Other entities represented in this entry:
ORPHA: 98879; DO: 0111899;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq27.1 | {Deep venous thrombosis, protection against} | 300807 | X-linked recessive | 3 | F9 | 300746 |
| Xq27.1 | Thrombophilia 8, X-linked, due to factor IX defect | 300807 | X-linked recessive | 3 | F9 | 300746 |
A number sign (#) is used with this entry because X-linked thrombophilia can be caused by a gain-of-function mutation in the gene encoding factor IX (F9; 300746) on Xq27.1.
Simioni et al. (2009) reported a 21-year-old Italian man who developed a deep venous thrombosis in the right leg after mild muscular stretching. Treatment with heparin and warfarin resulted in resolution and no further thrombosis.
In a study of 473 healthy controls, van Hylckama Vlieg et al. (2000) found that factor IX levels, as measured by enzyme-linked immunosorbent assay (ELISA), increased with age after the age of 55 years. Factor IX levels were substantially higher among 153 premenopausal women who used oral contraceptives. Ten percent of healthy control individuals had factor IX levels about 129 U/dl (90th percentile). More than 20% of 426 patients with deep venous thrombosis (DVT) had factor IX levels exceeding this cutoff point. The results indicated that individuals with factor IX levels above 129 U/dl have a 2.3-fold increased risk of developing a DVT compared to those with factor IX levels below this cutoff point. The risk of thrombosis increased with plasma levels of factor IX, indicating a dose-response effect. The risk was not affected by adjustment for possible confounders (age, sex, oral contraceptive use, and high levels of other coagulation factors). The risk for DVT was higher in women (odds ratio of 2.6) than in men (odds ratio of 1.9), and was highest in the group of premenopausal women not using oral contraceptives (odds ratio of 12.4).
The findings in the family reported by Simioni et al. (2009) were consistent with X-linked recessive inheritance.
In an Italian man with deep venous thrombosis of the femoral-popliteal veins, Simioni et al. (2009) identified a hemizygous mutation in the F9 gene (R338L; 300746.0112). Coagulation studies showed that he had normal levels of F9 antigen, but very high levels of F9 activity (776% of control values). His 11-year-old brother and mother, who were hemizygous and heterozygous for the mutation, respectively, also had normal F9 antigen levels and increased F9 activity levels (551 and 337%, respectively). In vitro functional expression studies showed that the mutant F9 had 8-fold increased activity compared to wildtype, consistent with a gain of function. The affected residue is important for binding to factor X (F10; 613872), and the R338L substitution apparently increases the efficiency of this binding. Simioni et al. (2009) noted that Chang et al. (1998) had generated mutant F9 molecules designed to locate the residues of F9a that bind FVIIIa (F8; 300841) in vitro and had identified a variant at the same residue (R338A) that appeared to be part of a macromolecular binding site (exosite) for factor X.
Bezemer et al. (2008) reported that the G allele (ala148) of F9 Malmo (300746.0028) was associated with a 15 to 43% decrease in deep vein thrombosis risk compared to the A allele in 3 case-control studies of deep vein thrombosis. This common variant has a minor allele frequency of 0.32. In a follow-up study from 3 case-control studies involving a total of 1,445 male patients with deep venous thrombosis and 2,351 male controls, Bezemer et al. (2009) found that the G allele of F9 Malmo conferred protection against deep venous thrombosis (odds ratio of 0.80). The pooled corresponding odds ratio in a comparable number of women with deep venous thrombosis was 0.89. However, factor IX antigen level, factor IX activation peptide levels, and endogenous thrombin potential did not differ between the F9 Malmo genotypes. Although F9 Malmo was the most strongly associated with protection from deep vein thrombosis, the biologic mechanism remained unknown.
Van Minkelen et al. (2008) sequenced the F9 gene in the cohort of patients studied by van Hylckama Vlieg et al. (2000) to determine if there were genetic variants that could explain increased F9 levels. Although several SNPs were identified, none had a significant effect on F9 levels or deep venous thrombosis. Haplotype analysis showed a decreased risk in men for certain haplotypes, especially those including the known protective variant F9 Malmo (T148A; 300746.0028), but the effect in women did not reach significance. The authors concluded that variation in F9 may affect the risk of DVT, but that genetic variation does not explain F9 antigen levels.
Bezemer, I. D., Arellano, A. R., Tong, C. H., Rowland, C. M., Ireland, H. A., Bauer, K. A., Catanese, J., Reitsma, P. H., Doggen, C. J. M., Devlin, J. J., Rosendaal, F. R., Bare, L. A. F9 Malmo, factor IX and deep vein thrombosis. Haematologica 94: 693-699, 2009. [PubMed: 19286883] [Full Text: https://doi.org/10.3324/haematol.2008.003020]
Bezemer, I. D., Bare, L. A., Doggen, C. J. M., Arellano, A. R., Tong, C., Rowland, C. M., Catanese, J., Young, B. A., Reitsma, P. H., Devlin, J. J., Rosendaal, F. R. Gene variants associated with deep vein thrombosis. JAMA 299: 1306-1314, 2008. [PubMed: 18349091] [Full Text: https://doi.org/10.1001/jama.299.11.1306]
Chang, J., Jin, J., Lollar, P., Bode, W., Brandstetter, H., Hamaguchi, N., Straight, D. L., Stafford, D. W. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J. Biol. Chem. 273: 12089-12094, 1998. [PubMed: 9575152] [Full Text: https://doi.org/10.1074/jbc.273.20.12089]
Simioni, P., Tormene, D., Tognin, G., Gavasso, S., Bulato, C., Iacobelli, N. P., Finn, J. D., Spiezia, L., Radu, C., Arruda, V. R. X-linked thrombophilia with a mutant factor IX (factor IX Padua). New Eng. J. Med. 361: 1671-1675, 2009. [PubMed: 19846852] [Full Text: https://doi.org/10.1056/NEJMoa0904377]
van Hylckama Vlieg, A., van der Linden, I. K., Bertina, R. M., Rosendaal, F. R. High levels of factor IX increase the risk of venous thrombosis. Blood 95: 3678-3682, 2000. [PubMed: 10845896]
van Minkelen, R., de Visser, M. C. H., van Hylckama Vlieg, A., Vos, H. L., Bertina, R. M. Sequence variants and haplotypes of the factor IX gene and the risk of venous thrombosis. (Letter) J. Thromb. Haemost. 6: 1610-1613, 2008. [PubMed: 18624978] [Full Text: https://doi.org/10.1111/j.1538-7836.2008.03066.x]