SCIENTIFIC BACKGROUND
The annual incidence of deep vein thrombosis is reported to be 1:1,000. Risk factors for venous thrombosis may be inherited or acquired. Epidemiological studies have already identified several genetic risk factors for venous thrombosis. Of these, the resistance of coagulation factor V to activated protein C (APC) and an increased plasma concentration of prothrombin play an important role.
APC resistance is currently the most common known risk factor for venous thrombosis. In 90%, the genetic cause is a variant in the coagulation factor V gene. As a result, activated factor-V cannot be sufficiently cleaved by activated protein C and is thus inactivated. Heterozygosity for the factor V Leiden variant (c.1691G>A, rs6025) is found in about 3-8% of the Caucasian population and is detected in about a quarter of all thrombosis patients. In contrast, homozygosity for this variant is very rare with a prevalence of 0.02% in the general population. Heterozygosity for factor V Leiden is associated with a 5- to 10-fold increased risk of venous thrombosis. For homozygous trait carriers, the individual risk of thrombosis increases 50- to 80-fold.
The risk of thrombosis due to the factor V Leiden polymorphism may also be further increased by the presence of other genetic factors, such as the prothrombin gene variant G20210A (rs1799963, c.*97G>A). Prothrombin (factor II) is the precursor of thrombin, which is involved in the conversion of fibrinogen to fibrin within the coagulation cascade. The prothrombin variant G20210A within the 3'-untranslated region of the prothrombin gene is associated with an increased prothrombin concentration in plasma. This results in hypercoagulability of the blood, which also puts affected individuals at increased risk of thrombosis. The prothrombin variant is the second most common genetic risk factor after the factor V Leiden variant. Approximately 2% of the Western population are heterozygous carriers of this variant, which increases the individual risk of thrombosis by a factor of 2-3.
In addition to genetic factors, several exogenous factors have an impact on individual thrombosis risk. These factors include immobilization, smoking, pregnancy, use of oral contraceptives, age, and obesity. Thrombosis prophylaxis is currently not recommended for asymptomatic carriers. In special risk situations, such as prolonged immobilization or pregnant women with additional risk factors, temporary thrombosis prophylaxis may be indicated. If severe thrombotic events or recurrences occur, long-term or permanent anticoagulation may be indicated.
Genes
- Factor II deficiency: F2
- Factor V deficiency: F5
References
Kujovich JL. 1999 May 14 [Updated 2018 Jan 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022 / Kujovich JL 2006 Jul 25 [Updated 2021 Feb 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022 / Gohil et al. 2009, Thromb Haemost 102:360 / Cullen et al. 2009, J Lab Med 33:283