Alternative titles; symbols
SNOMEDCT: 234468009; DO: 0111901;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.21 | Thrombophilia 10 due to heparin cofactor II deficiency | 612356 | Autosomal dominant | 3 | HCF2 | 142360 |
A number sign (#) is used with this entry because heparin cofactor II deficiency, which is a risk factor for thrombophilia, is caused by heterozygous mutation in the HCF2 gene (142360) on chromosome 22q11.
Heparin cofactor II (HCF2; 142360) rapidly inhibits thrombin in plasma in the presence of dermatan sulfate or heparin. Congenital HCF2 deficiency is associated with thromboembolism and is classified into type I (quantitative) or type II (qualitative) deficiency (Kondo et al., 1996).
In a 42-year-old woman with intracranial thrombosis, Tran et al. (1985) found that HCF II was about 50% of normal. The same was true of the mother and sister, both of whom had had thrombotic complications.
Sie et al. (1985) studied the family of a 36-year-old man with recurrent deep vein thrombosis and HCF II deficiency. The mother, half brother, and daughter likewise had low levels and some had an unusual frequency of thrombosis.
Matsuo et al. (1992) reported a Japanese family with type I hereditary HCF II deficiency. The propositus, a 61-year-old man, had coronary artery disease requiring percutaneous transluminal coronary angioplasty 4 times in 1 year because of restenosis. Heparin was apparently ineffective in preventing restenosis by thrombin generation. After the fourth angioplasty, a specific thrombin inhibitor was used with success.
Villa et al. (1999) reported a 29-year-old woman who at the age of 22 suffered a first episode of deep venous thrombosis in the lower right leg complicated by a pulmonary embolism 1 week after starting oral contraceptives. She was found to have type I deficiency of antithrombin III (613118) in heterozygous state and to be homozygous for HCF II deficiency. Her sister was also homozygous for HCF II deficiency but had normal levels of antithrombin III and had not suffered thrombotic events despite thrombotic risk factors such as the use of oral contraceptives, pregnancy, and surgery. Several other members of the family were heterozygous for HCF II deficiency but had not had thrombotic episodes despite circumstantial risk factors. This suggested that the thrombotic risk in an individual with HCF II deficiency and normal AT levels is low.
Using crossed immunoelectrophoresis, Andersson et al. (1987) were the first to demonstrate molecular heterogeneity of the HCF II molecule, the so-called 'Oslo variant,' in affected members of 2 Norwegian families with HCF II deficiency. Their findings were consistent with an autosomal dominant pattern of inheritance; affected individuals had half the normal amount of normal HCF II and were presumed heterozygotes.
HCF II deficiency results from mutation in the HCF2 gene, which maps to chromosome 22q11 (Herzog et al., 1991).
Using PCR, Blinder et al. (1989) amplified DNA fragments encoding the N-terminal 220 amino acids of HCF II from a patient with the Oslo variant. They identified a point mutation resulting in an arg189-to-his (R189H; 142360.0001) substitution in 1 allele. Blinder et al. (1989) created the same mutation in the cDNA of native HCF II by oligonucleotide-directed mutagenesis and expressed it in E. coli. The recombinant cofactor reacted with thrombin in the presence of heparin, but not dermatan sulfate, confirming that the R189H mutation is responsible for the functional abnormality in HCF II Oslo.
In COS-1 cells transfected with the Tokushima variant of HCF II (P443L; 142360.0004), Kanagawa et al. (2001) observed immunohistochemical staining primarily in the perinuclear area. They concluded that impaired secretion of mutant HCF II molecules due to intracellular degradation is the molecular pathogenesis of type I congenital HCF II deficiency caused by this mutation.
Andersson, T. R., Larsen, M. L., Abildgaard, U. Low heparin cofactor II associated with abnormal crossed immunoelectrophoresis pattern in two Norwegian families. Thromb. Res. 47: 243-248, 1987. [PubMed: 2443998] [Full Text: https://doi.org/10.1016/0049-3848(87)90381-1]
Blinder, M. A., Andersson, T. R., Abildgaard, U., Tollefsen, D. M. Heparin cofactor II(Oslo): mutation of arg-189-to-his decreases the affinity for dermatan sulfate. J. Biol. Chem. 264: 5128-5133, 1989. [PubMed: 2647747]
Herzog, R., Lutz, S., Blin, N., Marasa, J. C., Blinder, M. A., Tollefsen, D. M. Complete nucleotide sequence of the gene for human heparin cofactor II and mapping to chromosomal band 22q11. Biochemistry 30: 1350-1357, 1991. [PubMed: 1671335] [Full Text: https://doi.org/10.1021/bi00219a027]
Kanagawa, Y., Shigekiyo, T., Aihara, K., Akaike, M., Azuma, H., Matsumoto, T. Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima. Thromb. Haemost. 85: 101-107, 2001. [PubMed: 11204559]
Kondo, S., Tokunaga, F., Kario, K., Matsuo, T., Koide, T. Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor II Awaji). Blood 87: 1006-1012, 1996. [PubMed: 8562924]
Matsuo, T., Kario, K., Sakamoto, S., Yamada, T., Miki, T., Hirase, T., Kobayashi, H. Hereditary heparin cofactor II deficiency and coronary artery disease. Thromb. Res. 65: 495-505, 1992. [PubMed: 1615493] [Full Text: https://doi.org/10.1016/0049-3848(92)90201-k]
Sie, P., Dupouy, D., Pichon, J., Boneu, B. Constitutional heparin co-factor II deficiency associated with recurrent thrombosis. Lancet 326: 414-416, 1985. Note: Originally Volume II. [PubMed: 2863445] [Full Text: https://doi.org/10.1016/s0140-6736(85)92737-0]
Tran, T. H., Marbet, G. A., Duckert, F. Association of hereditary heparin co-factor II deficiency with thrombosis. Lancet 326: 413-414, 1985. Note: Originally Volume II. [PubMed: 2863444] [Full Text: https://doi.org/10.1016/s0140-6736(85)92736-9]
Villa, P., Aznar, J., Vaya, A., Espana, F., Ferrando, F., Mira, Y., Estelles, A. Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis. Thromb. Haemost. 82: 1011-1014, 1999. [PubMed: 10494755]