Alternative titles; symbols
SNOMEDCT: 46981006; ORPHA: 330; DO: 2231;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q35.3 | Factor XII deficiency | 234000 | Autosomal recessive | 3 | F12 | 610619 |
A number sign (#) is used with this entry because of evidence that factor XII deficiency is caused by mutation in the F12 gene (610619) on chromosome 5q35.
Factor XII deficiency was usually discovered because of the practice in some hospitals of routinely performing whole blood clotting times before surgical operations (McCain et al., 1959). Ratnoff and Steinberg (1962) analyzed data on 55 cases in 37 families. Parental consanguinity was present in at least 2 instances. Some heterozygotes show partial deficiency of Hageman factor. The Japanese case reported by Miwa et al. (1968) had first-cousin parents.
Egeberg (1970) described 4 Norwegian families with deficient factor XII (about half normal). Unlike the usual experience of no abnormality, they showed a slight to moderate bleeding tendency and a high incidence of cerebral apoplexy occurring at a relatively early age. Some of the patients had attacks of local edema, severe headache, abdominal pain, and various forms of allergy. Braulke et al. (1993) presented data suggesting that reduced levels of factor XII activity may be a risk factor for repeated spontaneous abortions. Gordon et al. (1981) showed that both the clot-promoting activity and the antigenic properties of Hageman factor are lower in Orientals than in American whites.
Factor XII deficiency seemingly inherited as an autosomal dominant was reported by Bennett et al. (1972). The authors hypothesized that the gene could be allelic with that responsible for the autosomal recessive form.
Superficial migratory thrombophlebitis (Samlaska et al., 1990) and leg ulcer (Goodnough et al., 1983; Lammle et al., 1991) have been documented as skin manifestations of factor XII deficiency. Sato-Matsumura et al. (2000) reported 2 individuals with factor XII deficiency presenting with livedo and painful leg ulcers who improved dramatically after anticoagulant therapy. They suggested that factor XII deficiency may lead to a hypercoagulative state in some individuals, predisposing them to painful ulcers and livedo.
In a study of 150 consecutive patients with retinal vein occlusion (RVO) compared with age- and gender-matched controls, Kuhli et al. (2004) found that factor XII deficiency was highly prevalent in RVO patients 45 years of age or younger. By contrast, the prevalence of factor XII deficiency in RVO patients older than 45 years appeared similar to that seen in healthy individuals.
Koster et al. (1994) and Girolami et al. (2004) concluded that severe (homozygous) factor XII deficiency is not a cause of deep-vein thrombosis. In a study of myocardial infarction and arterial thrombosis in severe (homozygous) factor XII deficiency, Girolami et al. (2005) likewise concluded that the role of the coagulation factor deficiency in the pathogenesis of arterial thrombosis is minor.
The F12 gene, site of defects resulting in factor XII deficiency, maps to chromosome 5q33-qter (Royle et al., 1988).
Soria et al. (2002) conducted a genomewide linkage screen to localize genes that influence variation in F12 levels. Two loci were detected: one on chromosome 5 and another on chromosome 10 (lod scores 4.73 and 3.53, respectively). On chromosome 5, the peak lod score occurred in the 5q33-qter region, where the F12 gene is located. Addition of the 46C/T polymorphism (610619.0004) in the F12 gene increased the multipoint lod score to 10.21. A bivariate linkage analysis of F12 activity and thrombosis further improved the linkage signal (lod = 11.73) and provided strong evidence that this quantitative trait locus (QTL) has a pleiotropic effect on the risk of thrombosis (P = 0.004). Linkage analysis conditional on 46C/T indicated that this polymorphism alone cannot explain the chromosome 5 signal, implying that other functional sites must exist. These results represented the first direct genetic evidence that a QTL in or near the F12 gene influences both F12 activity and susceptibility to thrombosis and suggested the presence of one or more functional variants in F12.
Bernardi et al. (1987) found that the factor XII gene alteration in the Hageman trait was detected by the TaqI restriction enzyme in 2 affected brothers and 11 members of the paternal lineage. Gene deletion was excluded. The TaqI polymorphic site was located within the 5-prime portion of the gene and the mutation in the polymorphic site was judged to be the cause of the factor XII deficiency. This may represent a CpG mutation of the sort that is found in a number of other genes such as F8 (300841) in hemophilia A (306700).
In 5 of 12 unrelated patients with low factor XII activity detected by chance during presurgery screening, Schloesser et al. (1995) found a splice site mutation in the F12 gene (610619.0003). The mutation was not found in 74 healthy control subjects. Two compound heterozygous patients and a homozygous patient lacked immunologic reactive protein. A mother and 4 of her children, all of whom had reduced factor XII activity and antigen, were heterozygous for the mutation; the authors stated that there were at least 2 more mutant factor XII alleles in this family of unknown nature.
Renne et al. (2005) found that F12-deficient mice, like F12-deficient humans, had normal bleeding times and no spontaneous bleeding. However, in vivo fluorescence microscopy showed that, even though initial adhesion of platelets at sites of injury was unaffected in F12-deficient mice, subsequent formation and stabilization of 3-dimensional thrombi was severely impaired. This defect was observed in several locations in the vascular system in response to different types of injury and was completely reversed by infusion of human F12. Renne et al. (2005) concluded that F12-induced intrinsic coagulation is important for clotting in vivo, suggesting that F12 may be a target for antithrombotic therapy.
Roberts (2003) gave an account of the medical and scientific career of Oscar Ratnoff (born in 1916), who discovered both Hageman factor (factor XII) and Fitzgerald factor (612358). Ratnoff is credited with recruiting Earl Davie to the field of blood coagulation, to which Davie introduced modern biochemical and molecular biologic techniques. Davie and Ratnoff (1964) and, independently and simultaneously, Macfarlane (1964) proposed the waterfall hypothesis of blood coagulation. Ratnoff was long resistant to the use of a system of Roman numerals for the various clotting factors.
Bennett, B., Ratnoff, O., Holt, J. B., Roberts, H. R. Hageman trait (factor XII deficiency): a probable second genotype inherited as an autosomal dominant characteristic. Blood 40: 412-415, 1972. [PubMed: 4626869]
Bernardi, F., Marchetti, G., Patracchini, P., del Senno, L., Tripodi, M., Fantoni, A., Bartolai, S., Vannini, F., Felloni, L., Rossi, L., Panicucci, F., Conconi, F. Factor XII gene alteration in Hageman trait detected by TaqI restriction enzyme. Blood 69: 1421-1424, 1987. [PubMed: 2882793]
Braulke, I., Hinney, G., Pruggmayer, M., Kostering, H., Melloh, P., Gunther, E. Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters? Fertil. Steril. 59: 98-101, 1993. [PubMed: 8419231] [Full Text: https://doi.org/10.1016/s0015-0282(16)55622-2]
Davie, E. W., Ratnoff, O. D. Waterfall sequence for intrinsic blood clotting. Science 145: 1310-1312, 1964. [PubMed: 14173416] [Full Text: https://doi.org/10.1126/science.145.3638.1310]
Donaldson, V. H., Stratman, E. J., Glueck, H. I. Fatal vascular disease in a patient with Hageman trait and a connective-tissue disorder. (Letter) New Eng. J. Med. 297: 1237 only, 1977. [PubMed: 917064] [Full Text: https://doi.org/10.1056/NEJM197712012972217]
Egeberg, O. Factor XII defect and hemorrhage. Evidence for a new type of hereditary hemostatic disorder. Thromb. Diath. Haemorrh. 23: 432-440, 1970. [PubMed: 5432188]
Girolami, A., Morello, M., Girolami, B., Lombardi, A. M., Bertolo, C. Myocardial infarction and arterial thrombosis in severe (homozygous) FXII deficiency: no apparent causative relation. Clin. Appl. Thromb. Hemost. 11: 49-53, 2005. [PubMed: 15678272] [Full Text: https://doi.org/10.1177/107602960501100105]
Girolami, A., Randi, M. L., Gavasso, S., Lombardi, A. M., Spiezia, F. 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: 139-143, 2004. [PubMed: 15306750] [Full Text: https://doi.org/10.1023/B:THRO.0000037670.42776.cd]
Goodnough, L. T., Saito, H., Ratnoff, O. D. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine 62: 248-255, 1983. [PubMed: 6348471] [Full Text: https://doi.org/10.1097/00005792-198307000-00004]
Gordon, E. M., Donaldson, V. H., Saito, H., Su, E., Ratnoff, O. D. Reduced titers of Hageman factor (factor XII) in Orientals. Ann. Intern. Med. 95: 697-700, 1981. [PubMed: 7305148] [Full Text: https://doi.org/10.7326/0003-4819-95-6-697]
Josso, F., de Grouchy, J. Localisation probable d'un locus Hageman (facteur XII) sur un autosome. Ann. Genet. 11: 95-97, 1968. [PubMed: 5303429]
Koster, T., Rosendaal, F. R., Briet, E., Vandenbroucke, J. P. John Hageman's factor and deep-vein thrombosis: Leiden thrombophilia study. Brit. J. Haemat. 87: 422-424, 1994. [PubMed: 7947293] [Full Text: https://doi.org/10.1111/j.1365-2141.1994.tb04937.x]
Kuhli, C., Scharrer, I., Koch, F., Ohrloff, C., Hattenbach, L.-O. Factor XII deficiency: a thrombophilic risk factor for retinal vein occlusion. Am. J. Ophthal. 137: 459-464, 2004. [PubMed: 15013868] [Full Text: https://doi.org/10.1016/j.ajo.2003.10.024]
Lammle, B., Wuillemin, W. A., Huber, I., Krauskopf, M., Zurcher, C., Pflugshaupt, R., Furlan, M. Thromboembolism and bleeding tendency in congenital factor XII deficiency--a study on 74 subjects from 14 Swiss families. Thromb. Haemost. 65: 117-121, 1991. [PubMed: 1905067]
Lucia, J. G., Ercoreca, L., Torres, M., Giralt, M., Raichs, A. Factor-XII congenital deficiency. A new family study. Thromb. Haemost. 42: 1009-1017, 1979. [PubMed: 505391]
Macfarlane, R. G. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 202: 498-499, 1964. [PubMed: 14167839] [Full Text: https://doi.org/10.1038/202498a0]
McCain, K. F., Chernoff, A. I., Graham, J. B. Establishment of the inheritance of Hageman defect as an autosomal recessive trait. In: Brinkhous, K. M.: Hemophilia and Other Hemorrhagic States. Chapel Hill: Univ. of North Carolina Press (pub.) 1959. Pp. 179-191.
Miwa, S., Asai, I., Tsukada, T., Shimizu, M., Teramura, K., Sunaga, Y. Hageman factor deficiency: report of a case found in a Japanese girl. Acta Haemat. 39: 36-41, 1968. [PubMed: 4968868] [Full Text: https://doi.org/10.1159/000208939]
Ratnoff, O. D., Busse, R. J., Jr., Sheon, R. P. The demise of John Hageman. New Eng. J. Med. 279: 760-761, 1968.
Ratnoff, O. D., Steinberg, A. G. Further studies on the inheritance of Hageman trait. J. Lab. Clin. Med. 59: 980-985, 1962. [PubMed: 14490552]
Ratnoff, O. D. A quarter century with Mr. Hageman. Thromb. Haemost. 43: 95-98, 1980. [PubMed: 7006141]
Renne, T., Pozgajova, M., Gruner, S., Schuh, K., Pauer, H.-U., Burfeind, P., Gailani, D., Nieswandt, B. Defective thrombus formation in mice lacking coagulation factor XII. J. Exp. Med. 202: 271-281, 2005. [PubMed: 16009717] [Full Text: https://doi.org/10.1084/jem.20050664]
Roberts, H. R. Oscar Ratnoff: his contributions to the golden era of coagulation research. Brit. J. Haemat. 122: 180-192, 2003. [PubMed: 12846885] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04459.x]
Royle, N. J., Nigli, M., Cool, D., MacGillivray, R. T., Hamerton, J. L. Structural gene encoding human factor XII is located at 5q33-qter. Somat. Cell Molec. Genet. 14: 217-221, 1988. [PubMed: 3162339] [Full Text: https://doi.org/10.1007/BF01534407]
Samlaska, C. P., James, W. D., Simel, D. L. Superficial migratory thrombophlebitis and factor XII deficiency. J. Am. Acad. Derm. 22: 939-943, 1990. [PubMed: 2110579] [Full Text: https://doi.org/10.1016/0190-9622(90)70130-a]
Sato-Matsumura, K. C., Matsumura, T., Hayashi, H., Atsumi, T., Kobayashi, H. Factor XII deficiency: a possible cause of livedo with ulceration? Brit. J. Derm. 143: 897-899, 2000. [PubMed: 11069485] [Full Text: https://doi.org/10.1046/j.1365-2133.2000.03800.x]
Schloesser, M., Hofferbert, S., Bartz, U., Lutze, G., Lammie, B., Engel, W. The novel acceptor splice site mutation 11396(G-to-A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients. Hum. Molec. Genet. 4: 1235-1237, 1995. [PubMed: 8528215] [Full Text: https://doi.org/10.1093/hmg/4.7.1235]
Soria, J. M., Almasy, L., Souto, J. C., Bacq, D., Buil, A., Faure, A., Martinez-Marchan, E., Mateo, J., Borrell, M., Stone, W., Lathrop, M., Fontcuberta, J., Blangero, J. A quantitative-trait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease. Am. J. Hum. Genet. 70: 567-574, 2002. [PubMed: 11805911] [Full Text: https://doi.org/10.1086/339259]
Thompson, J. H., Jr., Spittel, J. A., Jr., Pascuzzi, C. A., Owen, C. A., Jr. Laboratory and genetic observations in another family with the Hageman trait. Proc. Staff Meet. Mayo Clin. 35: 421-427, 1960. [PubMed: 13838083]