Genetics of Venous Thromboembolism

Updated: Jan 22, 2015
  • Author: Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP; Chief Editor: Keith K Vaux, MD  more...
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Venous thromboembolism (VTE) is a multifactorial disease driven by environmental/acquired risk factors such as age, obesity, oral contraceptives, and immobility, as well as inherited risk factors such as genetic polymorphisms. There have been a variety of investigations into the genetic determinants of VTE, ranging from candidate gene studies to genome-wide association studies. These investigations have led to the discovery of genetic variants that result either in an excess of a prothrombotic factor or a deficiency in an antithrombotic factor.

Factor V Leiden is the most common and well studied genetic cause of VTE, with the prothrombin G20210A gene mutation and deficiencies in protein S, protein C, and anti-thrombin accounting for most of the remaining cases. [1, 2, 3, 4, 5]

There are 6 introns and 7 exons in the gene encoding antithrombin (SERPINC1). Antithrombin deficiency leads to the highest risk of venous thromboembolism among deficiencies of natural anticoagulants. There are reports of more than 200 mutations in SERPINC1 that cause antithrombin deficiency. Antithrombin Rybnik is a new point mutation associated with quantitative antithrombin deficiency. [6]

Genetic variants in the ABO blood-type loci have also been associated with an increased risk of VTE. Specifically, persons with blood type O or A2 have a lower risk of developing VTE than do individuals with other blood types. [7] This difference is thought to result from the presence of higher levels of von Willebrand factor and factor VIII—2 known risk factors for VTE—in persons with non-O blood types. [8, 9]

An increased VTE risk has also been associated with variants near CYP4V2 [10] in the Factor XI gene [11] that increase Factor XI levels.

These associations highlight the critical balance that prothrombotic and antithrombotic factors must strike to maintain hemostasis and prevent pathologic thrombosis.

Finally, 2 studies have identified a genetic variant in GP6, a gene that encodes the platelet collagen receptor, that confers an increased risk of VTE. [7, 10] This discovery is the first finding to implicate a platelet-specific factor in the pathogenesis of VTE, although further study is required.

The risk conferred by the above genetic variants is magnified when they are coupled with acquired risk factors. For example, VTE risk in carriers of the Factor V Leiden or prothrombin gene mutation is multiplied by oral contraceptive use, [12, 13] hormone replacement therapy, [14] and smoking. [15] These associations highlight the idea that in many individuals, the presence of a genetic variant alone is insufficient to produce VTE, but that when this mutation is combined with a transient, acquired risk factor, it becomes a pathologic substrate.


Clinical Implications

Widespread testing for mutations that might increase the risk of VTE is not warranted. However, in patients presenting with a VTE, testing should be considered if the following factors are present:

  • Age less than 50 years

  • Thrombosis at unusual sites

  • Recurrent VTE

  • Strong family history of thrombotic disease

Susceptibility to venous thromboembolism (VTE) is very complex. Pathobiology of VTE involves both genetic and acquired factors. Patients who have had VTE have a genetic predisposition due to molecular abnormalities in the components of coagulation cascade. Common genetic abnormalities, particularly among whites, include Factor V Leiden and prothrombin gene 20210A mutations. Additionally, some abnormalities are found in gene loci antithrombin, protein C, and protein S. [16]

Although carriers of the Factor V Leiden or prothrombin gene mutations may have a higher risk of recurrent VTE, the magnitude is likely small, [17] and it is unclear whether genetic testing at the time of a first VTE improves outcomes. [18] The importance of obtaining a family history, a simple and frequently underutilized tool available to all clinicians, has been stressed by the Office of Genomics and Disease Prevention at the Centers for Disease Control and Prevention (CDC). [19]

Although the presence of a factor V Leiden mutation is not an absolute contraindication for oral contraceptive use, because of the high risk for VTE conferred by the combination, women who are heterozygous for Factor V Leiden should be discouraged from the use of oral contraceptives. Similarly women with a personal or family history of unprovoked VTE at a young age who are considering oral contraceptive use can benefit from genetic testing and counseling. [1]