Biol. Chem. 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 (1983). "Amino acid sequence of human beta-factor XIIa". J. Biol. Chem. 258 (18): 10924–33. PMID 6604055.
- Hovinga JK, Schaller J, Stricker H, et al. (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, et al. (1996). "The novel acceptor splice site mutation 11396(G-->A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients". Hum. Mol. Genet. 4 (7): 1235–7. doi:10.1093/hmg/4.7.1235. PMID 8528215.
- Hofferbert S, Müller J, Köstering H, et al. (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". Hum. Genet. 97 (6): 838–41. doi:10.1007/BF02346200. PMID 8641707.
- The MEROPS online database for peptidases and their inhibitors: S01.211
- Factor XII at the US National Library of Medicine Medical Subject Headings (MeSH)