SNOMEDCT: 1197595004; ORPHA: 436169; DO: 0111908;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p11.21 | Thrombophilia 12 due to thrombomodulin defect | 614486 | Autosomal dominant | 3 | THBD | 188040 |
A number sign (#) is used with this entry because of evidence that thrombophilia may result from variation in the gene encoding thrombomodulin (THBD; 188040) on chromosome 20p11.
The role of thrombomodulin in thrombosis is controversial. Although there have been several reports of THBD mutations in patients with venous thrombosis, clear functional evidence for the pathogenicity of these mutations is lacking. In a review, Anastasiou et al. (2012) noted that thrombomodulin has a major role in capillary beds and that THBD variation may not be associated with large vessel thrombosis. It is likely that genetic or environmental risk factors in addition to THBD variation are involved in the pathogenesis of venous thrombosis. However, variation in the THBD gene may be associated with increased risk for arterial thrombosis and myocardial infarction. This association may be attributed to the fact that thrombomodulin can modulate inflammatory processes, complement activity, and fibrinolysis.
Ohlin and Marlar (1995) reported a 45-year-old Hispanic man with thrombophilia who developed a pulmonary embolism. He had decreased soluble THBD fragments in serum compared to controls. His mother had died suddenly, apparently of pulmonary embolus.
Venous Thrombosis
In a 45-year-old Hispanic man with thrombophilia and pulmonary embolism, Ohlin and Marlar (1995) identified a heterozygous mutation in the THBD gene (D468Y; 188040.0001). His 23-year-old son, who had no history of thrombosis, was also heterozygous for the mutation. Faioni et al. (2002) identified a heterozygous D468Y substitution in 1 of 12 patients with thrombophilia and low serum THBD levels. The patient was a 52-year-old woman with deep vein thrombosis of a lower limb and a stroke. However, functional studies by Nakazawa et al. (1999) and Kunz et al. (2002) showed that the D468Y variant protein had normal expression and function, casting doubt on its pathogenicity.
Franchi et al. (2001) found 5 mutations in the THBD gene among 95 women with unexplained late fetal loss (after 20 weeks), and 3 THBD mutations among 236 controls. Two of the patients and 1 control had mutations in the EPCR gene (600646). The relative risk for late fetal loss for carriers of mutation in either the THBD or EPCR gene was estimated by an odds ratio of 4.0.
Faioni et al. (2002) examined 38 patients with recurrent, documented thrombotic events at a young age and a positive family history. One patient with thrombophilia was found to have a heterozygous -33G-A transition (188060.0004). This patient had a deep venous thrombosis of a lower limb at age 39 years, followed by 3 recurrent events at age 40, including a pulmonary embolism. The allelic frequency of an ala455-to-val polymorphism (A455V; 188040.0008) was identical in patients and controls. Faioni et al. (2002) concluded that mutations in the THBD gene are a very rare cause of severe thrombophilia.
In a woman with recurrent deep venous thrombosis beginning at age 76 who had a myocardial infarction at age 90, Kunz et al. (2002) identified a heterozygous mutation in the THBD gene (R385S; 188040.0009). In vitro functional expression studies showed that the mutant protein had reduced expression (50% compared to wildtype), as well as significantly decreased cofactor activity with increased Km values for protein C activation.
In the Chinese population, Tang et al. (2013) identified a variant, c.-151G-to-T (188040.0010), in the 5-prime UTR of the THBD gene that significantly reduced the gene expression and could cause a predisposition to venous thrombosis. Results from a case-control study indicated that heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. In a family analysis involving 176 first-degree relatives from 38 index families, first-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis, and their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant.
Myocardial Infarction
In a study of 560 men with a first myocardial infarction before the age of 70, Doggen et al. (1998) found that 12 were carriers of an A25T substitution in the THBD gene (188040.0002). In a control group of 646 men, frequency-matched for age, 7 were carriers of the A25T substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls, suggesting an odds ratio of 2.0. In patients younger than 50 years, the predicted risk was almost 7 times increased (odds ratio, 6.5). If smoking or a metabolic risk factor was present, the predicted risk increased to 9-fold and 4-fold, respectively. However, Kunz et al. (2002) found no abnormality in cell surface expression or thrombomodulin cofactor function in studies of the A25T protein.
Among 320 Chinese patients with coronary artery disease and 200 matched controls, Li et al. (2000) found a significant association between a promoter variant in the THBD gene (-33G-A; 188040.0004) and disease. The GA and AA genotypes were found in 23.8% of patients compared to 15.5% of controls (OR of 1.70, p = 0.031).
In a patient with myocardial infarction, Kunz et al. (2000) found a frameshift mutation in the THBD gene (188040.0003). Pedigree analysis suggested that a brother who had suffered a fatal myocardial infarction probably also carried the mutation. Known risk factors for MI, including smoking, increased blood pressure, elevated triglycerides, and elevated cholesterol, were present in the proband and other family members. Carriers of the mutant allele expressed significantly lower amounts of thrombomodulin on the surface of their monocytes and lower levels of soluble thrombomodulin in plasma. Reduced expression was observed in COS-7 cells.
Anastasiou, G., Gialeraki, A., Merkouri, E., Politou, M., Travlou, A. Thrombomodulin as a regulator of the anticoagulant pathway: implication in the development of thrombosis. Blood Coagul. Fibrinolysis 23: 1-10, 2012. [PubMed: 22036808] [Full Text: https://doi.org/10.1097/MBC.0b013e32834cb271]
Doggen, C. J. M., Kunz, G., Rosendaal, F. R., Lane, D. A., Vos, H. L., Stubbs, P. J., Cats, V. M., Ireland, H. A mutation in the thrombomodulin gene, 127G to A coding for ala25-to-thr, and the risk of myocardial infarction in men. Thromb. Haemost. 80: 743-748, 1998. [PubMed: 9843165]
Faioni, E. M., Franchi, F., Castaman, G., Biguzzi, E., Rodeghiero, F. Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia. Brit. J. Haemat. 118: 595-599, 2002. [PubMed: 12139752] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03644.x]
Franchi, F., Biguzzi, E., Cetin, I., Facchetti, F., Radaelli, T., Bozzo, M., Pardi, G., Faioni, E. M. Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss. Brit. J. Haemat. 114: 641-646, 2001. [PubMed: 11552992] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02964.x]
Kunz, G., Ireland, H. A., Stubbs, P. J., Kahan, M., Coulton, G. C., Lane, D. A. Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction. Blood 95: 569-576, 2000. [PubMed: 10627464]
Kunz, G., Ohlin, A.-K., Adami, A., Zoller, B., Svensson, P., Lane, D. A. Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function. Blood 99: 3646-3653, 2002. [PubMed: 11986219] [Full Text: https://doi.org/10.1182/blood.v99.10.3646]
Li, Y.-H., Chen, J.-H., Wu, H.-L., Shi, G.-Y., Huang, H.-C., Chao, T.-H., Tsai, W.-C., Tsai, L.-M., Guo, H.-R., Wu, W.-S., Chen, Z.-C. G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels. Am. J. Cardiol. 85: 8-12, 2000. [PubMed: 11078228] [Full Text: https://doi.org/10.1016/s0002-9149(99)00597-4]
Nakazawa, F., Koyama, T., Saito, T., Shibakura, M., Yoshinaga, H., Chung, D. H., Kamiyama, R., Hirosawa, S. Thrombomodulin with the asp468tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation. Brit. J. Haemat. 106: 416-420, 1999. [PubMed: 10460600] [Full Text: https://doi.org/10.1046/j.1365-2141.1999.01567.x]
Ohlin, A.-K., Marlar, R. A. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood 85: 330-336, 1995. [PubMed: 7811989]
Tang, L., Wang, H.-F., Lu, X., Jian, X.-R., Jin, B., Zheng, H., Li, Y.-Q., Wang, Q.-Y., Wu, T.-C., Guo, H., Liu, H., Guo, T., Yu, J.-M., Yang, R., Yang, Y., Hu, Y. Common genetic risk factors for venous thrombosis in the Chinese population. Am. J. Hum. Genet. 92: 177-187, 2013. [PubMed: 23332921] [Full Text: https://doi.org/10.1016/j.ajhg.2012.12.013]