Genetics of Venous Thromboembolism 

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 has been a variety of investigations into the genetic determinants of VTE, ranging from candidate gene studies to genome wide association studies. The results of these investigations have led to genetic variants leading either to 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] More recently, associations in genetic variants in the blood type ABO loci have been associated with risk of VTE. Specifically, those with blood type O or A2 are at a lower risk of VTE compared to those with other blood types.^[2] These associations are thought to be driven by higher levels of von Willebrand factor and factor VIII — two known risk factors for VTE — in those with non-O blood types.

An additional recent association was found in variants near CYP4V2^[3] in the Factor XI gene,^[4] which increase the risk of VTE through elevation in Factor XI levels. These associations highlight the critical balance that pro- and anti-thrombotic factors strike in maintaining hemostasis and preventing pathologic thrombosis.

Finally, two studies have identified a genetic variant in GP6, encoding the platelet collagen receptor, which confers an increased risk of VTE.^{[2, 3]} The association with this variant is the first to implicate a platelet-specific factor in the pathogenesis of VTE, although further study is required.

In addition to the individual risks conferred by these genetic variants, when coupled with acquired risk factors, their influence is magnified. For example, carriers of the Factor V Leiden or prothrombin gene mutation have a multiplicative risk when combined with concomitant oral contraceptives,^{[5, 6]} hormone replacement therapy,^[7] or smoking.^[8] These associations highlight the idea that, in many individuals, the presence of a genetic variant alone is insufficient to produce VTE, yet, when combined with a transient, acquired risk factor, the mutation becomes a pathologic substrate.

To see complete information on Deep Venous Thrombosis, please go to the main article by clicking here.

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 < 50 years; thrombosis at unusual sites; recurrent VTE; strong family history of thrombotic disease. Although carriers of the Factor V Leiden or prothrombin gene mutations may have a higher risk of recurrent VTE, the magnitude is likely small^[9] and it is unclear whether genetic testing at time of first VTE improves outcomes.^[10] The importance of obtaining a family history, a simple and frequently underutilized tool available to all clinicians, has been stressed by the Centers for Disease Control and Prevention, Office of Genomics and Disease Prevention.^[11]

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 against 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]