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Other entities represented in this entry:
SNOMEDCT: 111293003; ICD10CM: I82.90; DO: 0080701, 0111907;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | {Thromboembolism, susceptibility to} | 188050 | Autosomal dominant | 3 | MTHFR | 607093 |
| 6p25.1 | {Venous thrombosis, protection against} | 188050 | Autosomal dominant | 3 | F13A1 | 134570 |
| 10q25.3 | {Venous thromboembolism, susceptibility to} | 188050 | Autosomal dominant | 3 | HABP2 | 603924 |
| 11p11.2 | Thrombophilia 1 due to thrombin defect | 188050 | Autosomal dominant | 3 | F2 | 176930 |
A number sign (#) is used with this entry because susceptibility to thrombophilia (THPH1) can be conferred by heterozygous mutation in the thrombin gene (F2; 176930) on chromosome 11p11.
Thrombophilia is a multifactorial disorder of inappropriate clot formation resulting from an interaction of genetic, acquired, and circumstantial predisposing factors. Venous thromboembolism most commonly manifests as deep vein thrombosis, which may progress to pulmonary embolism if the clot dislodges and travels to the lung. Other manifestations include thromboses of the cerebral or visceral veins and recurrent pregnancy loss (summary by Seligsohn and Lubetsky, 2001 and Varga and Kujovich, 2012).
Genetic Heterogeneity of Thrombophilia
THPH2 (188055) is caused by mutation in the F5 gene (612309) on chromosome 1q23; THPH3 (176860) and THPH4 (612304) are both caused by mutation in the PROC gene (612283) on 2q; THPH5 (612336) and THPH6 (614514) are caused by mutation in the PROS1 gene (176880) on 3q11; THPH7 (613118) is caused by mutation in the AT3 gene (107300) on 1q25; THPH8 (300807) is caused by mutation in the F9 gene (300746) on Xq27; THPH9 (612348) is associated with decreased release of tissue plasminogen activator (PLAT; 173370); THPH10 (612356) is caused by mutation in the HCF2 gene (142360) on 22q11; THPH11 (613116) is caused by mutation in the HRG gene (142640) on 3q27; and THPH12 (614486) is associated with variation in the THBD gene (188040) on 20p11.
Susceptibility to thrombosis has also been associated with variation in additional genes, including MTHFR (607093.0003); F13B (134580.0003); plasminogen activator inhibitor (SERPINE1; 173360); and several genes encoding fibrinogen (FGA, 134820; FGB, 134830; FGG, 134850). Variation in the SERPINA10 (see 605271.0001), KNG1 (612358) and HABP2 (603924) genes has also been reported.
Protection against venous thrombosis is associated with variation in the F13A1 gene (134570) on 6p25.
Miyawaki et al. (2012) reported a Japanese family, originating from Yukuhashi in the northern part of the Kyushu islands, with recurrent thrombophilia. The family had originally been reported by Sakai et al. (2001). There were at least 9 affected individuals spanning 3 generations. The proband had onset of recurrent deep vein thrombosis at age 11 years, and many affected family members had onset of deep vein thrombosis or pulmonary embolism before age 50 years.
Associations Pending Confirmation
In a multistage study using a collection of 5,862 cases with venous thrombosis and 7,112 healthy controls, Morange et al. (2010) identified a locus on chromosome 6p24.1 as a susceptibility locus for venous thrombosis. The C allele of the single-nucleotide polymorphism (SNP) rs169713, which resides 92 kb 5-prime of the HIVEP1 gene (194540), was associated with an increased risk for venous thrombosis, with an odds ratio of 1.2 (95% confidence interval 1.13-1.27, P = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA sequences in their promoter and enhancer regions. Morange et al. (2010) concluded that these results identified a locus involved in venous thrombosis susceptibility that lies outside the traditional coagulation/fibrinolysis pathway.
In general, thrombophilia is a complex (multifactorial) trait. The genes involved in complex traits are, for the most part, susceptibility genes, not genes that represent the primary cause of the disorder, as in the case of mendelian disorders. Mendelian disorders fit the model which might be referred to as mendelian/garrodian; complex, or multifactorial, traits follow the galtonian/fisherian model. Archibald Garrod's conception of metabolic blocks in a biochemical pathway caused by a mendelizing mutation obtains for the inborn errors of metabolism which he first described and named. Francis Galton (1822-1911) conceived the notion of multiple genetic factors involved in quantitative traits such as intelligence and stature. His disciples argued against the relevance of mendelism in relation to quantitative traits, indeed in relation to most inherited traits. Fisher (1918) showed that the behavior of quantitative traits is consistent with collaboration of multiple genetic factors, each behaving in a mendelian manner.
Schafer (1999) discussed venous thrombosis as a chronic and polygenic disease.
The transmission pattern of recurrent thrombophilia due to an F2 mutation in the Japanese family reported by Sakai et al. (2001) and Miyawaki et al. (2012) was consistent with autosomal dominant inheritance.
Kearon et al. (1999) presented evidence suggesting that patients with a first episode of idiopathic venous embolism should be treated with anticoagulant agents for longer than 3 months.
Poort et al. (1996) found that a common 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (176930.0009) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls.
Chamouard et al. (1999) studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis.
De Stefano et al. (1999) found that patients who were heterozygous for both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V.
In a Spanish family, Corral et al. (1999) identified 3 subjects homozygous for the 20210A prothrombin mutation who were also heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event.
In affected members of a Japanese family with recurrent thrombophilia, Miyawaki et al. (2012) identified a heterozygous mutation in the F2 gene (R596L; 176930.0015). The family had originally been reported by Sakai et al. (2001). In vitro ELISA studies showed that the mutant prothrombin did not form a complex with antithrombin (SERPINC1; 107300) even when heparin was added. A thrombin generation assay showed that the mutant prothrombin activity was lower than wildtype, but its inactivation in reconstituted plasma was exceedingly slow. Miyawaki et al. (2012) concluded that although the procoagulant activity of the R596L mutant prothrombin was somewhat impaired, the antithrombin:thrombin complex was considerably impaired, causing continued facilitation of coagulation. The findings indicated that R596L was a gain-of-function mutation resulting in the resistance to antithrombin, and conferring susceptibility to thrombosis. The mutant variant was termed 'prothrombin Yukuhashi.'
Chamouard, P., Pencreach, E., Maloisel, F., Grunebaum, L., Ardizzone, J.-F., Meyer, A., Gaub, M.-P., Goetz, J., Baumann, R., Uring-Lambert, B., Levy, S., Dufour, P., Hauptmann, G., Oudet, P. Frequent factor II G20210A mutation in idiopathic portal vein thrombosis. Gastroenterology 116: 144-148, 1999. [PubMed: 9869612] [Full Text: https://doi.org/10.1016/s0016-5085(99)70238-6]
Corral, J., Zuazu-Jausoro, I., Rivera, J., Gonzalez-Conejero, R., Ferrer, F., Vicente, V. Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family. Brit. J. Haemat. 105: 560-563, 1999. [PubMed: 10233438]
De Stefano, V., Martinelli, I., Mannucci, P. M., Paciaroni, K., Chiusolo, P., Casorelli, I., Rossi, E., Leone, G. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. New Eng. J. Med. 341: 801-806, 1999. [PubMed: 10477778] [Full Text: https://doi.org/10.1056/NEJM199909093411104]
Fisher, R. A. Correlation between relatives on the supposition of mendelian inheritance. Trans. Roy. Soc. Edinburgh 52: 399-433, 1918.
Kearon, C., Gent, M., Hirsh, J., Weitz, J., Kovacs, M. J., Anderson, D. R., Turpie, A. G., Green, D., Ginsberg, J. S., Wells, P., MacKinnon, B., Julian, J. A. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. New Eng. J. Med. 340: 901-907, 1999. Note: Erratum: New Eng. J. Med. 341: 298 only, 1999. [PubMed: 10089183] [Full Text: https://doi.org/10.1056/NEJM199903253401201]
Miyawaki, Y., Suzuki, A., Fujita, J., Maki, A., Okuyama, E., Murata, M., Takagi, A., Murate, T., Kunishima, S., Sakai, M., Okamoto, K., Matsushita, T., Naoe, T., Saito, H., Kojima, T. Thrombosis from a prothrombin mutation conveying antithrombin resistance. New Eng. J. Med. 366: 2390-2396, 2012. [PubMed: 22716977] [Full Text: https://doi.org/10.1056/NEJMoa1201994]
Morange, P.-E., Bezemer, I., Saut, N., Bare, L., Burgos, G., Brocheton, J., Durand, H., Biron-Andreani, C., Schved, J.-F., Pernod, G., Galan, P., Drouet, L., and 17 others. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1. Am. J. Hum. Genet. 86: 592-595, 2010. Note: Erratum: Am. J. Hum. Genet. 86: 655 only, 2010. [PubMed: 20226436] [Full Text: https://doi.org/10.1016/j.ajhg.2010.02.011]
Poort, S. R., Rosendaal, F. R., Reitsma, P. H., Bertina, R. M. A common genetic variation in the 3-prime-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88: 3698-3703, 1996. [PubMed: 8916933]
Sakai, M., Urano, H., Iinuma, A., Okamoto, K., Ohsato, K., Shirahata, A. A family with multiple thrombosis including infancy occurrence. J. UOEH 23: 297-305, 2001. Note: Article in Japanese. [PubMed: 11570053] [Full Text: https://doi.org/10.7888/juoeh.23.297]
Schafer, A. I. Venous thrombosis as a chronic disease. (Editorial) New Eng. J. Med. 340: 955-956, 1999. [PubMed: 10089190] [Full Text: https://doi.org/10.1056/NEJM199903253401209]
Seligsohn, U., Lubetsky, A. Genetic susceptibility to venous thrombosis. New Eng. J. Med. 344: 1222-1231, 2001. [PubMed: 11309638] [Full Text: https://doi.org/10.1056/NEJM200104193441607]
Varga, E. A., Kujovich, J. L. Management of inherited thrombophilia: guide for genetics professionals. Clin. Genet. 81: 7-17, 2012. [PubMed: 21707594] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01746.x]