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Coagulation factor XII (Hageman factor)
Symbols F12; HAF
External IDs OMIM234000 MGI1891012 HomoloGene425 GeneCards: F12 Gene
EC number
RNA expression pattern
PBB GE F12 205774 at tn.png
More reference expression data
Species Human Mouse
Entrez 2161 58992
Ensembl ENSG00000131187 ENSMUSG00000021492
UniProt P00748 n/a
RefSeq (mRNA) NM_000505 NM_021489
RefSeq (protein) NP_000496 NP_067464
Location (UCSC) Chr 5:
176.76 - 176.77 Mb
Chr 13:
55.43 - 55.44 Mb
PubMed search [1] [2]

Hageman factor is a plasma protein also known as factor XII. It is the zymogen form of factor XIIa, an enzyme (EC of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.[1]



It is part of the coagulation cascade and activates factor XI and prekallikrein. Factor XII itself is activated to factor XIIa by negatively charged surfaces, such as glass.[2]

The coagulation cascade.


The gene for factor XII is located on the tip of the long arm of the fifth chromosome (5q33-qter).[1]

Role in disease

Hageman factor deficiency is a rare hereditary disorder with a prevalence of about one in a million, although it is a little less common among Asians. Deficiency does not cause excessive hemorrhage due to an apparent lack of involvement of the activated form of the zymogen, factor XIIa in thrombin formation. However, it may increase the risk of thrombosis, due to inadequate activation of the fibrinolytic pathway. The deficiency leads to activated partial thromboplastin times (PTT) greater than 200 seconds.

Two missense mutations have been identified in F12, the gene encoding human coagulation factor XII. These mutations are thought to be the cause of a very rare form of hereditary angioedema (HAE), called HAE type III.[3]


Hageman factor was first discovered in 1955 when a routine preoperative blood sample of the 37-year-old railroad brakeman John Hageman 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.[4] Dr. Ratnoff later found that the Hageman factor deficiency is autosomal recessive disorder, when examining several related people which had the deficiency. Paradoxically, pulmonary embolism contributed to Hageman's death after an occupational accident. Since then, case series clinical studies have identified an association of thrombosis and Factor XII deficiency, though the pathophysiology of the relationship is unclear. Hepatocytes express blood coagulation factor XII.[5]


  1. ^ a b 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.  
  2. ^ Encyclopedia Britannica Online, accessed 28/7/08
  3. ^ Cichon S, Martin L, Hennies HC, et al. (2006). "Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III". Am. J. Hum. Genet. 79 (6): 1098–104. doi:10.1086/509899. PMID 17186468.  
  4. ^ Ratnoff OD, Margolius A (1955). "Hageman trait: an asymptomatic disorder of blood coagulation". Trans. Assoc. Am. Physicians 68: 149–54. PMID 13299324.  
  5. ^ 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.  

Further reading

  • 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/ 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. 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. 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. 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.  

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