Factor XII deficiency D68.25

Oscar Ratnoff (b. 1916); Ratnoff discovered both the Hageman factor (factor XII) and the Fitzgerald factor (612358).

The heterogeneous clinical picture of factor XII deficiency is caused by a mutation in the F12 gene (610619) on chromosome 5q35. An autosomal dominant as well as an autosomal recessive mode of inheritance has been described (Bennett et al.1972).

Soria et al. (2002) performed a genome-wide linkage screen to locate 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 highest lod score was in the 5q33-qter region, where the F12 gene is located. The addition of polymorphism 46C/T (610619,0004) in the F12 gene increased the multipoint lod score to 10.21. 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 thrombosis risk (P = 0.004). A linkage analysis involving 46C/T showed that this polymorphism alone cannot explain the signal on chromosome 5, implying that other functional sites must be present. These results represent the first direct genetic evidence that a QTL in or near the F12 gene affects both F12 activity and thrombosis susceptibility and suggest the presence of one or more functional variants in F12 (Soria et al 2002).

Animal experiments have found F12-deficient mice to have normal bleeding times and no spontaneous bleeding. However, in vivo fluorescence microscopy showed that although the initial adhesion of platelets to injured sites was not impaired, the subsequent formation and stabilization of three-dimensional thrombi was severely impaired. This defect was observed at several sites in the vasculature in response to various types of injury and was completely reversed by infusion of human F12 (Renne et al. 2005). It is suggested that F12-induced intrinsic coagulation is important for coagulation in vivo, suggesting that F12 may be a target for antithrombotic therapy.

High incidence of cerebral apoplexy: Egeberg (1970) described 4 Norwegian families with deficient factor XII (about half normal). In contrast to the usual experience without abnormalities, they showed a mild to moderate bleeding tendency and a high incidence of cerebral apoplexy occurring at a relatively early age. Local edema, severe headache, abdominal pain, and various forms of allergy occurred in a proportion of patients.

Spontaneous abortions: Braulke et al (1993) presented data suggesting that decreased factor XII activity may be a risk factor for repeated spontaneous abortions. Gordon et al (1981) showed that both procoagulant activity and antigenic properties of Hageman factor are lower in Orientals than in American whites.

Superficial migratory thrombophlebitis/ulcers curis: Superficial migratory thrombophlebitis (Samlaska et al. 1990) and ulcers curis (Goodnough et al. 1983; Lämmle et al. 1991) have been documented as skin manifestations of factor XII deficiency.

Livedovasculopathy and painful ul cers curis: Sato-Matsumura et al. (2000) reported two individuals with factor XII deficiency who had livedo and painful ulcers curis that 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.

Retinal vein occlusion: In a study of 150 consecutive patients with retinal vein occlusion (RVO) compared with age- and sex-matched controls, Kuhli et al (2004) found that factor XII deficiency was highly prevalent in RVO patients aged 45 years or younger. In contrast, the prevalence of factor XII deficiency in patients with retinal vein occlusion older than 45 years appeared to be similar to that in healthy individuals.

Factor XII deficiency is usually discovered by the fact that whole blood coagulation tests were routinely performed in hospitals before surgical procedures. Ratnoff and Steinberg (1962) analyzed data from 55 cases in 37 families. Parental consanguinity was present in at least 2 cases. Some heterozygotes have partial deficiency of the Hageman factor.

1. Bennett B et al (1972) Hageman trait (factor XII deficiency): a probable second genotype inherited as an autosomal dominant characteristic. Blood 40: 412-415.
2. Braulke I et al (1993) Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters? Fertil. Steril. 59: 98-101.
3. Donaldson V H et al (1977) Fatal vascular disease in a patient with Hageman trait and a connective-tissue disorder. (Letter) New Eng J Med.297: 1237.
4. Egeberg O (1970) Factor XII defect and hemorrhage. Evidence for a new type of hereditary hemostatic disorder. Thromb Diath Haemorrh 23: 432-440.
5. Goodnough LT et al (1983) 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.
6. Kuhli C et al (2004) Factor XII deficiency: a thrombophilic risk factor for retinal vein occlusion. Am J Ophthal 137: 459-464.
7. Lämmle, B et al. (1991) Thromboembolism and bleeding tendency in congenital factor XII deficiency--a study on 74 subjects from 14 Swiss families. Thromb Haemost 65: 117-121.
8. Ratnoff OD et al (1962) Further studies on the inheritance of Hageman trait. J. Lab. Clin. Med. 59: 980-985.
9. Renne T et al (2005) Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 202: 271-281.
10. Samlaska CP (1990) Superficial migratory thrombophlebitis and factor XII deficiency. J Am. Acad. Derm. 22: 939-943.
11. Sato-Matsumura K C et al (2000) Factor XII deficiency: a possible cause of livedo with ulceration? Brit J Derm 143: 897-899.
12. Schloesser M et al. (1005) 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 Gene. 4: 1235-1237.
13. Soria JM et al (2002) 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.