Factor Xii Deficiency

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.

Clinical Features

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.

Mapping

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.

Molecular Genetics

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 heterozygosity for a splice site mutation in the F12 gene (610619.0003). The mutation was not found in 74 healthy control subjects. Both compound heterozygous patients and a homozygous patient lacked immunologic reactive protein.

Animal Model

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.

History

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.